Week 1

1.1.1

[FOREIGN]. Okay, the first one is the textbook. I used this one,

the Neuroscience by Mark Bear. This one I can see is

quite easy to understand. It's quite simple. But we also use another one. This one is the Principles

of Neural Science. Maybe, [LAUGH] you guys already

have this textbook, right? Everybody have this one,

a copy of the electronic one? Okay, good. So this one, then,

is actually quite comprehensive. A lot of stuff inside. And then you need to spend a lot

of time to digest those content. And actually,

there was another really good textbook, Principles of Neurobiology, Liqun Luo. Everybody knows.
These three books actually I use kind of

often when I prepare for these lectures. Okay, this is the first one, actually

I talk about it the textbook you can read before my lectures or in the future for your exam, I don't
know whether

you have examination or not. Okay the second one I want to

talk about actually this PPT, I will not release to any of you. So that means, you need really
participate in the lectures and

study really hard, and if you don't understand anything here,

then just usually ask questions, okay. I will explain to you. So that is two points I

wanted to talk about. I guess, and, Dr John already talked about

this on basics on neuroscience. For example, you know a neuron, the

properties is actually to be excitable. So we'll find action potential. And you have neuron to neuron
connections,

by the synapse. I guess that's,

you know what I'm talking about. So, at this stage, we are ready to learn the integrate of all

these properties of the neuron that is actually how a brain use to get the information from the
outside,

and then use this information to get a perception about the outside world and

also internal state of your own body. And then based on this,

you'll make a perception. Based on perceptions,

then you need to make a action. So the action then is to control your body to adapt to the outside
world. So this is really important for
the sensory system. Then you scan for quite comprehensive

part in the neuroscience study. So let's take a look. This is a experiment for to show, actually is a to
mimic a bird. So you looking at this picture and

you will see, this one can be a tail or a head. So, if this one is a tail

then this should be a head. So this is the wing. So, if you pretend this kind of a target, Moving in this
direction, then you will see actually this is

a bird actually with a short neck. The neck is very short, but

a very long tail, all right. But then you move the other side,

then it's different. You have a bird with a very long neck but

a very short tail. So, if you have a chicks,

the young chicks, special chick. Look at this target moving

about the In the sky, then the chicks will have

a different behavior. For example, if the target is moving, To the right slide, and

then it looks like a goose. A goose has a long neck, a short tail. And then for a chick, then it's okay,

it's not dangerous at all. But then when you move to the other side, then it's dangerous, then it's a.
So for a chick then, we'll respond in a very reproducible behavior. That is if you have a target,

this target moving this side, the chicks will immediately escape. This escape behavior,

actually, is quite robust. That means, actually, if you test,

definitely individual chicks, they would have the same behavior. It doesn't matter if it's very young,

very small chick, or adult chick. So that means, this behavior, kind of

escaping behavior, is an innate behavior. So that means when the chicks was born,

and already this behavior is

controlled by the gene, already programmed the neural

circuitry for this behavior. And of course if you go to this side,

the target, and then the chicks actually doesn't care. So that means this guy

use the sensory system, actually you see it's very important for

the animal. That is, the visual system to

judge whether there is a enemy or a predator like a and

then you need survive. They make the actions,

right, corresponding one. Okay, so from this,

you already know the sensory system is critical for the survival. And let's look at another one. Of
course, the sensory system
is also important not only for the survival or this escaping behavior. Also maybe for the prey or for
the food. This is a picture,

essentially in complete darkness. [FOREIGN]. So of course this is a [FOREIGN] it's a. Of course this
animal is

very keen in the auditory system and also the visual system. So, when in complete darkness this guy

still can catch the a small rat or mouse there, actually in the jungle. So, how this animal actually

detect this target, right now you don’t have any light coming. So that means this guy uses the
auditory system. Look at these pictures,

then you know it's very sensitive, because maybe this small guy

actually hide in the jungle. [FOREIGN]. This big animal then maybe

sit somewhere a tree. [FOREIGN]. Then you need to hear very far

away some small noise there. [FOREIGN]. So you need a very sensitive

system to detect this information. But then very important, so

sensitive is not enough you need actually a precise location,

you need actually [FOREIGN].

1.1.2

So and

this guy actually is moving very fast. Now of course,

that rat is also very sensitive. [FOREIGN]

The time reaction for this catching is very short. [FOREIGN] Okay, here are things that are difficult for
the animal, right? So you think about the situation. Very small rat, maybe 50 meters that way.
[FOREIGN]

So your speed is very fast. And then very short time usually that means you cannot actually

adjust your directions. So when you mixture move [FOREIGN]. Precisely locate the animals there,
right? [FOREIGN] How this guy can locate that rat's location is challenging. [FOREIGN] Now, what
kind of strategy can you think about should the animal use to precisely locate the rat? Just the sound
coming, okay? How you can make it the location. >> [INAUDIBLE]

>> Based on what kind of information, do you think? >> [INAUDIBLE]

>> The distance, between? >> [INAUDIBLE]

>> Good. >> [INAUDIBLE]

>> Fly away, right? >> [INAUDIBLE]

of the ultra [INAUDIBLE] some [INAUDIBLE]. >> Okay, so you're talking about echoing,

so the echolocation. That's like a bat, like a bat, right? Now they use this strategy. So that's a good
way to locate the target. And in this case here actually,

mainly used for information, is actually the sound. Made the noise, made by this target. Some kind
of a noise there. And then the noise of course

will travel to this big guy. And then, okay you travel but still you

cannot actually make the location, right? It's challenging. Okay, good. May be based on the sound
travel to the left and the right ear actually the timing they are different. And based on this they of
course for example even left is sit

here make some noise and then this ear will first

actually receive the sound. And then will be this one, right? And the difference, actually. So right
now, the difference

actually is very large, okay? What's the difference? And then basically it's my, the difference

is between the whole head, okay? It's the left and right. But then the target move to here, then

you'll look at this information coming. Then, maybe still first,

actually coming to this one. And then, will come to this one. Right? But then, the difference between
this

situation, actually, it's quite similar. Okay? So, in the brain, and in this guy,

actually, in the brain then you have different

neurons sitting in the brain. Of course in the auditory systems. [FOREIGN] And then each neuron
maybe

represents a specific location, map. All the same.

Okay, so when one particular neuron, they get excited, then you will know,

yeah, that's front, that spot. There was a target there. Basically, you use this information. We will
talk about that actually later,

okay? In this case the intersensory

system actually used for catching the food, right? It's also for survival of course. And then there was
another

one I guess actually, maybe already many of you know this story. Actually [FOREIGN] studies a
magnetoreception. [FOREIGN]

There is a real famous, actually,

this is a monarch butterfly. It's quite huge okay. It's butterfly. [FOREIGN]

The wing width came to about 10cm. [FOREIGN] But this fly, okay so, of course, this butterfly has a
cycle, a life cycle. It's very interesting, okay? The life cycle of course

starts from this egg right? [FOREIGN] From the egg, about four days, and they will hatch out this
larva. [FOREIGN] And then this guy doing nothing, but actually eating, okay just accumulating a lot of
energy. And to grow and about 14 days,

this guy, at it's larval stage. And then we'll go to this [FOREIGN]. Okay, so then it's quite interesting. A
lot of things will happen, although you cannot see,

because they're inside the case. In about ten days,

then a beautiful butterfly comes out. Now, this butterfly then can fly. So typically the butterfly, this
guy, the lifetime is about two

to six week [FOREIGN], about one and a half months. [FOREIGN]

So that's the kind of life cycle. And this guy also quite interesting

is actually the behavior. The behavior is, okay,

this one is a special tree in Mexico. [FOREIGN]

Now this butterfly, [FOREIGN]. Many, many of them are accurate together. [FOREIGN]

Biological significance for this wiring. [FOREIGN] This butterfly that's in Mexico, let's say Mexico.
[FOREIGN]

But in February, and maybe in February and March to. This guy then to move to the north.
[FOREIGN] Now, okay, so [FOREIGN] life cycle [FOREIGN]. [FOREIGN] Special differences. [FOREIGN]
>> They continue, okay? [FOREIGN]

The butterfly. [FOREIGN]

1.1.3

This generation is very special. In just one generation

they can fly to Mexico. [FOREIGN] sensory information including the light [FOREIGN], OK? [FOREIGN]

Okay? [FOREIGN]

It's really special, so they take a flight, like a cycle. [FOREIGN]

Right, so [INAUDIBLE] it's important for everything, right? And also of course, this one,

this special [INAUDIBLE] for this. Just take a look. This is a moth, this is a female. [FOREIGN] When
you turn

on the fan [FOREIGN]. You can see, actually, this male

actually smells something there, right? And then this guy came,

approached the female, okay? So it's definitely based

on the sensory information. Okay, so if you can find this guy. What kind of information does

the male base on to find the female? What's the information? What kind of cue? >> Chemical. >>
What? >> Chemical.

>> Chemical. Okay, yeah that's possible right. Maybe the thing you turn on,

like a funnel. [FOREIGN] A female, is she a chemical? [FOREIGN] Concentration? Okay. Right.
[FOREIGN]

The chemical, the [FOREIGN] you got, grade in and concentration and grade in. [FOREIGN]

Based on ingredient. [FOREIGN]

Wow, yeah, this male can seed a female [FOREIGN] To demo is really a chemical detection.
[FOREIGN] Okay. [FOREIGN]

It's clear, describe base on their chemo reception to detect the The Now there are many sensory
modalities

actually in different animals. Actually they're quite different. For example,

this infrared detection [FOREIGN], okay. In human we don't have. But actually for this guy, for the
snake, they can detect the infrared light. [FOREIGN] infrared detection. [FOREIGN] [FOREIGN] Of
course. Based on this information, you already know. The spatial information actually, since spatial
resolution is not high [FOREIGN] All right, so here is just some

demonstration of the sensory system. They're really important for the animals'

survival and also for the reproduction. For animal species, of course. Most important thing,

actually, you need survival. [FOREIGN] The second one is reproduction. [FOREIGN] Right? [FOREIGN]
Right?
1.1.4

Let's take a look. For us humans, then,

what's the sensory system we have? [FOREIGN]

Of course, this is your visual system. And then,

if enjoy the flavor of this wine, or it has a good sense of smell,

this olfaction. And of course,

then the flavor of this delicious fruit, then it's using your sense of taste. [FOREIGN] And of course,

if you listen to the music, then it's through the sense of audition. It's a hearing, timbre, and also the
touch is one of the five basic senses, right? For this five basic senses, the principles underlying this
thing, let's take a look. You're kind of appreciative

of the pictures, kind of enjoy the flavor, or

when you enjoy the music. All begins with the physical stimuli,

actually you need to transduce into electric signal

that our brain can understand. Okay, this is the first step,

this step is called sensory transduction. This is [FOREIGN]. Now it's a from the physical or

chemical stimuli. Then transduced into electric signal [FOREIGN]. Now let's take a look,

in the visual system, of course, this is achieved by the eye. [FOREIGN]. So for the smell, then you
have the chemical coming [FOREIGN]. For the taste, of course,

it's the use of the tongue. [FOREIGN] taste bud. [FOREIGN] detect bitter. [FOREIGN]. In most cases,
actually,

bitter is associated with the toxin. [FOREIGN]. Now, of course then sweet. [FOREIGN]. Okay, so this is
actually the taste,

the system, also transduced,

those chemicals actually into the electrical system by the tongue,

the taste bud. And the difference between these two,

what's the difference? Smell and the taste. Make it more specific. Both are chemical receptors,

those detect chemicals. [FOREIGN] What's the difference

between these two types of chemicals? Smell and taste. >> [INAUDIBLE]

>> Okay, that's a good question, good answer. So smell, then is to detect those chemicals, can
[FOREIGN]. [FOREIGN]. This distinction, [FOREIGN] taste system [FOREIGN] detect easier is a
chemical. [FOREIGN]. All right, so

the other one that's basically most actually the physical stimulation,

like the touch. [FOREIGN]. So it doesn't matter, okay? So the sensor system,
you need the first step. [FOREIGN] sensory organ. [FOREIGN]. Okay, so first actually we talk about
the sum of

these principles under the sensory system. [FOREIGN]. Now one important concept

is the receptive field. Now [FOREIGN] specifically the neuron, [FOREIGN]. The neuron can be excited.
[FOREIGN] or inhibited, [FOREIGN]. Spacial domain, [FOREIGN] you can

change the firing of the neuron. [FOREIGN] excitation. You decrease the [FOREIGN] okay?
1.1.5

Now click on the, [FOREIGN]. This one. It's special here. So you want to design a system, actually
don't leave a blank. Supported there, right? [FOREIGN]

See, this system is designed actually,

you can see. The receptor field of individual neurons,

they overlap. [FOREIGN]

Right. [FOREIGN] protection. [FOREIGN] [FOREIGN] easy to imagine. [FOREIGN] To a sensory map.
[FOREIGN]. >> Okay, good. >> [FOREIGN]

>> Okay. >> [FOREIGN] >> [FOREIGN] >> [FOREIGN] Okay, okay, actually is [FOREIGN]. You can map.
[FOREIGN] Okay? Yeah, this is the entire principle, right? [FOREIGN]

If I use a electrode. [FOREIGN] Stimulate. [FOREIGN] You should see a spike. I think I mentioned that,
right? To the action potential. You're wrong,

I'll talk about action potential. This is the action potential. [FOREIGN] Now action

potential sensory coding. [FOREIGN] What kind of

information you want to code? Strings, okay good, and then? [FOREIGN]

And then? Good, timing, it's very important. [FOREIGN] See the timing

is very important. Okay strange timing and then? >> [INAUDIBLE]

>> Okay petition. Of course yeah petition is the receptive

field can detect depth position. Good. >> [INAUDIBLE] >> Frequency, okay, good. Also, yeah, it's
important, right.

I guess also, another modality. [FOREIGN] Mechanical stimulation, or chemical stimulation.

[FOREIGN] modality. [FOREIGN] sensory information [FOREIGN] code [FOREIGN] code stimulus.
Three very important aspects,

features [FOREIGN] modality. Sensory modality. And then sensory strength. And also the timing of
the stimulation. Okay, so we know right now, okay? So you have a sensory stimulation. Then you can
transduce

into the electric signal. And this signal, actually coded. By the frequency of the file rate,

right, or the, okay, let me ask you a question. So if I give you I expect train just so

that you're trying to spike? Do you want to do the spike train? [FOREIGN] No? [FOREIGN] Right?
Okay, then what? [FOREIGN] Frequency [FOREIGN] possible. Okay? [FOREIGN] spike [FOREIGN]

frequency [FOREIGN] So for this topic, actually of course right now we

don't know the, [FOREIGN] Okay! [FOREIGN] timing [FOREIGN] frequency [FOREIGN] frequency
[FOREIGN] [FOREIGN] neuron coding. [FOREIGN]

frequency [FOREIGN]. To go a temporary information. [FOREIGN] Okay?

1.1.6

So, right now we have a spike carried by this neuron and

then we'll send it to the brain. Let's take a look actually how this

information actually travels actually propagate to the brain. Here, then I just used this

cartoon as my example. Take a look,

this one the skin the [FOREIGN]. Now this one thing is the muscle,

[FOREIGN], okay? Now, this of course things is the, the neuro the sense of the neuro. Take a look at
this, this is the neuro cell body you

going to you about it [FOREIGN] DRG. [FOREIGN] Okay, now [FOREIGN] process [FOREIGN] process
[FOREIGN] so have you talked about [FOREIGN]. So some of these little fibers, actually very sick
[FOREIGN] to the spinal cord. [FOREIGN]

Spinal cord [FOREIGN] this is the other route. [FOREIGN] We'll talk about this process actually in
detail, so they carry the information to the dorsal horn. And from here, they will also has some

processes direct to the brain stem. [FOREIGN] So now [FOREIGN] [INAUDIBLE] the projection, the
neuron projection is the opposite side [FOREIGN], okay? And then you take a look about this one,
this information, things different. [FOREIGN]

Cross the middle line of this spinal column [FOREIGN] the cortex [FOREIGN] spinal cord [FOREIGN]

okay? [FOREIGN] Now, take another look, there's another projection,

very interesting, right? This blue connection can actually project to these two areas [FOREIGN] your
tongue [FOREIGN] old, very painful. [FOREIGN] So you see that [FOREIGN]. Now so you know just to
[FOREIGN] okay? [FOREIGN] This is the brain representation of the sensory information, right? This is
the smell olfactory cortex [FOREIGN] visual system, visual cortex. Okay so, we'll talk about all this
sensory process actually one by one, okay? And by the [FOREIGN] this understanding,

so far, what we can say is that the visual system is the best

understood [FOREIGN] okay? [FOREIGN] The sensory transduction or the neural circuitry or the
transformation of the signal or the perception. This is the best answer to this so

far, so this
1.1.7

[FOREIGN]

This is the brain representation of

the sensory information, right? This is the smell, olfactory cortex. [FOREIGN] Taste. [FOREIGN]

Touch. [FOREIGN] Visual cortex. So okay, so we'll talk about

all these sensory process, actually, one by one, okay? And by the way, things just, this
understanding. So so far, what we can say is that

the visual system is the best understood. [FOREIGN] Okay? [FOREIGN] The sensory transduction

of the neurosecretory, or the transformation of the signal or

the perception. This is the best understood so

far, the visual system. And then followed by

this olfactory system. Olfactory system also is,

currently is a kind of hot topic, okay? [FOREIGN] If you know, then you say,

Richard Axel and Linda Buck, they cloned the receptors

of the olfactory system. And they got the Nobel Prize in 2004. And they have a lot of tools right now,

developed a lot of tools. Actually, to all the connections from the peripheral, from the nose, to the

brain, actually they can map, make a map. And also, right now,

the in vivo recording actually also is quite useful to understand the system. And this is a kind of
ongoing

progress about this system, okay? And of course, then taste, then,

is not so well understood. A lot of information actually

we don't know all, okay? But the good part is, the taste system,

at least in the human, in the mammal,

all the taste receptors have been cloned. [FOREIGN] Sweet receptor, bitter receptor, salt receptor,
[FOREIGN], umami receptor, [FOREIGN]. But the sensory coding part,

[FOREIGN] information, [FOREIGN], relay to the brain, [FOREIGN],

processing and makes a perception. [FOREIGN] Okay? [FOREIGN]

Touch. [FOREIGN] The hearing. [FOREIGN] Receptor. [FOREIGN] Mechano-sensory receptor.

[FOREIGN] Identity of the receptor. [FOREIGN] Okay, so, [FOREIGN], we will begin with this visual
system, because it's the best understood. Then we'll talk about

it from the first step, the sensory transduction to

the neurocircuitry in the retina. [FOREIGN] Information. [FOREIGN] Processed in the brain, okay? We
will follow this process.
1.1.8

Of course vision system

then begins with actually the light or

the imagery project through the eye. And then from here the eye will transfuse

those signals into electro signal, and then this information is encoded and

then by the spectrum, right? The different the extra potential. And then the information will be
transferred to the brain here is the LGN, light, [FOREIGN],

okay? And then this is a relay center, [FOREIGN] will flares are go to the visual contacts [FOREIGN].
Now this is the process, right? So, we'll first begin with what

happened in the eye, okay? Let's talk about its detection. So, the eye is actually very

similar to an artificial, okay CCDs [FOREIGN]. Maybe more as a camera, right? Yeah, so

what's the difference between the eye and the camera or was it the common thing or

the difference between these two? [FOREIGN] the difference is one of these is the focusing, right? In
the camera you move with a lens [FOREIGN]. >> [FOREIGN] >> [FOREIGN]. >> [FOREIGN]. >>
[FOREIGN] Okay lets take a look here. [FOREIGN] the focusing [FOREIGN] sensitivity unit. [FOREIGN]
sensitivity [FOREIGN] to the neuron. [FOREIGN] now just we know that the sensory system. They
came dynamically changes

again over the sensitivity, okay? [FOREIGN] if the light is too strong for a camera. What will you do?
[FOREIGN]

yes. For human then, for

eye what will happen to the eye? >> [INAUDIBLE]

>> Good. [FOREIGN]

if we feel the light is too strong, then the brain will make the action. The action is actually

to get a smaller pupil. [FOREIGN] only one side feel that the light is very strong. And then both eyes
will

have a small pupil. Okay, now [FOREIGN] detect them [FOREIGN] you cannot [FOREIGN]. So, they
means actually, this important a protection

[FOREIGN] try to protect you. That is actually [FOREIGN], okay? [FOREIGN] the effect is rest more at
the most it only can reduce about 16 of the same 15 fold of the 19 intensity. [FOREIGN] okay?
[FOREIGN] okay? [FOREIGN] how can we deal

this system right now? The light intensity is so huge arranged. Now, your total arrange, [FOREIGN]
not 15, not 100, not 1,000, not 10,000. [FOREIGN] to make arrange [FOREIGN]. Essentially, we never
actually have the problem actually in the [FOREIGN] the eye, the pupil. [FOREIGN],

so we have a neurosister. [FOREIGN]

focal for example, even the single neuron [FOREIGN]. What kind of mechanism can they use
to change this again over the system? For example, we have the adaptation. Adaptation is actually if
you

have a strong light coming and then the neuron can perceive this light. And then make a change of
the signaling pathway [FOREIGN] sensitivity [FOREIGN]. Okay, so this is the main difference.
[FOREIGN] what is the [FOREIGN] how will you design an experiment to examine the sensitivity of
our eyes. [FOREIGN] take a light. Light is a photon, right? [FOREIGN] so you do a question [FOREIGN]
what's the minimal photons needed to trigger a visual perception? [FOREIGN] this is 1942. A
psychophysical study. Psychophysical [FOREIGN]

human as a subject. [FOREIGN], okay? [FOREIGN]

you have I guess everybody has this experience. When you are sitting in a dark room. Then your
visual system will

actually get more sensitive, right? [FOREIGN]

sensitivity [FOREIGN],

okay? Now, here is actually in

the complete darkness. [FOREIGN] after half an hour [FOREIGN]. So, I guess this which would

not go to the details but if you are interested you

can look at this paper. Okay, this is a very classic

sensory neurobiological paper. [FOREIGN] okay? [FOREIGN]. Now [FOREIGN]

photon 9. The photons 9 [FOREIGN]

six photons per flash. [FOREIGN]. So, because this flash cover

about 500 photoreceptor. [FOREIGN] visual field [FOREIGN] calculation. Very simple. A calculation is
actually

what's the probability of one single photoreceptor

to detect more than two photons under this condition? Okay, let me repeat again. Six photos were
flashed and this flash covers 500 rod photoreceptors. So the question is,

what's the chance of lens single photoreceptor to

hit by two photons or more than two photons. [FOREIGN] there are six photons okay. [FOREIGN]
now take

a probability [FOREIGN], okay? [FOREIGN] why single neuron is unlikely to hit by two photons.
[FOREIGN] okay? Now what it mean? What it means is that the six photons are detected by six
different neurons. You agree? >> [INAUDIBLE]

>> Okay, another way to say this, actually, one single

neuron Six single neurons respond to these six different photons. Each of these six different photons.
And that means actually,

one single neuron is so sensitive to detect one single photon,

right? [FOREIGN] You know actually under these conditions that information already goes to your
brain. You can make the perception. >> [FOREIGN] perception. [FOREIGN] how can the eye achieve
this feature?
1.1.9

Let's take a look, this is the eye. The eye ball, if we look of course, these structures we know

this is a lens cornea. [FOREIGN] The most important thing actually here is the yellow tissue here.
[FOREIGN] tissue. [FOREIGN] The neuron responsible for the detectance of a photon. [FOREIGN]
Actually other

neuron types other than. This neuron is a output neuron and this sends its axon to the brain. Well
[FOREIGN] let take a look here. [FOREIGN] Make it a section. [FOREIGN] You can see this deep in the
layers [FOREIGN] is a structure. [FOREIGN] Okay, this side is this side okay? Is close to this black one,

you see this is a black tissue here. [FOREIGN] This photoreceptor and

then here. [FOREIGN]

This one, this is a, In the nuclear layer [FOREIGN] mainly bipolar cell. [FOREIGN] Horizontal cell and

endocrine cell. [FOREIGN] Output a neuron, send to the brain to have

it's axon go to the brain. Okay, this is the another cartoon to show this neurons,

this is actually the photoreceptor, okay? There are two types of

photoreceptors you can see, one is actually very long and very thin. This one is called a rod

photoreceptor [FOREIGN] now this one is a different one, okay? [FOREIGN]

photoreceptor [FOREIGN]

okay? These two type of cells

should be responsible for transduce the light into

the electric signal, okay? Detector and then you have bipolar cell, this vertical pathway. [FOREIGN]
Your bipolar

cell to ganglion cell. [FOREIGN] In this outer flexible layer. [FOREIGN] You get kind of horizontal cell.
[FOREIGN] very special, they don't have the axle send the information to downstream neuron. And
what they do is actually make the [FOREIGN] formation modulation [FOREIGN] okay? [FOREIGN]

Okay, so let's take a look actually how this guy, this photoreceptor detects the light. [FOREIGN] This
is a cartoon of the photoreceptor. Of course you know its easy to

[INAUDIBLE] photoreceptor, right? [FOREIGN] This is a cone for the receptor, and the light detection
region only happened at this region. [FOREIGN]

Outer segment [FOREIGN] this we call [FOREIGN]. We call segment here [FOREIGN]

this is outer segment. [FOREIGN] Terminal [FOREIGN] [FOREIGN] Okay. Why you need to make such
a system

with too many discs there? [FOREIGN] With the tender, harder surface area [FOREIGN] detector,
right? [FOREIGN] Design using a principle [FOREIGN] in the olfactory system [FOREIGN] [FOREIGN]
Region here, there is a pocket [FOREIGN] is this chemical able to absorb the photon, okay? This is
important,
it's not the protein, this is an 11 Cs. 11 Cs is actually between the [FOREIGN] okay, cyst. [FOREIGN] If
we have a photon,

here this molecule, this chemical where as absorbed

with the photon energy. The energy will be used to break the bond [FOREIGN] what will happen to
the protein? [FOREIGN] The whole [INAUDIBLE] protein act, this confirmation [INAUDIBLE]. Now
protein, [FOREIGN]

activate the protein, time to bind it to the protein [FOREIGN]

okay. [FOREIGN] Professor [FOREIGN] okay, the photoisomerization, [FOREIGN] okay? [FOREIGN]
Okay? Yeah, the same thing, [FOREIGN] okay? This actually, the lighting effect, so let's further take a
look

at this structure. This is the ROD photoreceptor out

the second one, in the second one, right? So, [FOREIGN] increases the surface area to, [FOREIGN]
this direction or this direction or that direction. [FOREIGN] Now let's take a look actually about the
disk membrane [FOREIGN] this is the real disk inside. This is actually the [FOREIGN] It's not
connected to the disc [FOREIGN] electric activity of the neuron, coming from where? [FOREIGN]
Here is coming from a very important concept [FOREIGN] so, you have a photon. [FOREIGN] How do
you have electric signal on this [FOREIGN] so you need something to

connect theses two processes. So why is happening here,

why is happening here? That means that you have to have a second messenger [FOREIGN]
1.1.10

It's a G-protein cascade,

so you have a Rhodopsin. Okay, you have a Rhodopsin, and

then you have the G-protein, and is this. G-protein, and then the downstream factor is a force for or
PDE. [FOREIGN] When you have this [INAUDIBLE] p concentration drops what will happen? This
channel will close. A channel closed in the cell

is hyperpolarization. [FOREIGN]. In the visual system,

the light stimulation caused the cell hyperpolarization. [FOREIGN]. In most other sensory system you

have stimulus to cell is excitation. They depolarize. [FOREIGN]. Okay, so. [FOREIGN].

Let's take a look actually about this arrange happen on this membrane. You have a photon come in,
and then you activate this guy, you see, this one. Go to a straight form, right? [FOREIGN] G-protein
binding site [FOREIGN]. Sub unit beta gamma [FOREIGN] Separate. Of course you need a, this guy
[FOREIGN] ADP [FOREIGN]. Activated protein, G-protein then will

make the separation, alpha, beta, gamma. In this case, alpha is the active form. [FOREIGN]. As a
case, there can be the beta

gamma is the active form, okay? [FOREIGN]. Gamma is the inhibitor sub unit. So the G-protein then
release

the gamma inhibition, okay? [FOREIGN]. Okay. [FOREIGN] [FOREIGN].

In the dark, high level of the right? Right now you have a light activation,

then it drops. [FOREIGN]

[FOREIGN] Now I will explain later

in the next lecture. Okay, so this is the important, this part. So this is the process of

the phototransduction. The light or the photo absorption

traduce into electric signal. And then this process actually

is quite complicated. So why you need such

a complicated process here? [FOREIGN] biochemical reaction cascade. [FOREIGN]

>> [INAUDIBLE] >> Amplification, okay, good. Okay, the advantage is you

gain the amplification. [FOREIGN]. We need a single photon detection. [FOREIGN]. Okay, that's good.
Amplification [FOREIGN] amplification [FOREIGN]. 1,000 cGMP molecules. So in total, then you have
20,000

amplification here, right? So you can detect a single photon. Yeah, of course here is the advantage.
You have the huge amplification. What is the disadvantage? >> [INAUDIBLE] resolution. >> You have
that temporary resolution. >> Yeah. >> Good. Now so this system,

you have a huge amplification but the problem is actually,

because this is a bio-chemical reaction. [FOREIGN] Each step you need the time. You build up these
molecules which takes time. So the temporary resolution is not good. Okay, here. [FOREIGN]. Okay
so that's it for this lecture. Any questions? If no questions that's fine.
1.2.1

Let's first get an overview

of the last lectures. So we talk about a couple of points. So first actually for a sensory system what
you need is actually the first step

actually is the sensory transduction. So, what's sensory transduction? Can somebody? [FOREIGN]

>> [INAUDIBLE] signal from outside [INAUDIBLE] >> [INAUDIBLE] >> Okay. So sensory transduction is
just one step. The step in converting the physical or chemical stimuli into electric

signal by the sensory neuron, right? So you talk about, actually,

it's a whole process. Okay, so we also talk about

actually when the sensory cue is transfuced into an electric signal. Then the electric signal actually
exchange

information, maybe its action potential. So, how the action potential

codes that sensory information. We talk about SUD maybe

a couple important features of the sensory stimuli need to be encoded. So what are important
features

of the sensory stimuli? [FOREIGN] So essentially stimulation you carry

some information to the brain right? What's the important features? >> [INAUDIBLE]

>> The strings, right. The intensity or the strings, okay. >> And the [INAUDIBLE]

>> What? Frequency? >> Okay. So what we're talking about is

the sensory stimuli, sensory cue. Where the frequency comes from. >> [FOREIGN]

>> Okay, yeah, is there anybody else that can help? [INAUDIBLE] Yep. [INAUDIBLE] >> Our insipid
fear? >> [INAUDIBLE] part of

the spatial [INAUDIBLE]. >> Okay, this is where you

are talking about the location or the receptor field. Okay so, yes, maybe this are the many

other features but there are the three very important features is the modality

is where there is sound or a light. Okay, there's the first one, the modality. And then the second one
is intensity or

the strength. And the third one, there is timing. So the timing is very important right? So whether
that stimuli right now happens,

or actually happened ten minutes ago. So these are the three most important

features of the sensory stimuli. And then how the sensory system encodes this sensory features is
what kind of of code to encode this information? It's a very Frequency. >> [INAUDIBLE]

>> Okay, so maybe right use the spike of frequency,

right? So maybe can coat those intensity

of strength of the stimuli. And also maybe the, we talk about

actually, the temporal coding. That it means actually the timing

of the first spike firing. Actually it's very important information. And also maybe the interval

between the different spikes also carries the information, right? Of course then it also

depends which neuron gives the firing, and

then we'll encode those modalities, right? Like if you have light coming, of course the neurons in
your eyes

will give the action potential firing. And by then, if you have a touch

maybe in the skin, so this neurons in the weight to the skin will give you

the action potential firing, right? Okay, so we also talked about the receptor

field, what's receptor field? [FOREIGN] [INAUDIBLE] So

we have one example, actually. Use the skin to illustrate

the receptor field concept, all right? So in the skin,

then you have a different neuron. Those may be with the sensitive receptors expressing those
neurons

exterior generate to the skin. If that neuron generate to that region and

you touch here. That neuron will give you a response or

not. Of course, actually it is far away

then they will not give any response. So then, what's the receptive field? [INAUDIBLE] >> Mm-hm,
okay, yep. Any other comments? >> [INAUDIBLE]

>> Yes, okay. >> [INAUDIBLE]

>> Mm-hm. >> [INAUDIBLE]

>> Okay, right, there maybe quite strict

meaning of the receptive field. It's the danger area,

the sensory danger area. Those areas where you can have

direct receipt of the stimulation, then excites the neuron, right? We always talk about,

actually, so, actually, it's not specific for the endangered area. Any area, if you record from one

sensory neuron, any area, so you give it the stimulation, if the neuron can

get excited, there's the receptive field. If at that region also inhibited

this neuron, inhibition. And that's also included

in the receptive field. Okay? So it's just any mega sensory

like a region areas, actually, give it the stimuli, can change

the activity of the [INAUDIBLE] neuron. Then that region is the receptive field. The receptive field
includes

both excitation and inhibition, this is important, okay? Yeah, then we talk about,

actually, your visual system. I'll talk about this new

circuitry in the retina. So, we'll talk about how

many types of neurons we mentioned the last time in the retina. You have photoreceptors, right?
And then you have horizontal cell,

bipolar cell. And then you have cell and cell. We have five types of neurons, right? Okay, so for

that Neurocircuitry, what's the, we talk about, actually,

the flow of the information. The vertical flow, then,

is from where to where? Of course, we talk about

the [INAUDIBLE] of the neurons, okay? [INAUDIBLE] >> Yes, sugar okay to call for

the receptor. >> [INAUDIBLE]

>> To. >> [INAUDIBLE] >> Okay, so we talked about the visual are information flow in the retina from
different neurons. The vertical one is, of course,

from top to the bottom, right. >> To the terminal. >> To the terminal, okay. The terminal, then,

is the terminal, of course. Then the information will be sent out. Then what's the next neuron

to receive that information? Shiao Yu? Good. So photoreceptor will transduce

the light information and then converted it into electric signal. Then will pass this information

to the bipolar cell. And then bipolar cell will transfer

this information to ganglion cell. This is the logical flow

of the information. How about the horizontal

information processing? What did we talk about last time? [FOREIGN] >> [INAUDIBLE] >> Horizontal
information, so okay, we're only talking about in the retina so

far, in the eye. So we have the information

flow is vertical one from photoreceptor to bipolar cell,

then to ganglion cell. And then, that ganglion cell, of course,

will send that information to the brain. This is the vertical flow. We also talked about, in the eye, in
the retina, there is

horizontal information processing. The lateral one includes two types of Neuron for

the information processing. Horizontal cell, without axon. We talk about, actually, the horizontal cell
can

connect to different photoreceptors. And also,

the amacrine cell will have two layers. [INAUDIBLE] >> Okay, no, let's see. Yeah, we talk about it
here. Look at this pictures of

the vertical floor for the information is a photo receptor to

bipolar cell and then to ganglion cell. Right, this is the floor

of the information. And also, they have this one,

this guy, horizontal cell. And also, we have this one,

endocrine cell. You see, these two new type of neurons, they only process information

in the lateral direction, okay? Okay, so we then talk about, actually, go to the first step of the visual
system, which is the phototransduction. So we talk about photoreceptor. So, for a photoreceptor,
what kind of

structure, like a rod for the receptor. [FOREIGN]

>> [INAUDIBLE] >> The structure, the structure of the cell, [FOREIGN] Yeah, like a rod shape, right?
[FOREIGN] So include,

what kind of regions? Actually we talked about outer

segment over a cell, right? Inner segment in a cell body,

and the axon terminal. [FOREIGN] You see, we talk about this structure, right? Of a cell, not the
photoreceptor. You have the outer segment here, and then you have the inner segment cell body,

axon terminal. And where phototransduction happens, [FOREIGN] [INAUDIBLE]

>> Right, only happened at, so the phototransduction only

happened at the outer segment, right? Okay. So in the outer segment,

that's where phototransduction happens. So we talk about, initially,

the outer segment has a lot of disk. Those membranes separate from

the cell cytosolic membrane. [FOREIGN] They separate. So on the disk,

then we talk about a lot of proteins. What kind of protein on the disk membrane of for the light
signaling? Rhodopsin. >> Rhodopsin, right, okay. Rhodopsin then if a photon activates it will do what
kind of thing? The next step is for

>> Information change. >> Information change. The 11-cis-retinal to all chains. Okay, and then the
rhodopsin

will be activated, right? What would happen next? Deprotein, yes. So then the rhodopsin will

activate the G protein and then the G protein will activate

the force [INAUDIBLE] BTE PTE right and then the PDE will hydrolyze

through [FOREIGN] second GMP. And then wonder what happened? There's a channel on the
cytosolic

membrane, there is a CNG channel. Because typically the channel is

opened by the binding of cyclic GMP. So if you have cyclic GMP

drops the concentration and then the channel will be closed. And what will happen to the cell? >>
[INAUDIBLE]

>> Right. It's a hypopolarization, that's

called light response over the cell, it's a hypopolarization. So, this is actually is very different

from other sensor remote entities. Other sensor in most case,

if you have a stimulation, the cell will deal a depolarization

called excitation. Okay, so this is the I guess important point actually in the last lectures. [FOREIGN]
1.2.2

So today we will continue

the phototransduction and also some signal processing in the retina,

okay? So, we talk about actually

this one in the next lectures. So this is a cartoon. Actually we publishing 2008 as a review. But then
look at here. So this is a membrane of the cell. You've got a photo receptor,

kind of [FOREIGN], okay? So we talk about there was a channel here. This channel is called a cNG
channel. cNG channel is actually,

the cyclic GMP bind to this channel. Then this channel will open, and

then the cell will depolarize, okay? That's actually happening in the dark,

[FOREIGN]. You have a lot of CGMP,

then the cell actually depolarizes it. So when you have a photon coming,

for example this is a photon, and the rhodopsin will be actuated, right? And the rhodopsin then

will actuate G protein. G protein then active with PDE. PDE then were hydrolyzed this CGNP,

and then this channel close. The cell has polarized. This is what we have talked about. This is called
the phototransduction

activation step. So these proteins have

sequential activation, okay? In any system, when we talk about actually

this signaling, it's important to know. Actually, a protein is activated, then you need the protein to
shut it down. Shut off. Otherwise, what will happen? You give a light shine on your eye and

then you turn off the light. This signal is still happen,

then the light is still on. You can see actually,

there is continuous light. Then there is a problem, right? So what you need in this system

is actually all these proteins, and then you need to be activated. Okay? That's actually an activation
step. Then what happened is actually

it's rhodopsin, this guy. You need to be activated. So for this protein, the activation,

then they are different process, okay? The first one actually,

this guy can had a simple decay. [FOREIGN], you don't decay [FOREIGN],

you don't [FOREIGN] okay? But there was another one,

actually different steps actually, this protein can be phosphorylated. [FOREIGN]

Okay? But it's a kinase. [FOREIGN] Rhodopsin kinase. [FOREIGN] Rhodopsin. In this case, the
phosphorylation will lower down the activity of this rhodopsin,

okay? And then after the phosphorylation,

another step will completely shut off

the activity of rhodopsin. That is arrestin. There is another protein called arrestin. Arrestin then will
bind to

this phosphorylated rhodopsin, and then the activity is completely gone. Okay, so the rhodopsin shut
off,

very important steps is actually first. Actually you have the kinase

phosphorylation, and then you have arrestin binding, okay? This actually is a typical GPCR signaling.
Most other GPCR cascade also

have this kind of steps, okay? And then, okay, so

we still have added proteins activated, like for example the G-protein, right? So for G-protein shut-
off, that is actually what happened

when a G-protein is activated. What happened to the G-protein? G protein has three subunits, right?
Alpha, beta, gamma. So in the resting state

the alpha binds to DDP, right? So when activation happens, the DDP is exchanged by GTP, okay?
Then the other beta gamma separate. Alpha still bind to the GTP and the beta

gamma, then they are separated, right? And then what happened? Actually this GR bind to the GTP,

they will act with the PDE, right? So, for a G protein shutoff, what happens is actually

the GTP is hydrolyzed to GDP. Because GDP, we talk about resting state,

no activity there, right? So that's actually the G protein, you see,

the binding of the GTP will go to the GDP. Of course, you need something else

actually participate this conversion. That's actually have a lot of

proteins in the cell called the RGS9. This actually is a gap,

G-A-P, gap proteins, okay? This protein actually help

the G alpha convert GTP to GDP. So the G alpha subunit actually

has intrinsic GTPH activity. GTPH is [FOREIGN]. So the G alpha is endogenous

this inter activity. But this activity is quite low. You need accessory proteins

to boost up the activity of the GTPH activity, okay? So when this G protein

actually shut off the PDE, of course we are automatically

to shut off. Because what we are talking about

last time, PDE, you have 4 subunit. Alpha beta is the enzymatic subunit. And you have two gamma
on each side,

right? So the G protein,

G alpha actually bind to the gamma subunit of the PDE,

release the inhibition. The alpha beta then will

actually hydrolize the CGMP. So when the G alpha unit is shut off,

the GTP converts to the GDP. Then they will release

from the gamma binding. The gamma again will

inhibit alpha subunit and the beta subunit of the PDE, okay? So this process actually

is quite important to allow with your system reproducibly and also very sensitively to detect the
light. Okay. Okay, there is another step, actually. This channel is quite interesting. This CNG channel
not only

lets the sodium come in, but also lets the calcium will come in. And actually, in this field,

in the phototransduction field, there's a huge debate for

about more than 10 years. That is we talk about the second

messenger of this phototransduction from the disc secondary to

the cytosolic membrane, right? We talk about you should have

a second messenger link the disk light absorption to the electrical

change across the membrane. We talked about CGMP. But actually, older days,

people think about this. Actually, this is the calcium

is is the second messenger. Okay? So because people found if

you change the calcium, actually the cell, maybe we are lost. It's a late response. So they think about
maybe

there was calcium there. But later is from the second messenger,

actually, it is the CGMP. But calcium, then we call it actually

maybe the third messenger, [FOREIGN]. That messenger actually is

coming from this channel, from the receptor site,

the calcium will come in, and then that calcium is really important. Next step. The calcium come in,
then will have a lot of things happen. [FOREIGN] Now look at this here. The calcium come in, and
then we'll have a three

major negative feedback. [FOREIGN] The first one actually, this calcium will inhibit this channel. You
see, they're quite interesting. The channels actually allow

the calcium go into the cell. But then that calcium will now have

a negative through the back to close this channel. [FOREIGN] And this actually is true. They're
actually calmodulin. Calmodulin is the calcium binding protein. [FOREIGN] Calmodulin will

bind to this channel and make this channel actually

less sensitive to the cGMP. Okay, another step,

actually is that calcium will activate this G cap protein. It's guanylate cyclase activating protein,

G cap. This G cap will then inhibit

this guanylate cyclase. Guanylate cyclase is to synthesizes. [FOREIGN] So right now you can see,

this calcium actually lower down this cycle GMP,

the final effect. But this cGMP, to open this channel,

that means again, the calcium coming through this pathway

will make this channel have less opening. Right? Next you see the back. There is another one,

very interesting is though, okay. This calcium will actually bind to this recoverin, let's see. And then
inhibit this. Let's see, okay. Yes, so this calcium actually will

inhibit this phosphorylation. And then how a light response happens, then the light response actually

is this channel close, right? This channel close,

then what would happen? The calcium goes up or goes down? Goes down, right? It goes down, then
this channel will be, by this cascade, what will happen? This channel then tend to

be more easily opened. Because through these steps. And also you have more

cycle GNP synthesized. You'll get more these molecules

to open this channel. And then also you have this step, actually you have, calcium drops, then this
phosphorylation

will be more active, okay? Then that means actually this rhodopsin actually is faster to be activated.
So the signal in the front here then

will be less than the downstream, right? So these three steps. The effects of these three steps is to

counteract the light signaling, okay? So the light coming from here

is to close this channel, right? But then you have this

negative feedback three steps. [FOREIGN] This is called the -3 negative calcium mediated feedbacks.
Okay so we talk about this signaling. This is kind of from these kind of molecules or

biochemistry you can easily understand. So all these steps, actually the final

output the electric signal with a cell. Because these molecules, of course,

cannot go down to the newer section. You need the electrical signal, right? And then for this one,
how you study

the electrical signal for this cell? Of course it's quite simple,

you just recount from this neuron, right? How you recount from this neuron?
1.2.3

Who is this gentleman? [FOREIGN]

Okay. This is Alan Hodgkin. If you study neuroscience, I guess you should be able

to recognize these pictures. Alan Hodgkin the father

of the neuroscience. I guess actually nobody will argue. Because actually he made great

contributions to understand the action potential, right? How those, [INAUDIBLE] Sodium channel
and

the potassium channel to shape the,

generate the action potential. And of course, the H there are the model the function

actually is so famous actually. So, but it's actually quite interesting. After he finished the classical

work on the action potential and

then he switched the research field. That's a switch to this research system. So, third time he
actually

he tried to identify a new research field that is actually

has very important questions here, but actually is solvable that's important. So then he tried to
understand

how the photo receptor actually convert the light

signal into the electric signal. There's actually studies

of photo transduction. And then, he trained quite a few people, here, in the photo transduction
field. Let's look at this four gentlemen. This one is Dennis Baylor and

this is King-Wai Yau. Dennis Baylor from Stanford. King-Wai Yau from

Jones Hawkinson Medical school. And Trevor Lamb from Cambridge University. And also Lamb. So,
these four actually are all

associates with Alan Hodgkin. And they play a key role in

the photo transduction field. This one and this one is the Academy of Mission Science USA. And this
one is also one in UK. [FOREIGN] Okay? [FOREIGN] These four, this one actually died quite early. But
at these three and this one and this one is still active in the research, and I was a poster of King Wai
Yau. And okay so, essentially actually all

those kind of photo transduction, the electrical signalling study

kind of related to these groups. Of course there are some

other researchers actually, don't have any connection with

Allen Hodgkin but actually his kind of methodology, the thinking of the research

actually influence is a whole field. Let's take a look here. So, look at here,

then the Baylor and the Yau and the Lamb are all just three are Allen
Hodgekin is a student, a post doc. And they developed a method called

the Suction Pipette Recording you see this suction pipe recording. This actually just after a few years,
the the development of

that methodology and then they kind of more with the idea

of suction-pipette recording. So as we said, the sales of the photo receptor has a kind of

long out segment here. This is a piece of the retina

from a frog okay from a toad. You are in the regional sales. And then you have a pipette here,

that pipette you can choose to open it. This is a glass pipette 40 inch, you can choose to open it here.
This opening should be

smaller than this one. Okay, then you use this opening to

suck this cell into the opening. Of course the inside you

had is the solution for the electrical combatant. And then, the cell, the membrane, we'll have a
contact with this pipette,

the wall. For [FOREIGN] and then you see this. Then you can recall the electrical signal. The outer
segment actually on the membrane

you have this c and g channel. You have a light coming,

that channel will close and the cell will hypopoloroid and

then you will recall this signal. And the reason is it very cool then you can differ the light

to stimulate the cell. You see easily use this vertical one or

horizontal one. Or use a full field like stimulation or use different columns, or

use different intensities. Okay, then you can do the recording. Here is the recording they got. Look at
it here. This is the electrical, current okay. This is the time. This is the light stimulation, quite short
just a pulse of the light. And then this is the response at

higher and higher light intensity. And the eventually

actually saturated there. The response will not grow bigger, but actually just get longer if

we increase the intensity. The response lasts longer. This is kind of typical. Maybe essentially for

any neurons we have this kind of behavior. You have a threshold, a threshold

in the cell giving the response. And then, essentially in the cell will

be saturated because of the channel. The maximum channel on the membrane then

you'll feel open to those channels and they all close, then the cell

will not give anymore response. So, look at this one. Immediately you will

trigger your thinking. The thinking is that this

is actually relative light. Happens. Happen at this region. So what it tells you? But actually look here.
All these response actually start from the end of the stimulation and then the maximum response
actually happens maybe 1.5 second later. That's quite strange right and they

base it on this kind of thing actually. They kind of course, they think very

hard about this issue because you, what you can have is just actually

electric signal and it happens so late. But actually, you should imagine in

the cell a lot of process happens here. And finally generate

this electron response. So, the is actually, there was a lot of

biochemical actions happening in the cell when you have stimulation. We mentioned, what's the
steps? The reduction activation you need it

some time for the activation to happen. The the confirmation change takes time. And then the
activation of

the G-protein also takes time. And with the G-protein to activate PDE. PDE hydrolyzed CGMP. All this
takes times. [FOREIGN] That the one that has slow kinetics, right? But at the same time, they're
found

actually this series very sensitive. It just gives a little light. Then this cell can be

with a huge response. That is actually, they also found

a higher amplification of the cell. Because a G-protein cascade, you have about 20,000 amplification.
We talked about, from one Rhodopsin, you can act to maybe around

20 G-protein molecules. And 1 PDE, you can hydrolyse

about 1,000 cGMP molecule. So, in the last lecture, we'll talk about actually the sensitivity

of our visual system. How sensitive we talk about actually

to the eye can perceive with the light. You need how many photons?
1.2.4

Yeah one photon for

one photoreceptor, right. That's actually amazing. And then can you really see

that one photon the signal for one cell because measured that. When your perceive the light you
just need one photon to activate

the one receptive neuron and then of course happen maybe five to six

simultaneously different neuron, right. But in any case

the mediation it's one cell you need to respond to one single photon. And with this technique they
found this

Single-Photon Response from the one cell. Look at that here, this is a picture

showing the photo recording. Again, such impact

the recording [FOREIGN]. And then this is

the Single-Photon Response. So this actually is continuous recording,

okay. It's just from here, connect here, for

the display to show you, the brick, easy for viewing, for the display. And then at different times,

you see it equals a interval. Give it a light flash. This light stimulation actually makes the intensity
quite low. And average may be just

0.5 photons per flash. And then what you can see is sometimes

there's actually no response. Sometimes maybe it is small bumps. Sometimes larger bumps. This
larger one you can easily

think it's two, a small overlap. This is the quantum response. Look at here. The small one is

the Single-Photon Response. The larger one is the two

fold photon response. How you can achieve such like 0.5 photons per flash stimulation. We know
the light

the minimum unit is a photon you cannot just divide

the photon into half. [FOREIGN]

>> Do you think do you know someone with a question. >> The question is actually how can you,
given the light intensity, only have 0.5 photons per flash. [FOREIGN] >> [INAUDIBLE] >> What? >>
[INAUDIBLE]

>> A mirror. >> [INAUDIBLE]. >> [FOREIGN] [FOREIGN] This kind of fluctuation. [FOREIGN] response
[FOREIGN]. Says vesicle transmitter release, right? Is a counter release, right? [FOREIGN]
Distribution. [FOREIGN] distribution [FOREIGN]. If you collect all this data

like a mixture of this plot. This is actually OK. No response how many times happens, right? And here
you can count, of course,
this is maybe not enough. You have many, many more recordings. And you make this plot. So at one
picoampere here,

then you count how many times happen. And then of course then

you have two picoampere. And from this you can fit by

the [INAUDIBLE] process exactly. That means actually indeed this is

the single photon response, okay? Just like here. This is a single, this is actually the response to two
photons. [FOREIGN]. If you have a partial distribution, you know the average lambda of the events,

the lambda. Just a partial [FOREIGN]

function [FOREIGN] lambda. [FOREIGN] Okay? Exactly [FOREIGN] describe

the [INAUDIBLE] distribution. Okay, so we talk about actually

this single photon response. This only happens in the receptor. [FOREIGN] photo receptor. Because,
they [INAUDIBLE] photo

receptor actually is very sensitive and then responsible for

the [INAUDIBLE] edition. [FOREIGN] Okay. For the cone [FOREIGN]. No, this is a different scenario.
[FOREIGN]. They don't have this

single photon response. [FOREIGN] So we still have the, rely on the cone for the receptor quite
heavily, okay? So because actually in the daytime

you want to see the color. You want to see the motion,

this all coming from the cone, photo receptors, okay?

1.2.5

This is, okay. So, look at these pictures. This one, then you apparently for you to see the rich colors.
Then you are using your

cone photoreceptor. Also, look at this picture,

so no much colors. What kind of photoreceptors you are using? Okay, it's quite tricky. So, the cone
photoreceptor of

course can give you a color vision. And this one with color but it's still

you are using your cone for the receptor. You don't see the colors because

the picture yourself with no colors. You still using your cone photoreceptor,

because this is the bright light vision. Under these conditions,

your photoreceptors are not working. It's saturated, okay? [FOREIGN] Like a rod photoreceptor.
[FOREIGN] It's not it's

the same meaning as we talk about the evening

right now because you have the artificial lighting, right? So, when you can see the colors that

kind of light illumination those conditions you are not using

your rod photoreceptor, okay? [FOREIGN] You cannot see any colors array, it's just black. And then
gradually you can see,

maybe some kind of images happens. Maybe your friend sees some whale. You just see the ships
there but you cannot recognize the colors

of their clothing, right? So, in those conditions,

you are using rod photoreceptor. And then maybe under some conditions you

will use, it's like a light illumination. It's a bit brighter but not enough

to saturate the rod photoreceptor. Then you both [FOREIGN]

reporting to your brain, okay? So, this one, of course, it depends on our color photoreceptor. This is
color vision. For color vision, actually, we need to go to this gentleman, Newton. He did quite famous
experiments,

actually, in those days. The first one actually is this one. If you just use a prism and

then you can split the light in two and

deepen the colors, right? This is the [FOREIGN]. And then of course you can isolate this single color
[FOREIGN] but interestingly, if you give two lights. Let's say this green and

the red together shine on the same spot. What happened? You will see a yellow here. If you
compare this yellow and

this yellow, they're completely different. I mean, maybe for

you the perception they're the same. Both are yellow but then the physical property of these two
yellow lights, are completely different. This is actually the single

wavelength here. Not single. It's just a more pure

band of the yellow light. But this one, actually is two. LIke a combination of the red and

the green, okay? Then that tells you something already. If you think hard. Indeed, in those old days.
Like a, [FOREIGN] that is actually how we can see color, yep? The color, as we said here. These two
yellow are so different,

the physical properties. But for us,

they're actually the same perception. So, this actually- These two gentlemen we should talk about

Thomas Young and Helmholtz. These two actually really great thinker, actually in those days,
actually, didn't know any anatomy or

electrophysiology, and they tried to think about how we

can really make the color vision. See color. And then the purpose that you see this is the theory,
actually, called [FOREIGN] 1802. This gentleman proposed [FOREIGN]. So, we only have three kind of
basic

type of photoreceptors in the eye, okay? And each of the three

types of photoreceptors sensitive to particular

range of visible light. Each cell's actually responsible for

different light sensing. And then in 1850 Helmholtz then

developed this theory further. [FOREIGN], so [FOREIGN] just three types of cone photoreceptors,
blue and green, and red, [FOREIGN]. And then the relative strength of

these signals detailed by the three types of cones are interpreted by

the brain as a readable color. [FOREIGN] the brain. [FOREIGN]

of course, at those days, actually, no any other evidence. This is just actually,

by this kind of experiments actually, they really kind of have great insight. [FOREIGN]
1.2.6

So, in those stage actually,

they don't have any evidence to demonstrate this is true,

so what happens actually? Okay, later, of course actually

they not for scientists, actually, really do

the experiment to prove. Like this one,

Jeremy Nathans Jeremy Natham is also from Johns Hopkins University

just like Kim Y Yao. [FOREIGN]

Now what's his contribution? He cloned. All those different colors which are pigments. [FOREIGN]

They got protein. [FOREIGN] Okay, so

he cloned these three receptors, and they look like here. [FOREIGN] long distance. [FOREIGN] Your
alignment actually makes the comparison. All these red dots right here,

these registers are different, but the others all are the same. So look at this protein,

there you have about 96% identity [FOREIGN] But, [FOREIGN] That's strange, okay? These two
proteins,

they are quite identical. And then, as we talk about the light effect in the membrane is only to
[INAUDIBLE] retinal. It is the retinal absorb the photon. But right now you have two different

proteins, one is response for the red detection, one is for the green. But only one chemical to detect
a photon. How can you achieve this

wavelength detection? [FOREIGN]

Those all change the retina. It leverages the retina. [FOREIGN]

A lot of people actually started this how a protein structure can change the spectrum of the
[INAUDIBLE]. [FOREIGN] Spectrum, or this important differences, actually it's closed, through the
binding pocket, okay. [FOREIGN] Like a [INAUDIBLE]

binding pocket, because this kind of acid,

then you have a different chart. A different polarities. These actually will affect the absorption

of the [INAUDIBLE] retina, okay? This is a tuning called

the the protein tuning. So if you take these different proteins,

then you're express in a. And then you put a into the. And then you can get this measurement,

then you can see, okay. So each protein is a chromophores they

will absorb given the light to light. Indeed, they found actually this

is the blue pigments, okay? Absorbs the photons actually

mainly in the blue region and then you have the green and there is red. This is called absorption
spectrum

then this is the molecular base of the color vision. Three deep in the proteins and they indeed as the
young and hammer has, actually they propose three

[FOREIGN] molecular basin. So close, right? Here, right. Okay so, this is a good question. So, actually
if you overlap this three you [FOREIGN] all this three actually,

are identical. The shape are the same. It doesn't matter if it's this one or

this one, all these are the same. But then we see that they're quite

close only 30 millimeter difference. This actually is because this difference

is a tuning from the protein. This should not shift a lot

because there's a binding pocket. It does the charge actually,

not so different. Okay, so all this actually absorption

is by the [INAUDIBLE] retina, right? But the protein make the change shift

from here to here, to here, to here. And then you look in here. On this other green two

drops in difference. Actually quite a lot. The residual difference. And this actually,

they're quite close absorption. It's a file 60. Okay, good. Yeah, this is good. So this one actually, this is
a long kind of history here, okay. So it's just actually a base

order Young-Helmholtz, they propose actually three

types of cone for the receptor, blue, green, and red, right? And here, actually, the absorption
actually here

is not really the red region. It's yellow.

And then we should have called it called this actually yellow color for

the receptor, right. But actually because of

the tradition we just actually naming this one [INAUDIBLE]

sensitive photo pigment. Or corresponded to red, so

it's not exactly right, okay. You are right. But it was still called the red pigment,

because it's tradition. Uh-huh. >> [INAUDIBLE] color [INAUDIBLE] Red and

the green. Red and the greens will become yellow. You mean? >> And they're doing an experiment
and find the red color light Of other colors. Actually the is that

>> I see. I see, I see. Not this yellow one,

you mean the detection. No, if you use this one you still

can create the whole spectrum. Yeah so what's the question? >> [INAUDIBLE]

That [INAUDIBLE] And [INAUDIBLE] >> Okay. >> [INAUDIBLE]

what the [INAUDIBLE]

>> Yep. >> [INAUDIBLE] so [INAUDIBLE] the septum did not divide it more but-

>> Okay, okay. There's a good point here. Also some insight. Looking at this one, I guess chemation,

the red and the green. Because they're so identical. So maybe they come here from the same,

evolved from the same thing. Maybe the green is the first and

then the lung actually starts from green, make some mutations during the evolution. And then you
create the. That's a good point, okay. So why during the evolution

actually not separate further? I guess this,

no I don't know the true answer okay. So we can talk about it maybe just for

some discussion. I guess actually maybe for

the human or the monkey, their turn,

it's the environment which those colors actually just use

these two combinations. Then you can chew. So the main need for the food is seeking. For example
if you find a red fruit [FOREIGN] will detect

light [FOREIGN] you got selection pressure [FOREIGN]. This may not be true, but

just for a thinking, okay? Yeah? >> [INAUDIBLE] >> Intensity. >> [INAUDIBLE] >> [FOREIGN] intensity
[FOREIGN]. >> [INAUDIBLE]

>> Okay. >> [INAUDIBLE]

>> You fix the intensity [INAUDIBLE] >> [INAUDIBLE] >> Yeah. >> [INAUDIBLE] four [INAUDIBLE] >>
Comparison [FOREIGN]. Okay, so this is the absorption spectrum, absorption spectrum [FOREIGN] is
the light absorbed by these molecules,

this absorption. But this absorption doesn't mean it really actually triggers

a visual processing, right. So you still have a step, actually, a gap between these two, and

then, this is important. So we have a, call it, action spectrum. Action spectrum should be,
[INAUDIBLE]

measure the electric signal from a cell. Then you stiffen the light

to stimulate the cell. Then, see how many photons you need to

produce a certain kind of a response. And then frankly then you have

the relative like a sensitivity, just call it real action

spectrum of the cell, right? Now, fortunately these two

are actually similar okay. But you look at these pictures,

they are so different actually. This one You can see, or

you can go down to zeroright? But this one is far away,

actually more sensitive, you can units. No units, 0.0000001 maybe six 0s here, you can do the
measurement here. But this one [FOREIGN] to activate this pigment is around this region right
several hundred. What happened? Actually their photo energy to

see [FOREIGN] to the pigment. [FOREIGN] There is not any light information there. You can
sometimes occasionally perceive

maybe there was some flesh there. [FOREIGN]

Backlight. [FOREIGN]

Okay. Let's take a look here. So this is a different cone. The spectrum, right. So, the cone allows us to
color. And let's compare. There, the common response, this is

a common response [INAUDIBLE] a monkey. And then this is a monkey

[INAUDIBLE] recording. Look at it, just two response,

they're different. Obviously, what's the difference? The connects is, are very different. This is very
fast. This is very slow, right? [FOREIGN] Our brain actually uses this cone photoreceptor the motion.
[FOREIGN]

Okay, so the motion detection. [FOREIGN] Color, also you need rely on this comfort receptor.
[FOREIGN]

29 appear in the inside, right? [LAUGH]

>> [INAUDIBLE] >> [FOREIGN] >> [LAUGH] >> [FOREIGN] The right side, I'm sorry, the right side is
same

thing happened here, but actually for a patient. [FOREIGN] Because they are very close, these two
proteins, and on the same chromosome sometimes the recombination will happen. [FOREIGN]
Okay? Now, because it's in the X chromosome, the red and the green, [FOREIGN] One copy of x
chromosome, [FOREIGN] copy, all right? [FOREIGN]
1.2.7

All right, we have right now finished topic about phototransduction

and photosignaling in the photoreceptor. And this photoreceptor signal then needs to propagate or
process by

the the retinal neural secretary. So, for the retinal neural secretary, of course they all the retinal

interaction origin. Actually, this gentleman make

a huge contribution in 1967, because he work in the on

the Retinal Physiology origin. He got a Noble Prize. So, when they recall from

the Retinal Ganglion cell, so in the photoreceptor,

people used suction pipette recording. And then in the ganglion cell, then people

typically used the other recording method. You can maybe just put a sharp electrode. [FOREIGN] You
can detect the spikes, these extracellular recording. Or you can use the patch clamp

recording from the single cell. It doesn't matter which kind of recording,

but when you record from a ganglion cell,

you give a light stimulation. Here, it's different. The ganglion cell will give

the action potential firing. [FOREIGN] Action potential

[FOREIGN] spike. So, when you have this one,

this is actually, we saw in the dark

without any stimulation. Interestingly, the therapy was

spontaneous action potential. But the retinal is quite low. But when you give a light spot. [FOREIGN]
Quite strange here. If you give a larger,

the light spot stimulation, the response gets smaller. [FOREIGN] And then interestingly, if you do a
ring of the life simulation, the center is still black. [FOREIGN] The ganglion cell here

actually inhibited, no any response. But actually,

this spontaneous also disappear. [FOREIGN] Now, this actually, if you define, actually, in the center,
then this one, in the center, this spot actually is the excitation. And then in this region,

around the region, there is an inhibition. So, we talked about the receptor field,

right? It doesn't matter excitation or inhibition, those all

are the receptor field. So, for this retinal ganglion cell, the receptive field covers this region but has
two separate regions. In the center, there is excitation

in the surrounding inhibition. This is called center

surround receptor field. [FOREIGN] A lot of computation came based on this [FOREIGN]. Of course,
actually,
you can record from another cell. Maybe just has that opposite receptor

field that it means actually in the same term, then you give

it a supporter here inhibition. But it will give you

the surround like stimulation. Surrounding, then you have the excitation. Okay, this is what we call,
this is the on center,

on center offs around, this is called off center, offs around, [FOREIGN] digit off. Yeah? >> Receptor of
this experiment. Retinal stimulates the ganglion

cell through the concept. And then this goes to the ganglion cell. >> What's your own answer? >> My
answer [INAUDIBLE] >> Yes, only. Detect light, right? Photoreceptor detect the light. >> So, the
[INAUDIBLE]

of the [INAUDIBLE]

>> In the? >> [INAUDIBLE]

>> Yes, yes. Is it just aware in the rat. You shine the light, spot actually. It doesn't matter, you sign
the light

from the ganglion cell side or the photoreceptor side because

it's transparent the retina. So, the hollow region of

the retina covered by this light, then that's the receptor field, okay? >> [INAUDIBLE]

Cell [INAUDIBLE]

>> These two? >> Yeah. >> So,

you just recalled from this cell, okay? You called it from one cell. And then,

you give it the light stimulation, and you need actually move around

as a light stimulation. Sometimes, you cannot get any response

because it is out of the receptor field. And then when you move one

region you see the excitation. And you increase the light. And then you see inhibition. And then you
define this

area is the receptor field. And for another cell, of course,

you do the same thing. Maybe it's a different

region to receptor field. >> So, before you do the experiment,

you have to distinguish which retina cell? Or [INAUDIBLE]. >> You don't need. You don't need. >> Do
you have to to do

the past stimulation- >> Stimulation, you just you just arrange them. >> [INAUDIBLE]

>> Your screen, your screen. Yeah, you came up with this slight spot. For example, you have this
huge
rectangle piece, like this size, okay? This size, and then you move the spot. The stimulation around
this whole area. You record from the beginning of the sale. You see a response, and you know there
is

a effective receptor field there, right? >> [INAUDIBLE]

>> Yep. Okay, so let's look here. It's quite interesting, right? So, we know, actually,

in the photoreceptor here, the response is as it is,

is hyperpolarization and no spiking, okay? But actually, if we recall from the ganglion cell,

then you have the spiking firing. And also, you have excitation, and

also have inhibition corresponding the excitation is depolarization,

inhibition is for hyper polarization. But in this the input of

the signal here is only hyper polarization [FOREIGN]. Right? That means there's a lot of

processing happening inside here. Okay. So, let's take a look, actually,

what actually happened at this synaptic region from the photoreceptor

to the bipolar cell. Let's take a look at the process here. Actually, the first one, I want to

show you is a picture of this one. This is a from a new paper, 2015,

Annual Review of Neuroscience. So, this is actually a cartoon

to show the retinal connection. This is the photoreceptor. This horizontal cell. This is a bipolar cell.
And the bipolar cell,

actually, look at it here. This one is short. This one is actually quite long. These actually are two

types of bipolar cell. This one is called off. Because actually,

if you give a light to this bipolar cell, this bipolar cell actually

is a hyperpolarization. But then if you give a light

to this bipolar cell, this bipolar cell will

give depolarization. Things owned by polo as they are. If they just by this anatomy,

they what you can recognize this, this, bipolar cell, the danger area is quite

close to the photoreceptor layer. This is called off, but this one, the axon terminal is

closed to the ganglion cell layer. This is called on, okay? So, there are simultaneous,

actually, pathways, on and off. And in the photoreceptor, just off, right? Because they have
polarization. But here, became two layers. Let's look at what happened. So, you see this is the short
one,

by polar cell this is off by polar cell. This is owned by polar cell,

a long door one. So, and I guess you want to talk about
this in your train meter, right? In these lectures, so how it happens, the same input here is
hyperpolarization. But then, these two cells,

[FOREIGN] how can you achieve this one? Two different cells, okay? That's one way to achieve,

but it's quite a challenge. But here, if you see one to here

to specific another one to here. There's a huge demand for the cell. So, you need to find a specific
release. We know right now, okay? This cell radiates the same

neurotransmitter rudiment. >> Give a different receptor

from your [INAUDIBLE]. >> Okay, good.

So, then you can achieve, actually, express, your transmitter

receptor on the bipolar cell. Why?

Actually, we know right now, okay? This whole bipolar cell that

express the emperor receptor. AMPA receptor is the most abundant

receptor in the brain, okay? [FOREIGN] AMPA receptor, A-M-P-A. And this one, bipolar cell,

they use a mglurs6. Metabotropic glutamate receptor type six. [FOREIGN]

Now, because the empire receptor is always,

actually, you have a glutamate binding. The receptor then will open and

then the cell depolarize. So, in the dark,

this cone cell is depolarizing. Because it is that TCP open the CNG

channel, then the cell depolarized. And then depolarization make

a lot of glutamate release, okay? So in the dark,

glutamate release to this bipolar, then depolarize,

then you have a light coming. This cell has polarized, and the release reduced. And then this cell will
hyperpolarized,

right? But [FOREIGN] they opted. Because this receptor is really different. You need to couple to a G
protein,

mGluR6, and then when you have glutamate

released in the duct, the glutamate binds to the mGluR6. And then this mGluR6

acting with a G protein, then somehow, through a cascade. To close a channel, of the TRP channel,

T-R-P channel, in the membrane. Then the cell have polarized,

but when you have a light coming, less glutamate release. And then, this hyper,

the channel, TRP channel, T-R-P channel, will be open

again because it's a receptor. Activation, actually, now it should

be less activation with mGluR6, and the TIP channel, TIP channel open. Still depolarize. [FOREIGN]

Yeah. This is actually a cycle. Y is actually from the same cell,

cone cell go to a empire receptor. And then go to off bipolar cell

to [INAUDIBLE] and receptor. And then through the gene protein. And with this channel,

we know right now is TRP channel, T-R-P, TRP channel, okay? Identified. We know right now, okay,
so the ganglion cell has the same

surround the receptor field, right? So, using this, we can actually look

at this computation in the retina. So, how the center-surround

cell receptive field achieve? This is, okay, let's take a look for

this one, this is the photoreceptor. And then, you have a bipolar cell here. This bipolar cell is

an off bipolar cell or hyperpolarizing or H bipolar cell, okay? And then, if you have a light coming,

this cell, hyperpolarized. This cell also hyperpolarized. Because these cell express

empire receptor, right? Okay, this is the center response. How does the surrounding? The
surrounding actually, right now,

this is quite important, okay? So, you see this dendrite actually of the bipolar cell does not

connect to the other photoreceptor. But actually, this region still considers

the receptor field of this cell. Because there is another cell,

horizontal cell, connect all these cells. A horizontal cell receives the input from

this cell, but also, at the same time, this horizontal cell will feed

back to each of these cells. Okay? So, let's take a look. This horizontal cell receives

the input from these cells. And then we have a neck to

feed it back to the inhibitor. Feed from the neurons. And this inhibition, from this cell,

it also depends on the depolarization. So, if the cell has depolarized

the feedback, then it's less. So, when you have a light only active

in this region, what will happen? I will give you a clue. This is the horizontal

express empire receptor. Hyperpolarization here,

this also is hyperpolarization, right? And feedback, then let's feed it back. Feedback is actually the
best thing here, it reduce in your transmitter,

and then in this case, the neurotransmitter will find this cell, will have more neurotransmitter
release,

right? More neurotransmitter released will cause. This is empire receptor

expressing in cell, then, be polarized. So, you kind of, you say summary the [FOREIGN]
okay, we can explain in next lectures. Take a financial [FOREIGN] concept

[FOREIGN] receptor field knowledge system. [FOREIGN]

Computation. Same thing with [FOREIGN].

Week 2

2.1.1

So, today, let's continue. The last time we still left

the center-surround receptive field, the neural mechanism. So the first actually [INAUDIBLE]

is actually the ganglion cell. We will have the center-surround

receptive field because pupillary from the ganglion cell. If you give a light spot maybe

the cell will fire action potential. But then you increase the light spot size,

got very strange results. The cell actually would be more silent. Give it less response there,

right, and then if you give it kind of a ring of light in the center

there should be no stimulation. Then you will get the inhibition response,

right. So this ganglion cell receptive field actually it's coming from,

inherent from the bipolar cell. That means, actually in the retina, the center-surround receptive field
is

first generated in the bipolar cell. Okay people, recording from bipolar

cell also found the same thing. Okay, we talk about actually, some point here, talk about the bipolar
cell,

the generation for the Center-Surround Receptive Field. So, remember, when we talk about there is
a another important cell

called horizontal cell, right? Horizontal cell is actually a between the photoreceptor and

the ganglion cell, this region. And then the cell will make a, like a lateral connection to many,

many photoreceptors. But they would not send it to exxon,

to the other cell. Only connect which is the photoreceptor. This is so special, and

this is so important. We talk about the functions used to

generate the center-surround receptive field. Let's look at how it works. So, this is a cartoon, these
are photoreceptors and then this is the artificial bipolar cell. This cell has an expressed

empire receptor. So of course then you know this bipolar cell will be an off bipolar cell right? Or h
bipolar cell hyperpolarization

bipolar cell, okay? So because HDT bipolar cell you can

see the dendrites here, actually can connect, meaning photoreceptors,

but here, to demo, make a distinct for the demonstration,

we omit the other photoreceptors. We just show one, okay. It doesn't matter if it's 10 or 20. So the
one work, okay, so this is called

a center-surround receptive field, it's the photoreceptor directly

connect the area of the photoreceptor. This is the center. Let's see how it works. So if you view a
spot like only illuminate

or stimulate the center region. These photoreceptors

will not activated right? Only the center would be activated. Then the cell will be hyper polarized.
And the cell really is less glutamate. And this bipolar cell

also hyper polarized. This is the central response, okay. So, let's look at the surround response. So
the surrounding,

okay we can give you a light stimulation. A ring offers the light stimulation, so

the center is black, no stimulation. That means this cell is still kind of,

will be polarized in the dark. But these cells, right now, you stimulate them with the light, okay. So
these cells actually does not

directly connect with the bipolar cell. All right, because you have a horizontal

cell here, make the connection. Let's see what happens

to the horizontal cell. The horizontal cell,

one important feature is actually we are get the synaptic input

from the photoreceptor. At the same time,

it will feed back the photoreceptor. That means it's a kind of

mutual bidirectional synaptic connection from input from

the photoreceptor and then output also to the photoreceptor. And then this output to the
photoreceptor, actually, is inhibition. So this inhibition mechanism

is not clear yet, okay. But people talk about this, there is a lot of like a GABA effect. That means the
photoreceptor

can release GABA. The GABA is the gamma

angiotensin 1 like lecture. You probably talk about it,

actually it's the inhibition right? [FOREIGN] is a [FOREIGN] channel and

then the cell will hyper polarize. So look at this one will

release the GABA for example maybe we will have some other

mechanism for the feedback, but at this point we can use GABA as a discussion

with this mechanism, okay? When the cell be polarized, this cell will

release GABA to the photo receptor and the photo receptor will be inhibit and

then release less glutamate. Okay this is in the dark where it

happened because this all this cells, they polarize, and also this cell
express the n-paraceptor, and then we are also depolarized in the dark. But they way you have a
light phenotype. This cell, what would happen? These cells have been polarized,

these cells also have polarised right? And then feed it back, less feedback. And then just these
inhibition. [FOREIGN]. This inhibition will cost

this this photoreceptor more and then released more will be polarized. You see? This is how the
Center-Surround Receptive Field works. [FOREIGN]

Horizontal photoreceptor. It's this inhibition, this is a key point. [FOREIGN] Of course, these cells,

you're looking at these cells. These are photoreceptor. They also receive their feedback

from this horizontal cell, right? But because this cell

already kind of hyperpolarize so strongly by the light signaling. And then these cells actually

to feed back depolarization will be very minor because you have

very strong light effect. But for this cell you don't have

the light stimulating, right? So you have a depolarizing effect. Then the cell will be more depolarized,

okay? All right so

if we talk about a center-surround for example if we talk about

actually this cell is its own bipolar cell

expressing the mGluR6. [FOREIGN]. You will get a cell with

a center of its own. Center if you add stimulation

it will depolarize. If you have a surround stimulation then you will get inhibition, right. For this right
now in

the middle is a minus. It's inhibition, is off response. The surround is it's own response, okay. But if
we switch this bipolar cell to

a non bipolar cell then quite simple, just flip the polarity. In the same then you get excitation. In the
surround,

then you'll get inhibition. I can see three to four, right. Okay, so this is the bipolar cell you can

generate the centers around response. And you just imagine, okay, the down stream of

the bipolar cell is ganglial cell. Ganglial cell direct

connect with this cell. If one ganglial cell direct

connects with this bipolar cell what happened to the ganglion cell? Because this bipolar cell

also releases glutamate. And the ganglion cell, in most cases,

they express receptor. So then it means the ganglion

cell will directly follow the response prompt is

off of the bipolar cell. Right? So this receptor field actually

there is very elegant, actually it's a mechanism actually where

people work out, those connections. And also this one can explain some

kind of psycho-physical study.

2.1.2

For example, look at this photo, and then you will obviously

see some lines that are between the neighboring bands here. Actually, for this individual band here
they are uniform from

the intensity [FOREIGN]. Why actually, on this edge,

do you have so like a huge contrast? You will see a line there. There is actually no line. So with this,
then we can connect with

the receptive field center surround. Let's take a look. So for example, if you have a ganglion

cell in which the receptive field, it's a center surround. Center is on, for

example, surround is off. So if the ganglion cell receptive

field is covered by one band, ahatever happened to ganglion cell? This ganglion cell, of course right
now,

you don't have strong stimulation, and also canceled, surround the center. The cell would be quite
especially quiet. But then when you move this

cell to the left, yeah, to your right side. And if the cell moves to this region,

let's see what happens. For example, B is the same thing, right? You're perceiving the more

kind of bright band. Because the cancellation

contains a surround and a center, the cell is quite silent. And also,

if we move this cell to this region, you can see right now, the center actually get a lot of stimulation

by this bright light here. And the surround, of course you also get

a sound stimulation from this region. But this region,

actually you don't have stimulation. Okay, we talk about actually the center

surround is almost cancelling each other. If we have complete, like this situation,

then you don't have the activity. But here, actually this cell

is most strongly excited, because under this situation,

and then this is strong response. But the surrounding,

you cannot have a full cancellation, because in this region you

don't have stimulation. If you move to this region,

what would happen? And then this node excitation. But then this actually

have the inhibition. So, in this case, this is very strong. You just, the center,

just sitting on the edge of the band, then you will have a strong excitation. Then you see straight
lines. So this is the information processing, actually in the retina. And the one very important feature
about the processing is center
surround receptive field. And the center surround receptive field

also related to the on off pathway. So in the retina, actually, we use our eye to look at

the visual information. Actually, you need to get

a lot of information. For example, color and brightness and also the shape and

also maybe some other features. So, all these features,

you need go to the brain, and then you can really make

a complete perception. So, in the retina, we talk about actually,

okay, this is on, off pathway. And also, there is some kind of color

pathway generated in the retina. So this pathway, in most case actually,

they are parallel. [FOREIGN] So you have so many different channels to process the information like
a motion and color and on, off brightness signal. So this information,

you need processing the brain. Let's take a look actually, what's the visual pathway in the brain? This
is the light information

will go from the eye, retina, then go to the first brain center, it's called lateral geniculate nucleus,

LGN. Translate into Chinese it's [FOREIGN]. [FOREIGN] And

then the information from the LGN. And then we'll further transfer to the primary visual center.
Racial context, okay
2.1.3

Let's first take a look at this LGN. LGN, if you make a slice the brain then

you will have these kind of pictures. This is how LGN looks like. Is the dorsal thalamus. [FOREIGN]

This LGN is quite interesting. You can see these stripes, right? There are total six layers, okay?
[FOREIGN] This is a link coming from,

okay? [FOREIGN] It is it is like a unique here,

okay? There are six layers. So in the brain at most, in context, okay? This kind of typical kind of
structure. All the brain's structures,

you have six layers of cells. So let's take a look at how

the eye connect to LGN, okay? This is the eye,

of course what comes out from the eye? So, what comes out from the eye

to connect to the brain? >> [INAUDIBLE]. >> Is the axle of the gengnis there,

right. So the gengnis there, the axle coming from the eye then will

through the LGN, make the connection. But it's quite interesting, okay? Depth targeting. So the laser,
[FOREIGN]. Now, look at here. This is considered right eye. This is the left eye. And then you can see
for this side, LGN. You have two, three, five, layers two, three, five will receive the input

from the same side of the eye. And then one, four, five, we see the opposite side, the eye input. So,
the there we go from this side,

layer two, three, five, right? How about the visual cortex, let's really go to the next step,

the visual cortex. The visual cortex is this region, right? If we make a section again,

this is how the visual cortex looks like. You have a six layers. One, two, three to six, okay? So from
this one it's quite interesting,

okay? So the LGN, you have six layers, and the LGN receives

the input from the retinal ganglion cell, and then this visual contact of course

also receives input from LGN, right? But only this layer, this layer four. They are 4C. Okay, look at this
tractor. The layer 4 is most like

abundant occupation here, right? And then you have ABC. And even within the C you have alpha
beta,

the layout. So the LGN input, majority of the LGN input only comes to you, Layer 4C. This is a makes
synapse with the dendrite of

the neurons within this cortex, okay? And the other layers different output. For example, like
[FOREIGN] targeted, project to the other brain region, okay? The information from this cortex area
then will transfer to other areas for

the processing. So we talk about LGN you had

with eyes specific input, right? And how about this region? Now this region as we discussed, only
layer 4C is the major input from the LGN. This is, there is a beautiful work,

actually from and [INAUDIBLE]. What they did is quite dramatic, okay? So they inject some dye into
the eye. There, that actually is

the radioactive crawling, and this one [FOREIGN], and then this can be used to

synthesize some protein. [FOREIGN] And if this guy was taken by the cell [FOREIGN] so those can be
transported to the terminal. [FOREIGN]

LGN [FOREIGN] by the transport to the tubes axon terminal [FOREIGN] If you inject this protein here,
and then the cell will take up this guy, and that protein, and the protein will go the the LGN by their
excellent delivery. And then, because it's a bit over,

and the danger. Only those LGN cells, with the dendrite, have the snap

connection, with those neurons. Dendrite can pick up those protein. And then you can go to the
Visual Cortex,

okay so you did this experiment. What you need to do is actually [FOREIGN], if you get the leo four
as we talk about the Visual Cortex, leo four. Get an input from the LGN. Right now if you only inject
one eye, then you can see these kind of stripes there, they're kind of strange. [FOREIGN] You got
staining. What it tells you It tells

you it's actually eye specific connection from the LGN. You have the eye specific input from

the eye, from the ganglion cell. And then you still preserve this eye

specific information in the cortex. [FOREIGN]

Okay? [FOREIGN] If you do the recording. So the site of these stripes actually

Is about to occur 500 micrometer. [FOREIGN] On the stripes, [FOREIGN]. But these stripes, they
actually can be. If you go down to different layers,

these stripes also [FOREIGN] ocular, dominance, colors. [FOREIGN]

If you do a recording from those neurons,

then you have a pipette. At a different layer. Go down go down. All these cells actually in this
pathway

will respond to only one eye stimulation. If you recall that from this one and

the different layers and you will only activate a nozzle eye,

then you can get a response.

2.1.4

We talked about actually the signals

around receptor field in the retina, right? And they house this information,

actually process it in the brain. There's a very important topic. And from this study, then you can
really try to understand

how the brain works, right? Now, these two gentlemen, Hubel and Wiesel, and

that they did a beautiful work, including the [FOREIGN] and also a quite important

the electrophysiology of the receptive field started. And that they got the 1981 Noble Prize

in Physiology and Medicine. Let's look at their approach for

this study. The approach, actually, they want to

study the visual cortex function, okay? And visual cortex,

how can you study it, right? So typically they use a cat. [FOREIGN]

And you open, of course the cat is fixed here. [FOREIGN]

okay? And then, you insert a electrode

into the visual cortex. Visual [FOREIGN], just so

you can input the default, right? Layout for C, for example. And then, you have a TV monitor. To
show the light stimulation to the cat. The cat [FOREIGN] quite disappointed at the beginning. They
try to use the light

because in the In the retina, the study actually just uses a light,

a spot stimulation. You can get a response from the neuron. But when it went to trial,

they used the light stimulation. One light here. One light there. Even here across the whole screen.
And those neurons, there should be numerous response, okay? Laser is fun actually, very special.
Those cells actually, can only

respond when you have a light bar. Just so you [FOREIGN]. Then you can see it.

[FOREIGN] The cell [FOREIGN]. And if you [FOREIGN]. For example, this one. You change the
direction and

the cell doesn't care [FOREIGN]. [FOREIGN] special, okay? So these are from the same cell recording,
then you cannot [FOREIGN]

only this direction the response system the strongest one. And then [FOREIGN]

and [FOREIGN],

okay? How will you think about this observation,

if you get the recording, get these kind of results? [FOREIGN]

This is what we observed. No. They then actually think very hard about this observation, okay? So
because in the cell, as we said, the receptive field is a center
[FOREIGN] you know, send us around. [FOREIGN] In either case. [FOREIGN] Cortex, so dramatic
different. Of course, maybe a lot of computation [FOREIGN]

[FOREIGN] If take a look at the, we took a look at the photo receptor. [FOREIGN]

So, in the bipolar cell, the computation mainly happens by the horizontal cell, right, making circles
around. [FOREIGN] the cell is

near the same is around. But to this stage then became a directions important and

also you need a light bar. [FOREIGN] Of course, then if you want to study system mechanisms
[FOREIGN],

what will you do? It's actually, let's first actually

record from the LGN, right? Because we know cell is like a bar,

and this cell is like, you need a. But then in the middle there was LGN cell,

right? So let's record from the LGN. And actually, when people did

the recording from the LGN, those neurons, the receptive field is

exact the same as the cell. Sent us around, okay? So then the question comes

down to how the LGN, the input to this visual cortex,

just one synapse. Then you make a transformation, right? Can you imagine a way,

especially to achieve which is centers around to this this light bar, and

also direction sensitive receptor field.

2.1.5

Yeah actually indeed they think

this is the way how it works. Now let's take a look, this is the LGN. LGN as I said is the same as the,
retinal ganglion cell. This simple cell here. You have an input from

three cells of the LGN. And those LGN cells or

retinal ganglion cells, somehow the receptive

field links to each other. [FOREIGN] So you take a look,

they have some overlap here. It's response off [FOREIGN] what happened? [FOREIGN] In the center,

if we have a light bar, then this cell will be very excited. And also this one, excitation, under the of
this one

of course excitation. If the light covered only this region, then it's inhibition of response. Also, this
region is

[INAUDIBLE] responsive, you can compare this site, right? [FOREIGN] Now, they also formed, during
the recording, right? Of course,

this is kind of called simple cell. [FOREIGN] [LAUGH] They also

found some other cells. The property is actually a little

bit different, take a look here. [FOREIGN] Simple cells from layers four and six mainly, right? And
complex cells from two, three, five, they don't have clear excitation and

inhibition regions, okay? And [FOREIGN] a bar about

one third to one half of the receptive field

invokes maximum responses. A stimulus [FOREIGN] receptive field [FOREIGN] cancellation, right?
This actually, from the receptive field, either looks like you

have really some simple interactions from the different neurons. Then you can create very
dramatically

different properties of the cell, right? [FOREIGN] Somehow, they'll make different combinations
[FOREIGN] [FOREIGN] This is just a hypothesis, [FOREIGN]. [FOREIGN] If you have an imaging
technique for this study, then you can simultaneously examine many, many different neurons. Say
sometimes maybe 1,000,

sometimes maybe a few hundred or a few tens of neurons, simultaneously. You just actually set the
computer monitor

to give the different stimulation. [FOREIGN] Of course imaging Has this kind of huge advantage at the
same time may be, Not so sensitive as this kind of recording,

okay, sometimes. Because if in the brain, actually those

neurons actually give only a few spikes, they don't have a huge

cancelling signal there. Then maybe you will miss certain

information by the imaging technique. Okay, so the a lot of computations to extract those feature
from the visual field, right? DM from the patch or

the [FOREIGN] centers around and then to simple cell,

complex cell, complex shapes. [FOREIGN]

To date actually, no specific cell was found to respond only to one phase [FOREIGN] phase cell.
[FOREIGN] One sale responds to the model, a phrase, that's too risky, right? [FOREIGN]
2.1.6

We talked about actually the signals

around receptor field in the retina, right? And they house this information,

actually process it in the brain. There's a very important topic. And from this study, then you can
really try to understand

how the brain works, right? Now, these two gentlemen, Hubel and Wiesel, and

that they did a beautiful work, including the [FOREIGN] and also a quite important

the electrophysiology of the receptive field started. And that they got the 1981 Noble Prize

in Physiology and Medicine. Let's look at their approach for

this study. The approach, actually, they want to

study the visual cortex function, okay? And visual cortex,

how can you study it, right? So typically they use a cat. [FOREIGN]

And you open, of course the cat is fixed here. [FOREIGN]

okay? And then, you insert a electrode

into the visual cortex. Visual [FOREIGN], just so

you can input the default, right? Layout for C, for example. And then, you have a TV monitor. To
show the light stimulation to the cat. The cat [FOREIGN] quite disappointed at the beginning. They
try to use the light

because in the In the retina, the study actually just uses a light,

a spot stimulation. You can get a response from the neuron. But when it went to trial,

they used the light stimulation. One light here. One light there. Even here across the whole screen.
And those neurons, there should be numerous response, okay? Laser is fun actually, very special.
Those cells actually, can only

respond when you have a light bar. Just so you [FOREIGN]. Then you can see it.

[FOREIGN] The cell [FOREIGN]. And if you [FOREIGN]. For example, this one. You change the
direction and

the cell doesn't care [FOREIGN]. [FOREIGN] special, okay? So these are from the same cell recording,
then you cannot [FOREIGN]

only this direction the response system the strongest one. And then [FOREIGN]

and [FOREIGN],

okay? How will you think about this observation,

if you get the recording, get these kind of results? [FOREIGN]

This is what we observed. No. They then actually think very hard about this observation, okay? So
because in the cell, as we said, the receptive field is a center
[FOREIGN] you know, send us around. [FOREIGN] In either case. [FOREIGN] Cortex, so dramatic
different. Of course, maybe a lot of computation [FOREIGN]

[FOREIGN] If take a look at the, we took a look at the photo receptor. [FOREIGN]

So, in the bipolar cell, the computation mainly happens by the horizontal cell, right, making circles
around. [FOREIGN] the cell is

near the same is around. But to this stage then became a directions important and

also you need a light bar. [FOREIGN] Of course, then if you want to study system mechanisms
[FOREIGN],

what will you do? It's actually, let's first actually

record from the LGN, right? Because we know cell is like a bar,

and this cell is like, you need a. But then in the middle there was LGN cell,

right? So let's record from the LGN. And actually, when people did

the recording from the LGN, those neurons, the receptive field is

exact the same as the cell. Sent us around, okay? So then the question comes

down to how the LGN, the input to this visual cortex,

just one synapse. Then you make a transformation, right? Can you imagine a way,

especially to achieve which is centers around to this this light bar, and

also direction sensitive receptor field.

2.2.1

So the auditory system

is the sense of hearing. So here in the front is a picture. You can look at this picture so

you appreciate actually when you enjoy the music,

it doesn't matter what kind of music. So all the sound should detect

by the auditory system. So we also actually showed you last time, the hearing, also important for the
survival of the animal. For example, for

this bird to catch the food. Here is a mouse or rat. So this is actually in complete darkness. And then,
we talked about it last time, how this bird can really precisely

locate the target without any other cue, only by the sound cue? So, today we'll talk about it more,
those kind of underlying

mechanism to achieve this. So if I ask you to describe the process of the hearing, how will you
describe it? >> So I guess even in the high school,

everybody, I guess, learned their kind of biology,

so of physiology. Apparently you know

something about the hearing, without the book knowledge actually, I guess you also know some of
the process. How can you describe

the process of hearing? Any volunteers? >> Well actually I

[INAUDIBLE] I have a theory. [INAUDIBLE]

If I can [INAUDIBLE] the physical sound is mechanical oscillation. And it will-

>> It's a wave, a sound wave. >> Yeah, it will cause oscillation of

maybe a sound or something like that. And the mechanical oscillation will transduce into
[INAUDIBLE]

and transduce into neuron. >> Okay. >> [INAUDIBLE] or

maybe something like that [INAUDIBLE] >> Okay, I'm very surprised. [FOREIGN] >> [LAUGH] >>
[FOREIGN] >> [FOREIGN] >> [LAUGH] >> Yeah, surprise, okay. [FOREIGN] Okay, so that process
actually is quite complicated, okay? It's more elegant than

what [FOREIGN] described. So let's take a look, actually there is another book actually

describes the process. It's a writer [FOREIGN]. Yeah, I guess you can read quite a signal. And then this
process. So this is the whole process

of the sound propagation from the outside to your auditory system. So this actually is quite elegant

a description of the hearing process. So today we'll go through each steps,

talk about this issue. So let's begin with the first,

actually the sound wave propagation. So from here this is actually, those are particles actually will
vibrate by the sound of the wave. And then you look at here, i says the sound of the wave

somehow collected by either on the outer ear, and then you will

have the biological process here. So let's take a look,

there's the sound propagation. So the sound wave come in,

and the wave hit a membrane. And then you see these

three bones actually will relay the sound wave to the cochlea. This cochlea is giant snail,

this actually varies. This region is some cells

within this cochlea, we transduce sound signal into the electric signal, happen here. So, let's take a
look, the next step, what happened within this cochlea. Actually, we want to take a look

at the anatomy of this structure. So you make a section, and then you

will see these kind of structures. Right? Then, apparently, this is a cell,

transducer sound signal. We have this some movement of this

membrane across some hair bundle. Waiting the tip of this hair cell to move. And then somehow,
this neuron then will

have the electrical activity happen. And then will transfer this electric

activity to the neuron, to the brain. This is what happens in

the first step of the hearing. So actually this is

the anatomy of this structure. So you can take a look. This is what we call hair cell. This is called inner
hair cell. There are two types of hair cells,

one is the inner hair cell, the other is the outer hair cell. So for the hair cell,

it's a little bit different from the photoreceptor,

the light detector. So, this cell has a huge cell body for

the inner hair cell here. And then there is a process, actually, for the tip there is a feel, those kind of
cilia is hair bundle. [FOREIGN] Now, this hair bundle, and then we'll receive

the mechanical force. And then somehow, for this hair bundle, they have mechanosensory

channel at this place. So where you have a mechanical

force move this bundle, like deflected, and

then the channel will open directly and then produce the electric signal. So for this one, thing is,

all the hair cell looks a little bit different,

it's more kind of elongated. [FOREIGN] But it's a process

actually that's quite similar. They also have the hair bundle to

transduce the mechanical force into electrical signal. But this cell actually quite interesting,
they don't have the axon. So you can look at this process, and, this process, the red one. It should be
a neuron,

it sends a process called maybe a dendrites or

some other process that shoots it into the neurons to make

it's connection there. So, this is form another cell to relay the signal from the hair

cell to the brain stem. [FOREIGN] Why there are two

types of these cells? It's quite interesting. Now we know, actually,

this inner hair cell carries a lot of information to the brain. That means, this actually, take a look. This
is actually called afferent,

this red one. Afferent, this exon

carries the information found in the hair cell to the brain. And this actually to make

the sound perception is carry the signals mainly carried by

this afferent in the hair cell.

2.2.2

But actually, for this type of cell,

the outer hair cell, they don't have so much afferent fibers connected. Many uses their efferent.
There is actually this one,

this process actually is those neurons from the brain stem [FOREIGN]

so the information actually is coming down from the brain

to control these cells okay? Quite important here, the distinction. Later we will talk about actually
how

these two type of cells function. Here, the picture of

the two type of cells. This one called outer hair cell, okay. I think you should partition when

you make a section of the cochlea and then,

you have a three layer to the some type. Three roll of the outer hair cell but, only one row of the in
outer

hair cell make it is so it's quite interesting why you

arrange it this way, right. Okay, so we talk about actually this, actually hair cells locate in the cochlea.
The cochlea is like a snail, like a [FOREIGN] so if you open this cochlea, what you can see. It's like this,
you open this one,

and then you can make it straight, like this, right? So on this cochlear and then there is a special
membrane called the basilar membrane. This membrane can actually vibrate and then this
membrane actually

sit in the middle there. They're very different. This one this grey band

is a basilar membrane. And on the top and

on the bottom actually they are a lot of [FOREIGN] so

take a look here. The sound actually propagates

by those tiny bones. [FOREIGN] Okay? When this one look at this membrane not [FOREIGN] okay.
[FOREIGN] Basically a membrane that you. [FOREIGN] Well this is base, the base of the membrane
vibrate, because it's a hair cell just

to sit on top of this membrane. Okay? So, the hair cell will also be

kind of a move up and down. So, the hair cell it's a hail bongo

we showed actually just a few, maybe two slides ago that

there is another membrane actually on top of the hair bundle. So when this basically membrane

actually move up and down and then you will cost the shift

force [FOREIGN] hell bundle another membrane between that membrane and

the hell bundle, okay? So that way the cost are hair cell to
receive the mechanical force okay. There is another property of this basilar membrane, okay? This
one. Okay you can take a look. It's quite strange all right,

so this site, this cochlea, we call this site actually this is a base,

okay. When you opened, and

then the then we cut apex. And then this site, of course

actually looks much larger, right. But then actually this basilar membrane at

a disc location is quite actually narrow. It's orbital, okay? So this side is much wider, this side. So this
basilar membrane,

so at this region will be more region and is far wider. And it's in this region they will be. Sound that
you propagate

along this basic membrane. The frequency of properties

will be different. That is actually the high

frequency sound like this region because this

region is much smaller and this region will be more

sensitive to the low frequency. Okay? Or you can take a look. This is actually the frequency

distribution along this basic membrane. So high frequency at the base. Low frequency detection or

low frequency vibration mainly happen on this at the top, at the tip of this cochlea, okay. We know
actually the sound, what's the features of the sound,

when we detect a sound, what kind of thing we are particularly

interested in, the features. The sound, one is frequency, right? And the second is the strength,

the intensity, its loudness. And the third one is location. Where is the sound coming from. The
frequency right now,

as we can see from this slide, the frequency is already encoded with this basilar membrane, the
properties, okay? [FOREIGN] Took a base from. So if we locate on top of this region. The base region.
That it means those hair

cells we mostly receive the high frequency stimulation right? And then of course at this

region there is low frequencies. [FOREIGN] Okay, [FOREIGN]

2.2.3

Let's take a look. How the hair cell to detect

the mechanical force. So, if you isolate a hair cell,

it looks like this. This is the isolated cell. This is, of course,

this is a cell body, right? And then, what's this? This is the hair bundle. Hair bundle is the part to
receive

the sound stimulation, okay? So, you can do a function essay

using a [INAUDIBLE] recording. Then you can record from the single cell,

so their pipette to record

the electric signal. And then you use another

pipette to stimulate this hair bundle to move up and down, okay? Then you will see this is a signal.
So, this one that uses a stimulation,

okay, so, this simulation is the micrometer, that means you have

a pipette to move the cell to maybe forward by one micro meter and 0.5 micrometer and to 1
micrometer. And also, you can put another

direction of the hair bundle, okay? So, any direction,

you can do with a simulation. Take a look at the response. This is the response of the sale. Okay. In
the resting state,

not much happened to the sale. But when you have a stimulation

of the hair bundle. The cell will give a immediate response. You can take a look here. This is a
response to a small stimulation,

and then to larger stimulation and

again, much larger. And then what happens here,

quite interesting, okay. What's the feature of this response? Can you describe? [INAUDIBLE] So,

take a look at this response, okay? So immediately, I guess it's very obvious,

some features of this response. So, what kind of important

features you are looking, you can seeing about this response? >> Okay, that's good. So you mean.
You mean, this wrist bones cannot

stimulation, will get smaller. Okay, good. This is called adaptation, okay? And that's the only one? >>
After the stimuli,

you have also the [INAUDIBLE]. >> Okay.

That's the second yep. The [INAUDIBLE] response right? >> [INAUDIBLE]

>> Direction. >> [INAUDIBLE]

>> Good, okay. So, if you give approach and

that's a direction, right? So, the response would go

to another direction, okay? This is the certain features. Anymore? >> [INAUDIBLE] >> [INAUDIBLE] >>
Yes. >> [INAUDIBLE]

>> Okay, good. You mean the cell can be saturated, right? That's good, okay. Yes, these are all
important features. Good, any more? So, the crew is actually,

think about actually last hand. I show you the photo response to light. You give light stimulation,

the photoreceptor, will also give Response, right? That response compared with this response,

they kind of very- >> [INAUDIBLE] >> Okay, good. That one is a hyperpolarization. Yes, outward,
going up, right? This is [INAUDIBLE], good. This is a very important difference

between this hair cell and the photoreceptor. Another key feature,

real difference between these two? We emphasized it actually

quite a lot during the discussion about the photo response. >> [INAUDIBLE] Photo

receptors [INAUDIBLE]. >> Yes, yes. >> [INAUDIBLE]

>> Yeah, yeah. [LAUGH] That's actually corresponding

to hyperozation and depolarization, we already talked about this feature. It just repeated the same
feature. So, in the photo receptor, we talk about actually there is a lot for

biochemical reaction. So depth, right? And then, from there,

when you have a slight stimulation, the response does not appear. And actually, after the delay,

then the response appear. Sometimes, it may be, what,

about one second, right? For some species. And take a look here. This is the stimulation. Almost
immediately the response appear. Right? So, this is actually a key

feature of hair cell, that means the cell respond to

the stimulation without too much delay. So, if you. Compare the stimulation, and

this is raising over the response, that delay is waiting maybe 10

to 100 micrometers, microsecond. There should be a high pressure,

a high hung up into it. For this,

then there was a thing about okay, how this transduction happens with

this hair cell take a short time? So apparently, so,

during this process of the signaling, the second messenger does not involve. Because second
messenger, you would take a lot of time to

accumulate from one step to another step. So for this one, you can, and

be to think about it is maybe, okay. So, there is a one channel

sitting on the membrane. And the data force coming

directly open to the channel. Just so they got gate, you just open. And then the Ion can influx into

the cell make it depolarization. Okay. So, indeed,

this is actually the hair bundle. Okay.

So we take a look at, this is a hair bundle. So, the hair bundle actually is mainly meaning [INAUDIBLE]

[FOREIGN]. Quite a lot. [FOREIGN]

If you have a M structure. [FOREIGN]

Okay. Well, this is what you can see founds that Structure of [FOREIGN] a spring, right? [FOREIGN]

This structure is called the tip link. Okay, tip link is from again, is a link that the shorter

one to the longer one. Okay.

[FOREIGN] So, you can imagine if we have our channel. [FOREIGN] Channel sit at this region. And the
channel, the gate [FOREIGN] is pulled by this tip link. So when your hair bundle move in that
direction, [FOREIGN]

okay? [FOREIGN]

Okay? Here, there is the real model at the resting state. So, there was a channel up to this region.
And then there was, the channel,

of course, has the gate. You can [FOREIGN]. Our channel unit open has a gate there. And this gate
connect to the tip link,

okay? So, if you have a mechanical force,

the hair bundle in that direction. You see,

this one will pull the gate open and is a cell immediately give the response. So, okay, this is
hypothesis for

the mechanical transduction. How can you approve? Your experiments demonstrate

this isn't true. >> [INAUDIBLE]

>> Good. So, you may be, in some special way, to break the link and

see what happen right, okay?

2.2.4

The tip link,

actually people later found actually some special molecules actually in for

the tip link. There are two here. These molecules,

you can use the antibody for CDH23. You can see this is antibody staining. For another one,

you have also the PCTDH15 antibody. And so if you knock out these proteins, the structure of tip

link are destroyed and then you have hearing loss. You cannot hear anything. And also, for the
experiments

it's actually quite simple. In the early days people just actually

switch this so when isolate the hair cell, put it in the solution, do the recording,

you can get the mechanical response. But if you put the cell in a solution, that solution is the low

calcium without calcium inside. And then this tip link will break. And then you give another

mechanical stimulation. You cannot get any response. So that's actually link the proposal

actually to the reality. So it seems the tip link can really, even

the drop, we're pulling the gate open. So also it's quite interesting, the hair cell sit, this region, the
tip region actually is in

a link solution, [FOREIGN]. Now the link solution actually quite

different than the ionic composition. It is different from they have

quite high potassium ions. Just like a solution. This is quite strange. So if we have high potassium
solution for whole cell like a neuron,

what ever happened to the neuron? Okay, we isolate the neuron and

then you diffuse with high potassium solution,

what will happen? [FOREIGN]. Well it'll cause depolarization, why? >> [INAUDIBLE] >>
Depolarization? Reverse potential? >> Yeah, reverse potential where [INAUDIBLE]

>> Okay, so we know actually for most there, actually, including neurons, the intracellular solution

is a high potassium. Low sodium, but the isolyte solution and the extracellular solution there

is low potassium, high sodium ion. So if you increase

the extracellular potassium and then the cell will depolarize. So for this region, because actually, it's
special, actually, just covered

by the high potassium solution. When you have these solutions there, you think about, this cell is
already

depolarized at its resting state, right? But actually either way not, why? >> [INAUDIBLE]. >> Okay,
potassium changes. No, or another way to say it maybe is
obviously no potassium channel, right? So either you have some

potassium channels there. But the potassium channels always close. And another situation would be

there isn't any potassium channel. And then of course you

increase the potassium then you will not affect the potential. Indeed for this region there is no other
channel except for this channel. So this high potassium actually will not

affect the resting membrane potential of this cell. It's okay for then. And then, when you have a
mechanical

force to open this channel, then the potassium ion

will go into the cell. Then the polarization of the cell, okay? Causes depolarization. Depolarization
will activate those

voltage, created a calcium channel. The calcium channel open and

then the calcium will go in and the neurotransmitter,

they will be released. This is the cell respond to

the mechanical stimulation. So, we also know actually the cell can be, if you give another stimulation
in another direction,

maybe the cell will have been polarized. That's actually the recording

demonstrate already. So can you think of a way

to achieve this for a cell? So if at a resting state

already some of those channels open, and

then you push another way, the tip link then will more relax and

channels are closed. And of course,

then you have polarization, right? Indeed, this is what happened to the cell. At the resting state
there was

already some of the channel open. Keep a basal depolarization. So if you move to another way

the channel will be closed. So these cell respond to

the mechanical force by such a direct way that is without

any biochemical steps, intermediated biochemical steps

you can work with, right? It's really just a direct gating,

a spring, pulls the gate open. So, for this, of course,

the speed is good. It's a very fast response. But what's the problem? No amplification, right? We talk
about,

actually in the photo receptor because it's a biochemical reaction. One single molecule activated.
The signal will be amplified
about 20,000 fold. LIke, why are you adopted where

active with about 20 GMP molecules. And 1 PDE will hydrolyze about

1,000 cyclic GMP molecules, right? But here,

then you don't have the amplification, there's a problem, for this system Because we need really

sensitive auditory detection. How can you achieve

the amplification here, okay? Neurotransmitter release,

how you amplify the signals? If 1 kelvin comes in, the mass

increase might be just, for example, the release is just one reciprocal and then you want to amplify
this signal. Simultaneously you can

release multiple vesicles. That's actually amplification, right? Then the signal propagate to

the downstream is quite strong. Indeed, actually in the hair cell, there

are some kind of, multi vestibule release. But it is not the main

strategy of the system. Remember we talk about actually,

there are two type of the hair cells. Why is the inner hair cell? Why is outer hair cell? Which hair cells
responsible for the sound

perception in the hair cell, right? In the hair cell,

actually will transfer signal through the axon, actually through the brain,

but the other hair cell does not. When the hair cell receives

the input from the brain. This is really quite strange. Why should the sensory cell need

to receive the brain input? Actually people have found

is quite interesting, the outer hair cell, actually the

mechanical change the length of the cell. When you have a sound simulation, that is actually the
outer hair cell is so

special. Yeah, you can take a look

at these molecules. These molecules actually are expressed

in this cell body of the hair cell. And this is a membrane protein.
2.2.5

This protein called prestin and

they are multi sensitive. They are not I only our own channel. [FOREIGN]. These proteins are
sensitive

to the voltage and at the same time the voltage

can drive the protein, actually wether elongate or

just the short one. Okay, it's quite unique. Now the situation is actually

when the cell is hyperpolarized this protein actually

is in the long state. Okay? [FOREIGN]. But when the cell is depolarized, those proteins actually get
very short. So imagine, okay, there is a force coming,

mechanical force. Moves the hair bundle, okay,

moves the hair bundle in this direction. And the mechanical sensitive

ion channel will open. And the potassium ion will go into

the cell and the cell reacts. And then because this protein

is sensitive to the voltage, then this protein will get shorter and

the whole cell actually will get shorter. This is the first phenomenon for

this cell is actually the soma can change the lens, responding to a sound simulation. At the same
time this hill bundle also can have some movement when

you have a force coming. And the cell, they polarize calcium. The potassium ions, and

the calcium ions will go into the cell. The calcium will move. Actually, it's [FOREIGN] further away

from the stimulation, like this. This is also another step for the amplify. The sound stimulation. Okay,
take a look. There are two steps. Y is actually the hair bundle if you

have a mechanical A stimulation. And then the mechanical sensitive

ion channel will open, and then the calcium will go into the cell and

make the bundle further move. [FOREIGN] The second thing is actually the sound coming to move

the hair bundle and then of course is the basal membrane will make the movement and

then the cell will depolarize. And this will make the cell

depolarization, right. Depolarization will make

the cell became shorter. Because this protein. And make shorter and

then [INAUDIBLE] Basic membrane will further displace and then. You that sound information. And
stimulation in the. And there are two steps for the of this cell signal, okay? Is it true? How can you
demonstrate this

properties of the cell? >> [INAUDIBLE]

>> Good. >> [INAUDIBLE]

>> Good. So If you look at this protein and the inner health cell,

the sensitivity will be decreased right? Okay tasted good but

does not actually directly demonstrate. That change of these cell lens, right? It's just actually the
down stream effect. How can you directly demonstrate

that point about the cell mortality? Okay, good. So if you isolate distant cell and

then you give the mechanical stimulation. Then just by looking at

it under the microscope, see [INAUDIBLE] the cell can

really change the [INAUDIBLE]. If you see the change, of course,

then is a direct demonstration. I guess I should give another lecture for

the physiology class. So, indeed, people did the experiments. They isolated a hair cell. Of course, this
one,

this is an outer hair cell. And, then you can see actually this is we have a [INAUDIBLE] here, okay?
Doing the [INAUDIBLE]. And then this region

actually it's the [FOREIGN]. In this case we just want to

demonstrate is the cell depolarized or hyper polarize strength which

changes the length okay. So it's quite easy to achieve

with this manipulation that is the biggest way we can

do the sample with the cell. Then we can inject the current,

into the cell make it depolarized. Or we inject sound as a current current. Then the cell will
hyperpolarized. Okay? So here actually at demonstration was the, then inject the sound current. You
cannot see it, listen to it. But you can see the injection

of the current. Actually you follow that

music the rock music. You can see here. [MUSIC] So I guess this already

very convincing actually, is really direct,

is that the cell can move. So then you can think okay,

in the natal condition, then you can because of this cell,

see it here right? This is the base cellular membrane and

then this is another membrane. Now, but the main is because the sound coming

is actually wipe away to this membrane. We talked about actually the frequency

of this distribution, right? And then right now if we have our

stimulation coming in the cell get shorter and then this will first move. As the hair cell we receive

a larger sound stimulation, right? So okay, this is a cartoon to

show this is a normal condition. For example,

if you give a sound stimulation to this structure of the cochlear. Then, this is maybe, for example, a
high frequency stimulation. And then this basilar membrane will make this movement okay. This is
under normal conditions

that's included two signal cells. Why is real sound coming outside? The second is the inner

hair cell contribution. So if you kind of, if you disrupt this outer hair cell of course then, you limit the
hair cell

contribution, that's what happening here. The response, they're in the,

this tract treatment under their hair cell cannot transfuse the light

signal, to electric signal. And then you have very tiny

movement of the basilar membrane. This is actually a mechanical

movement by the sound of surf. Okay? So it is quite obvious obviously then the

other hair cell can contribute for the. This summary about this part. So mainly we talk about the
transduction

from the hound cell is a direct mechanical gating of the own channel,

and the compare is the G mediated protein signaling,

for example, into further receptors. Then this is the key difference

between these two signaling. In the G protein signaling you

have a huge amplification. But then the speed is quite slow, okay. For this then you have low
amplification by

the transduction itself cascade. Okay? But you have a very fast response. At the same time, in the
auditory system,

in order to make it sensitive to the sound, then you have another

type of cell called outer hair cell. To have with the pressed in expression,

and then you can further amplify

the mechanical force. So we talk about, actually, after this mechanical force, coding by

the electric signal in the hair cell. Next step of course then, is how this

signal actually go to the brain. Right? So, in the visual system how

does the visual information flow from the photoreceptor

to the visual cortex? [FOREIGN] So from the photo receptor. First actually,

coming down to the bipolar cell right? >> Okay and then? [INAUDIBLE]

>> Yes, to ganglion cell. And then? >> [INAUDIBLE]

>> To LGN, yes, and visual cortex. Good, thanks. So that's actually the light signal. First they produce
by

the photo receptor and then go to the bipolar ganglia cell

to LGN then to a racial context. During each steps actually the signal

is not passively transported. There is a lot of connotation. You talk about actually

there is a receptive field. From the center surround to the the light bar and

also maybe to free cell. Right? Of course and then for this system,

again signal strategy again what happened.

2.2.6

This is actually the auditory pathway,

take a look, from here, let's take a look at this one,

this is the cochlear, right? This is the organ actually to transduce a sound signal to the electrical

signal from here. And then will be relayed by those axons. Those axons actually coming from

this ganglia, spiral ganglion. You remember those red axons

connect with the inner there. Those axons are actually coming

from this spiral ganglion. And this spiral ganglion

will further relay this auditory information

to the brain stem. [FOREIGN]

okay? But in the brain stem,

it's quite interesting. So for example,

this is the left side input. And there in the brain stem, you can see the signal will target to

the left side and also the right side. So in the brain stem

the signal already make the left and the right targeting, okay? Just [FOREIGN] with the brain stem,

[FOREIGN]. And then of course from this

brain stem the information will further be relayed to the mid brain. [FOREIGN]. To mid brain,

then will further relay to the. [FOREIGN]. In the visual system,

we talk about the LGN, right? And this also [FOREIGN] okay? But here, this MGN,

we can just had [FOREIGN] lateral geniculate nucleus

in the visual system. This is a medial geniculate nucleic, MGN. And the front is Q now. The first relate
to the auditory cortex. [FOREIGN]. This is actually the auditory pathway, so quite similar actually

compared to the visual system. But there was once more step is the here. [FOREIGN]. This is the
brain stem and

it's a midbrain. [FOREIGN]. Why? You need a such a more

complicated processing here. >> Good, so you think actually auditory

information need more computations. >> [INAUDIBLE]

>> Ignores those noises. So, okay that's a good point. But also, it's important. So remember in the
eye,

the outer [INAUDIBLE] actually. Not the front the photoreceptor. In this auditory system

the output actually is directly from the hair cell

to spiral ganglion, right? [FOREIGN]. We talk about issue in the retina there was lots of
computations, centers around [FOREIGN]. So the brain stem and the midbrain so [FOREIGN]. Of
course we will talk about it later. Actually there are more

computations indeed actually happen in the brain stem. Okay so this is the auditory pathways. Lets
take a look further about some

processing of the auditory system. So for auditory system, we talked about the key

features is the frequency and the intensity and the location, right? So, let's first take a look

at the frequency coding. For the frequency coding,

we talking about in the cochlea already there was some

structural basis for the coding. What is the structure there? The basilar membrane, right? So, at the
base the frequency

actually is high or low? High. And the tip of the cochlea,

then the frequency is slow. Okay, how did the brain. You see this is a cochlea, right? This is a cochlea
and this is the base, the base is actually,

is quite large, right? Just the base of the membrane

is narrow in this region. So, high frequency happens here. And they go into the inside. Actually, then
go to the low frequency. So, if you have a hail

cell sit in this region, what's this hail cell's properties? Of course this [INAUDIBLE] cell where

high frequency was lost here, okay. And then this region maybe

the frequency is not so large but this region,

the frequency is quite low. Quite interesting. So this inner cell was connected

by the spiral ganglion and the spiral ganglion

connection is quite specific. That is actually this one axon

only connect to one cell. It's one connected to one. Of course it's quite strange when we

actually talk about this is axon. It's actually dangerous to

lose sight with a signal. Yeah, in some textbooks

they call this axon. This is kind of special cell type, okay? Because, actually,

people found, maybe, this one, the process is really quite long. So, for a signaling trail without the
action potential,

then you have problem. The signal will decrease,

because this process is so long, without any action potential,

[INAUDIBLE] and then the signal will receive from here,

come to the spiral ganglion. Cell body will be very, very tiny. So in this case, the spiral ganglion,
actually they can fire action
potential somehow along this way. To actually really guaranteed

the signal information can go down through this process. But is important to think

is this frequency coding already preserved in the spiral ganglion. This one you see is the high
frequency,

this one compare this one is the low frequency,

this one is 2 kilohertz frequency. And also, from this spiral ganglion

then we'll go to the brain stem, right? And then to the mid brain and then to

the sediments and then to the cortex. All these steps, this frequency,

is a relation is maintained. That means there is a map in the brain. All of this steps. There was a map
there. The map is actually correlate

with the different frequency. At each different region

the cell respond to a specific range of the frequency, okay?

2.2.7

So these equalities can map,

s for your center. If you recall, around this spiral ganglion here is a extra set of the recording. There's
a spike for

the extract of the ganglion cell. Then, this of course is a hair cell,

then you give it a stimulation. And this cell actually can give us but you can find if you stimulate

the cell with different frequencies. And then sometimes [INAUDIBLE] the cell

will not give any response to some of the frequency. But then, the other times, if we have

the right frequency stimulate the cell, the hair cell, and then this cell

will fire a lot of extra potential. Okay, then it means this cell

specifically sensitive to a range of frequency stimulation. If you go to the brain,

the same thing happens, this is a auditory cortex here. So people do the recording

from these cells, you said electrodes inset into the brain. They found actually for example, this is a
stimulation to see

a response to this region. And then you feel this region and the response will differ the frequency
and

there is a map again. Okay, here is an important point, so

what's the frequency range we can detect? From? Good, 20 to 20,000, right? Okay, for each region
and then you have the different frequency selection cell,

so. Once the action potential,

the duration, one spike, the duration roughly one millisecond or

yeah, in some cells. Other cells has maybe 1.5 or 2 millisecond

but it's in the range of 1 millisecond. If we use 1 millisecond as that kind

of spike to code the information about. How can you achieve that, ten kilo [FOREIGN] [FOREIGN]
Okay, so if we want to coat the [INAUDIBLE] information

below maybe one kilo count. Maybe, it's quite easy, you just actually

are used to coat the spike duration. It's like one millisecond you

can follow those stimulation but if the stimulation is beyond

the time resolution with the spike. Then how you encode the information, the interval between the
two

different spikes, okay? So the interval here. >> [INAUDIBLE]

>> Different cells? >> [INAUDIBLE]

>> Okay, so your strategy would be use population coding from many,
many different cells, okay. Yeah, that's possible, yes? >> [INAUDIBLE]

>> But, still you need to work out all the details, how you use the population to

coat those high frequent signals, right? So there was another strategy you can use,

because there is already we have our map there,

okay? It is a map, so

if only those cells appear in this region if you can [INAUDIBLE]

16,000 cell stimulation. Only cells in this region

give us a response, they know this is the one 16

kilos stimulation, right? This is the map already

tells you that information, but it is still for some frequency coding to use another strategy, okay? So
below two kilohertz and

actually it's coding, actually not just single

based on this map. So there's another strategy for frequency

coding, there's actually a phase lock. This is quite important concept

here in the auditory system, okay? So if you think about it sound

stimulation is what kind of stimulation? You say, wait should be [FOREIGN] right? So the wave of
course has

those kinds of peaks, there is a top and

also has a very low bottom part. So phase lock means if the response of the cell is spiking fiery of the
cell. Only happen at a cycle

phase over one cycle and then every time,

you have one cycle coming, only at that particular phase. You'll be with a spike and again,

that's called a phase lock, okay? Maybe this figure is much better

to demonstrate, take a look. This is the sound wave stimulation

the tension board and the sound wave. So, if the cell, action potential at these falling phase, every
time, every cycle, you have this happen at this region, okay? This is called the phase lock, indeed
people did the recording

from the spiral ganglion cells. What they found is actually many cells

actually only fire action potential during a specific phase

of the stimulation. So in most case we think about lots of ways [FOREIGN] action potential respond
to you, okay? So for this one then you can code those information and this is one case, actually for
every cycle. And is the same phase you will have

a corresponding action potential okay? But in other case that neuron

actually phase locked but not for every cycle,

will skip some cycles. But when the response appear,

still it's the same phase, okay? But then, you go to high frequency sound

and then it's quite challenging for this spike to follow the phase

because it's a resolution. The spike firing also has

some variation to timing. You spike firing you should have a,

go beyond the threshold and then the voltage-gated

sodium channel need to open. That would take some time

dinner time is not enough to compensate for the short stimulation

in the [INAUDIBLE] you cannot follow. Okay, this is the Phase Lock for

the coding of sound frequency. So the next important point we want to

talk about actually is location, okay? So we talk about actually

the frequency coding and also the kind of phase lock for

both frequency. For the high frequency then

you use the map, okay? The frequency map and Daniel came,

really coded this information. So for

an animal to really use this information then you need to locate where

is the sum coming from? For example, if you just walk in

the street there was a traffic light. Now you hear a sound, so

you walk a cross the street. Then maybe there is a car coming, right? [FOREIGN]

It's very critical [FOREIGN]

so for the sound location, then there are a lot of kind of a series. So far maybe this kind

of research actually, we have not really figured

out the mechanism. But there are some hypotheses,

and there are some experiments maybe give us a clue about

the coding of the location

2.2.8

Okay, first, let's take a look, what kind of information can

we use to locate a sound? Like the bird catches the rat, you need to actually

locate this tiny there. How can you make the location? The one is the timing,

last time shall we talk about. So the timing will be, okay if a sound

happened on my right side, of course, the sound will come in through it, so

the key through my right ear, right? And then, my left side will receive

the sound actually, by delay. What's the delay? It's the hair sights, right? Okay, do a calculation, for a
typical human being, maybe it's a hat, let's say, 20 centimeters this side. And then, what's the delay,
maximum delay between

the two sides of the sound? 20 centimeter the sound speed

is the 340 meter per second. Calculation, what's the delay? 0.05 media second, okay? 0.05 media
second just 500 microsecond, right? There's actually shorter than one duration of the actual
potential, right? What is my one millisecond for the action potential to time,

quite impressive, right? So we can detect the difference between these 500 millisecond, this already
maximum, okay? [FOREIGN]

>> [INAUDIBLE] >> [FOREIGN] 600 microsecond difference is the maximum delay, okay? Now, even
the sound source move to the middle side [FOREIGN] there's no delay [FOREIGN] right? [FOREIGN]

The sound coming from this side, and then you need first this detection organ here. And then, you
need to first all,

go to this side, so we're about to make, At the delay, to them, the 600 microsecond is the maximum
[FOREIGN] microsecond [FOREIGN]. A bird flying, okay, across, over your head, and then the bird
make some sound [FOREIGN]

okay? [FOREIGN] This depends on this information [FOREIGN] for the horizontal location we may
need depends on take a time delay [FOREIGN]

okay? [FOREIGN] Okay? Okay, so this is the time delay

we can use to locate a target, and also we can also use

the intensity difference. [FOREIGN]

You get shadow, right? [FOREIGN] This is also another cue for the brain to interpret,

where is the sound location? Okay, so this information, [FOREIGN] easy to calculate [FOREIGN]. You
got information [FOREIGN] how

can you use the neuromechanism? [FOREIGN] 600 microsecond delay, sometimes maybe only 10 or
20 microsecond delay [FOREIGN]

to detect [FOREIGN]. If I ask you to design

a device to achieve with this location, you just use the time. How can you achieve this one? Of
course, there is a comparison between
the left and the right side, right? [FOREIGN] >> [INAUDIBLE] >> [FOREIGN] Okay. [FOREIGN] Okay.
[FOREIGN] We talk about in the brainstem already the input is too from one side you can go to both
sides, right? [FOREIGN] Responsible for the auditory detection device [FOREIGN]. Okay, take a look,
so this neural

connection is from the left ear, okay? So they are in the brain,

in the brainstem, right now, we have seven neurons, okay? Seven neurons, of course,

they sit at a different location, and then this is neural pathway

to make the connections. This input to this one and of course, this red one from the right ear, okay?
And also they make the connections, that means each individual neuron, we see simultaneously
from the left and

the right input, okay? We know the action potential can travel the axon of the spiral ganglion, right.
And if that the neuron, for example, the sound is coming from the right side,

what happen? For this neuron, okay,

take a look, for this neuron, the first input we're coming

from the right, right, because there's actually about maybe

600 microsecond delay from the left. And then this neuron will first

receive input from right ear, okay? How about the left input? So this actually happened

about 600 microsecond delay. And that the same time

that neuron propagation, that go a long distance. We have another delay over the action potential
propagation [FOREIGN] microsecond [FOREIGN] microsecond later. Okay, for the first ten those
neurons kill [FOREIGN] you got synchronization. This is not a coincidence detectors [FOREIGN]
detection. [FOREIGN] Delay [FOREIGN] neuron [FOREIGN]. So you have to show because actual

potential to the propagation, take your time [FOREIGN]. [FOREIGN] Compensate [FOREIGN]
detection [FOREIGN] difference. [FOREIGN] This is actually, in some animals people found this,

maybe the, the way actually to

achieve some localization. Let's take a look actually the sound

localization for MSO [FOREIGN]. This is human for mammal connection,

so this is actually from the ear, okay, coming down the spinal ganglion and then to the brainstem
and

how make this connection. [FOREIGN] It's symmetric, this symmetrical map here. And from this side
[FOREIGN] intensity, lie detector, and sound [FOREIGN]. Okay, so for the last one so [FOREIGN] deep
in the location, you can use time information. Also use the intensity but

for the vertical one, right now [FOREIGN] you don't

have any time difference. [FOREIGN] Information [FOREIGN] in many animals [FOREIGN] okay?
[FOREIGN] Vertical line [FOREIGN].
3.1.1

Today, we will talk about

the chemoreception. Actually this lecture and the next one, both of these will talk

about the chemoreception. So for chemoreception, of course, that is to detect the chemical

information in the environment. So, for these two pictures what

kind of chemoreception do we use? The first one, this one,

of course this is smell right? The sense of olfaction. And the other one

probably involve the two, smell and also the taste, or the sense of taste or gustation, okay. What's
the difference between these two? The obvious difference is they detect

different kind of chemicals, all right? For this one, for

the olfaction, they detect those chemicals can be we into the air and then diffuse, and then go into
your cavity of the nose. So those chemicals have

different properties, okay. And for the sense of taste, and then

those chemicals they should be is direct, can contact your sensor in the tongue,

right? So those actually consider

not the chemical, okay? So for example,

sugar can cause the sweet taste, right? And the bitter,

you cannot smell a bitter substance. Most likely you need directly contact

with your tongue with those chemicals, then you can get the perception, right? So these actually are
two broadly

distinct chemoreceptions, okay? So of course there are other

chemoreceptions in our body, can you cite examples? These are actually for the touching,

the external world chemical. But in our body, we always need to monitor the chemical information
from the blood, from the other source, right? In the blood,

what kind of chemical you detect? >> [INAUDIBLE]

>> Oxygen, CO2, right, and also pH, right, so this also used to detect those chemicals. So the
chemical reception,

so in this lectures we only talk about the sense of smell,

okay? This is just with our nose, and

the next time we will talk about mainly the taste perception or detection. So, the chemoreception,
especially the olfaction

it's quite unique. The uniqueness is sometimes

actually across a long term memory. Do you have any experience

with the olfactory memory? Search your memories, maybe you can

find something to share with us. [INAUDIBLE]

>> [INAUDIBLE] >> Okay. >> [INAUDIBLE] >> Okay, yeah, that's good, yeah. This indeed,

the olfactory system is really profound, actually, effect our lives and sometimes, especially the
emotion or memory. [FOREIGN] Maybe I consider a pretty short,

like last year memory. Here we have one example actually, again, it's from a book. There was a book,
a quite famous book, Memory of Things Past. There also actually is,

I guess it's a French and then this book actually

translates into quite a bit of different language including Chinese. [FOREIGN] Apparently from here
they also, the QA, this liking,

you can appreciate it, what we're talking about, okay? [FOREIGN] [FOREIGN] >> [INAUDIBLE] >>
[FOREIGN] [FOREIGN] Sometimes you have those kinds of emotions appear from nowhere.
[FOREIGN] The smell. [FOREIGN] Memory. [FOREIGN] [FOREIGN] The olfactory system, that is really
profound for a human being for example, long term memory and also the emotion. And for most
animals actually

that is more critical. The olfactory system helps them

to survive in the environment and also reproduce for the next generation. There's actually, for
example, when they needed to look for food or some avoid enemies. And then basically olfactory

queue is very important. For example like in the dark

if kind of predator approaching of course you

can hear the sound but sometimes also to carry

some special smell and then they can recognize immediately. There is another quite Famous case is
the salmon homing. The homing [FOREIGN] The cue, a lot of cues, kay? For this guy, actually,

they mainly rely on the olfactory cue. For example, this salmon, they were born in the fresh water,
okay? And then they will stay

in those fresh water for maybe one to two years to grow up, okay? And then when they, Are large
enough,

then they will swim to the ocean. [FOREIGN] Okay. When, in those waters, there is a lot of food,

those kind of food, very rich food and in the end they just actually eat a lot,

and they grow up, grow much larger. And then they are ready for the mating, for example sexual
mature. And then they will swim back

to the fresh water, okay? And then they eggs there and

then [FOREIGN] there's a cycle okay? So people did a field experiment okay? [FOREIGN] It's like this,
they treated the

salmon are when they Ii the fresh water, they treated the salmon with morphing and

also another chemical, is PA, two different chemicals, okay,

different groups of fish. And then they release

the fish here in the ocean. And later as we talk about,

when they're really ready for mating, reproduce the next generation. They will swim back to the
fresh water,

the river, to dip in the river, okay. You just need to collect those salmon

from the river when they come back. And then you count, see what happens. And then here, this
stream of the water,

this stream of the river and then has individual chemical treatment. For example, here,

this river is PA, this is morphing. And then this award,

this reward costs nothing special. And then you count the fish you

caught from different locations. You found actually that

morphing M-treated the most likely actually happened here,

in this region, 90%. Of course how a sound. Occasionally a sound as a kind of fish or

salmon would go to this region, and of course for this one,

again is special because of the this chemical attracts those fish. And of course in this control region,
most of those fish are not treated and

then you count from this region. So, what it tells,

it tells you when the fish, when they live in this fresh water and

it's a local environment. For example, maybe it's the soil,

could be these chemicals and then they imprint it in their brain. [FOREIGN] Later when they came
back in order to lay eggs in the fresh water, they will use those memories actually, to find the same
river they were born. And, of course,

actually it's quite a challenge then, because the environment, actually, maybe some other river
actually

when you swim in this direction. If you followed this direction, then you

were contaminated by different chemicals. And in any case, they're quite precise

it's kind of a 90% fish cracked. These apparently, this fish, this fish,

salmon, rely on chemical cue. And also the homing is usually, sometimes actually the swim

may be 1,000 miles, okay? That is quite long and then these kind of

cues help then to find the home, okay?

3.1.2

For us human. And again the olfactory system of

course begins with the nose right? Let's take a look. What happens? So when you have a wine and

those chemicals will release from the wine and enter cavity through your nose,

nasal cavity. And then these chemicals with activate

the olfactory sensory neuron, actually on the top of

the notes okay [FOREIGN]. And then this neuron transfers this

signal into electrical signal and then will pass those signals

to the brain and then we go to the cortex of the olfactory

perception we have in there. And then of course the first

step of this olfaction is actually these chemicals binding to these cilia off the olfactory

sensory neuron in the notes. And then they are receptors,

special receptor on the membrane and then that protein

wheel will combine to this chemical. And then the receptor will be

activated and then just so they can say the photo receptor right? Then they can produce the electric
signal,

okay? This is what happens. Here, there is another cartoon

to show the organization, okay? Take a look here. These are this is a nose carried to,

right? So in this region then we have

the olfactory epithelium. This is [FOREIGN] it's just like very thin layer of the tissue. That tissue is of
course a lot of neurons. Those neurons are olfactory sensory

neurons to detect the chemical, just like in our eye there is a retina,

right, that tissue. And then quite interesting,

okay, so these cells, only one type of cells in

this olfactory epithelium. In the retina, we have so

many types, right? But here only one type, okay? And then they will send axon to the brain,

directly to the brain, from here across these bones there

is some kind of passageway or holes. Actually and axon can enters the brain. And and they make
connections

which is a brain neuron. And take a look here. This is the location where the, Olfactory detection

happens is at those cilia. As we discussed last time,

for the visual system the photoreceptor has a lot

of commemorating, right. Those to you increase the surface

area to catch the phone call. And here again the same thing happened,

you see maybe the principles. So those are cereal,

al lot of cereal to increase. The surface area to catch

those chemical molecules. And take a look here. This is actually the real

cilia of the cell. This is actually, you can see

this is the one cell, the region. This region we call dendritic knot here. Okay, let's take a more

complete view of this cell. Cell body here, and

then axon go to the brain. And then there was a dendrite. Is a bipolar cell. Dendrites will go to

the needs of cavity and then, from the dendrites and

the end of the dendrites, there is a knock there is kind

of twitching, you cannot. Now, Frontal Lobe,

then a lot of cilia then begins, okay? This is a cilia, you can see. This is a [INAUDIBLE] and

then it's the cilia. The cilia locate mainly in

the mucus in your nose, okay? [FOREIGN] A lot of cilia actually are located here. And in that layer
actually,

you have a lot of things happen. You can see that when there are some

chemicals in the air enter your nose. What would happen then? The chemicals need first

dissolve in that layer of mucus. [FOREIGN]

And then a lot of chemicals actually,

the odorant is really hydrophobic. [FOREIGN]

So it's difficult to dissolve

in the in the mucus. And then we have a system

we call the protein. There is some protein in the mucus. And then they can bind to

the odorant chemicals. Molecules and facilitator to diffusion

of those chemicals in the mucus. To bind to the receptor. It is called binding protein. Okay?

So there of factor detection. As we mentioned, it only happens

on this cilia region, okay? That means, those receptors or any other related

proteins actually need to be highly enriched In this

serous membrane region, okay? And let's take a look. How the olfactory detection begins? This is a
cartoon to show

the olfactory sensory neuron. Again, it's a bipolar neuron. You have the cell body, you have the axon,
and you have the dendrite. Dendrite have a knob and then the cilia. Okay, the cilia, of course, inside.
Those actually cytosomes, [FOREIGN] connected with this dendrite and

the cell body, right? This is the on the membrane. Then you have a lot of proteins. Just so that they
can

photoreceptor into disc membrane. What do you have? You have receptor. Okay? This receptor
needed to

recognize some specific odorant molecules and bind those

molecules and this receptor will activate by the odorant molecule

then will activate a G protein. This G protein we call G, O. G, O L, F, in the photo receptor

we have density protein also. Density protein is called transducing,

okay, GT. Here is GO. The GO activated and this GO we activate with another enzyme called

endnocyclase type 3-863. This is a specific one,

is specific to the olfactory system. And they activate this enzyme. This enzyme will synthesize

a second messenger called CANP. Sythensized from the ATP

converted to CCAMP. And the CCAMP is the second messenger. Where bind the two to a channel

called cytonucleotide channel. The CAG channel. Okay? And then bind to there,

this channel will open. Open then whatever happened

is sewed in calcium, we are going into the cell, and

then the cell will depolarize okay. And then of course the fire action,

potential, all right? But here,

there's another quite interesting feature. That is when the sodium and the calcium come into the
cell,

they polarize the cell. And this is not the end of the signaling. There is another step quite interesting
It is that this calcium, the intercellular calcium will again to

actuate another channel, called calcium actuate co-act channel. So if you have a core channel
activated, what will happen to the cell, typically? Like receptor, like a. Those receptors,

especially is a core channel. And then mainly GABA is inhibitory effect,

right? So yes. So here then, why you need this then? For the cell excitation,

of course it's depolarization. If you have opened another channel,

chloride channel and the hypochlorite to the cell

[INAUDIBLE] Why you need these thing? It's strange, right? Adaptation. Okay. So, the signal increase
and then, you somehow you need

a shutdown the signal right? Okay good. So but actually here is

quite unique to this system. This kind of canal does

not have polarized a cell. It's actually again depolarized a cell. That's special here, okay? Why this
quiet channel can further

depolarize the cell, okay. We'll talk about it. First, let's look at it here. So first, the same transduction
happens

as should a cast G protein cascade Is the cell and another channel. First it'll depolarize the cell. This
another beautification right? So we are this may be the step. And also this enzyme step and

beautification, but in the olfactory system. Another, correct channel,

further amplify the signal. If this is indeed a correct channel and

also the open this channel you need that in

fact this produce deprivation. So what conditions should hold for this quite concentration

inside is it high or low? >> High. >> High? >> High inside. >> High inside.

Why? >> So it can reach in [INAUDIBLE]

flow out. >> Flow out. Okay.

If a current flows out what happens to the inside? Is depolarized or hyperpolarized? Good, good,
yes. So the answer is actually the inside

you need to keep high concentration, relatively higher concentration

than the extracellular side. And then if we open this channel,

then we'll go out, then inside there will more positive because there's

negative charge moving out, right? That's good. So how can you maintain a chloride

concentration inside the hive, because in most neurons,

in most case in the brain, the chloride concentration

inside is quite low. This means if a chloride opens,

the chloride ion should go into the cell. So this cell actually has a special exchanger called the sodium
potassium chloride exchanger. And that one can really pump those from the outside to inside to
keep it high
3.1.3

So actually,

this feature is quite interesting, right? So it's [INAUDIBLE] of the cell. In our brain,

in the very early development. Actually, a similar thing. The garber effect is depolarized

to depolarize the neuron. Okay, in the early development, some of

those neurons actually inside the neurons may be the correct concentration,

it's higher than the extra cellular. And then in this case,

you have a carbon release, and the cell receives the carbon input,

and then depolarized. But there is a transition

during the development later, and then the garber effect for

sure is inhibition okay? Why you need this kind of amplification? Our research system. We talk about
a g protein cascade. There is a good and there is a bad. The good is, actually,

you can amplify the signal. One single molecule signaling, can be

amplified by maybe 20,000 volts, right? And here, you already, so

you [INAUDIBLE] resistant. We already used that amplification

can detect a single photon, or a single molecule response

is large enough already. Why you need another step

to amplify the signal? >> [INAUDIBLE]

>> Okay. Good.

So, you're saying that actually, the signal actually is produced

in this region, then this signal is propagated to the cell body, to

the axiom to fire up transportation here. There may be this signal,

somehow we are partially lost, and then if you further boost the signal,

and then the compensation will happen. And then to maintain the quality

of the propagation, right? That's a good thought. Any other sort about this identification by the
channel? >> [INAUDIBLE] Limited by long distance by the air, so [INAUDIBLE]. >> Okay. >>
[INAUDIBLE]

>> Okay, so you're still, I think,

actually, there's to amplify the signal is

because the input is low. The chemical concentration

is quite limited, because it's a hydrophobic issue. And then if one could come in,

then you have a huge signal. There's your arguing, right? But if the signal is already big enough,
for example, the single photon response, already big

enough, then actually we don't need, actually, another empirification, if that single molecule

response can go to the brain successfully, then why you need

actually further boost the signal? So, olfactory system is special. Again, because actually,

there is a sensory neuron directly contacting

the environment. This is a clue to think about

if there's an amplification. Now, the other sense, like our eye. The photo receptor is so well
protected. [FOREIGN] But the olfactory system

directly contacts your environment. Odor happen. To then understand conditions, all right? For
example if, for a fish,

if you live in the water, and we talk about actually

the olfactory system, actually this is a transduction region. Where is this located? Over a layer of
mucous. And it's the mucous for the animal. Actually, direct contact with the air,

that's fine. But if for a fish, that mucous actually

always contact with the water. Contact with water, what will happen? Well, it is destroyed by
something, right? Let's think about it signaling here, okay. The signaling. So when you have a channel
open,

you need what kind of thing? You need the ion. [FOREIGN] The channel. [FOREIGN] What would
happen? No current, no depolarization,

if the mucus actually diluted by the water

[FOREIGN] quite a few, you don't have many [INAUDIBLE]

to depolarize into the cell. That's the trouble, right? Especially in the fresh water,

for example. The sodium is low. And the calciums are low. But actually, in most cases,

it's the animal extra cellular solution. The sodium is about 120 mini

molar in that range, okay? The sodium. And the potassium would

be maybe two mini molar. And the calcium,

it may be one mini molar into the range. But in the water,

those ions quite, quite liter. So, in that case,

even for a fish, if those sodium ion, you own a little so

the ion, or calcium. So, if you open this channel, if you have a chemical bind to

this receptor, open the channel. Maybe nothing will happen. But think about this quiet channel. If
the out of [INAUDIBLE]

concentrate is low, actually, this channel,

depolarization would be larger. It's beneficial if you diluted

those concentration outside. So, the key thing, that is the calcium. Calcium, what's the difference

between the inside of the cell and outside of the cell, the ratio? If you learned [SOUND]
neuroscience, these things should be quite clear. >> [INAUDIBLE]

>> Yes, outside is the minimal arrange. Because of the [FOREIGN]. How about the inside of the cell?
At the resting state, most of those neurons actually

not at that range, it's too high. It's in the non-normal range, maybe tens to hundreds of

non-normal range in the cell. When the cell does an excited situation, maybe they can sometimes go

to micromolar range, okay? Of course,

we're talking about the global calcium. So, in this case, if in the cell is nanomolar range, and

let's make a comparison. The sodium ion in the cell is

about a tenth, maybe a tenth of a nanomol range, outside the thing

is about 100 nanomol range. So, the inside and

outside is about 10-fold or 15-fold. But for the casing, actually,

the inside and outside is huge, right? It's from mini molar to nano molar. So, then is about a, what is
the ratio? 10 to 26, right? But actually, as we talk about actually, it's a tenth of nano molar or

hundreds of nano molar. In that case, maybe ten to four,

ten to five, this kind of range, okay? [FOREIGN] So, if you have those freshwater diluted at the
mucus, even the calcium maybe was

lowered down by a few fold. Still, inside, outside,

is a huge difference, right? So, when the channel open, calcium,

for sure, will go into the cell. But not much,

maybe this sodium in the fresh water. And then this calcium come in,

then we're active here, and. So, I guess this is already clear. Why, during the evolution

we have this kind of right. Another step right channel to

identify the signal, okay? >> [FOREIGN]

>> Yeah. >> [FOREIGN] Fresh water diluted. >> [FOREIGN] >> [FOREIGN] >> [FOREIGN] >> [FOREIGN]
This cyclic channel actually not only exists in

fish, in amphibians, but also in mammals. And also in us humans. [FOREIGN] Later, actually. So, this
channel, as we discussed, is really important for

the fresh water, right? The animal. Actually, in the mouth,

just actually a few years ago, one Germany group, delete this channel. Yes, the [INAUDIBLE]

channel, and then do the behavior

study of the mouse. And then to fault,

actually know much, actually, bad things happen to the mouse,

affect the detection, quite normal. If you,

I guess if you take all this in the fish. In the zipper fish. Or some frog. You do the behavior study.
Maybe there was some problems. As we said, actually, in the land animal,

our mucus is actually quite intact, okay? Contact with the air, that's fine. Still a lot for iron there,
right? And this already is acute

identification steps. Then you have first one. According to this study, of course,

actually, just one study there, and then is not so much improvement for

the signaling.
3.1.4

So this one cartoon here, for

the research actually then, it will takes really quite

a lot to get these pictures. It will take a few decades actually

really to complete this story. So for example, if this channel

is really true important for the transaction, then you can do a study. Then you'd look at this channel,

see what will happen. And indeed we would do the study,

and then the knockout, the CNG channel, and

then do a kind of essay. This essay is called EOG recording. EOG is kind of for feel the potential

recording record from many, many neurons, okay. Is not a single neuron recording. And take a look,

this is the olfactory epithelium, right? Where the olfactory sensory neuron locate. And then if you
insert

an electrode to this region, then you can pick up the electric

signal from those neurons. And so with that, if those neurons

stimulated by some chemicals for example, you can puff some odorant

chemicals to this region. If this alternate can stimulate those

neurons, those neurons will depolarize through the G protein cascade,

especially the CNG channel opening. Okay? Then you can recall here. Then you will see those electric
signals. If you knockout the channel. what do you expect, actually,

there's nothing, okay? Flat, indeed the is the recording. You can take a look. This is actually a
knockout trace. Knockout recording is the red one. White tap is the blue one. So if you use different

chemicals stimulate the nodes, you can get different signals. Some small, some large,

some actually nothing will happen. But here only show all those

actually responding ones. But when you knock out the channel,

essentially, the nose cannot smell anything, okay? Then you give your evidence. Indeed the CNG
channel

actually is important, is critical in the transaction

of the odor and its information. And also, actually,

people then, for example, they can knock out the adenyl

cyclase type three. The AC3. They got this similar answer. If you knock out the G protein,

you got a similar thing. Okay? So this actually indeed

happened in the field, already were done by different groups to

knock out different component. And it take really a long time

to achieve that understanding. When a chemical stimulation

happen to the cell, the cell will be activated, depolarized. So for the signaling it will be critical. If the
signaling can be

fashioned to be shut of as we mentioned before,

the photoreceptor, right? Photoreceptor. When you have activation,

then you have the inactivation, right? What happened? What is the inactivation steps for

the photo-transduction? [FOREIGN] >> [FOREIGN]

>> Okay. >> [FOREIGN]

>> Okay. [FOREIGN] >> [FOREIGN] >> [FOREIGN] [FOREIGN]

Rhodopsin activated by photon. And then rhodopsin will activate

a G-protein, transducin. Then transducin activate. We have with the G-alpha

binded to the GTP, isolated from, dissociated from,

the beta gamma subunit, binded to the PDE. Right?

Those proteins activation. And then later in the activation,

each protein should be activated. Rhodopsin, activation by

what kind of procedure? Steps. Phosphorylation and

resting binding, right? This should be very clear actually if you

learn this kind of signaling, cascade. Because GPCR, typically all GPCR use

this type of signaling, cascade. Activation, phosphorylation,

and resting binding. And then also maybe have similar decay to the protein active [FOREIGN]. For the
G protein deactivation,

reactivation, what's the steps? The GTP hydrolize to GDP by the intrinsic

GTPase activity of the G alpha, with the help of some other protein, such as adenosine, those
proteins. Okay, so here, the same thing should

happen to the olfactory system. Each set of steps, you need,

actually, when you activate it, then you need actually shut

off those proteins, okay? For example, the receptor,

you have the ONN binding activate this receptor, and

the receptor of the ONN unbind. And then you activated G protein, the DTP

changes to the DDP then activation. As your cycles three also need activation. So we also talk about
it
in the photo receptor. We also have the negative feedback, right? The negative feedback may need

by the calcium steps, right. So here the same thing,

what happened to the olfactory system. Mainly actually I will

see the calcium coming, the first thing actually

is amplify this signal. And at the same time this calcium

actually will bind to the calmodulin. Calmodulin will do the same

thing as in the photo receptor, will inhibit the CNG channel, okay? And also calmodulin can

activate a calmodulin kinase to phosphorylate adenocyclase to inhibit the synthesizing of cAMP. And
also, possible here, I didn't put it there that route down. That is actually, calmodulin also can active
the PDE, the phosphodiesterase. [FOREIGN] Now calmodulin can also activate the PDE. [FOREIGN].
The same thing happened here. This calcium meeting the negative

feedback is to counteract. [FOREIGN] The odorant response. [FOREIGN] Olfactory adaptation.

[FOREIGN] >> [FOREIGN] >> [FOREIGN] Okay, yep. There's actually a experience of the olfactory
adaptation. [FOREIGN] If you go to a restaurant [FOREIGN] Means you adapt. Olfactory adaptation
have actually

can achieve by different ways, okay. One is actually a sensory neuron. For example,

this calcium mediated signaling can counteract the olfactory detection. [FOREIGN]

This is actually a key step in the olfactory adaptation. Why is the, the key step is

the olfactory sensory neuron. And also, actually,

even if the olfactory sensory neuron not completely adapted the signal

still goes to the brain. Our brain has a mechanism to adapt, okay? [FOREIGN] a network adaptation.
By neural circuitry. And you can achieve

the olfactory adaptation. This is not so well-studied. But actually some labs including our lab,
actually, we actually

pursue this direction. The network olfactory adaptation. This is the olfactory sensory neuron. We
talk about signaling and

some as a related issue. It is quite a long time in the field. That is actually how factory sensory
neurons detect those chemicals. Because actually we have really extraordinary ability to detect
thousands, even maybe tens of thousands different type of chemicals. You can smell them.
[FOREIGN] this ability actually always puzzled the researcher. How can we achieve the ability? Now,
in the visual system

we detect the colors using three kinds of visial pigment, red, green and blue. [FOREIGN] So your
olfactory system, how does it work? [FOREIGN]

So these questions always puzzle the field, okay? So how do you solve this problem,

if you are interested in these questions? Apparently, we are talking

about this step, the receptor. We need to clone these receptors out,
right? [FOREIGN]
3.1.5

[FOREIGN]. Linda Buck and Richard Axel, [FOREIGN] in 1991 they published a paper. That paper
actually a cloned the OR gene, odor receptor gene from the rat,

from the [FOREIGN]. And they found actually,

it's quite surprising. In the rat,

there are about 1,000 OR genes, more than 1,000 OR genes in the rat. In the mouse is about 1,400.
And then, there are some pseudogenes but then the functional gene is over 1,000. In rat there is
actually much, is more than the mouse genes. So the total gene in the genome,

roughly how many? It's about 20,000, right. So if we have more than 1,000

then almost actually about 45% of the gene in the genome devoted for

the olfaction. This is surprising, right? Olfaction [FOREIGN]. So it's important the olfaction,

obviously. For a lot was animals, as we said, they detect the food of the worst

enemies for their survival or maybe find the mating partner,

they need olfactory cues. They cloned this gene and

then as they really make a huge impact in the field,

then people start to okay, so this system actually is different

from the visual system. It's also different from their hypothesis, each receptor detect one chemical

because right now you only have 1000 for example in the mouse, the functional gene. And then the
mouse can detect

tens of thousands of chemicals. So then you already have a flavor

how the system should work. [FOREIGN] Use one thousand gene to

detect tens of thousands of chemicals. [FOREIGN] Okay. >> [INAUDIBLE] >> [FOREIGN]. That's good.
That's a very good insight. [FOREIGN]. Indeed, laser a lot of studies

confirmed that hypothesis. Really good. So actually in 2004,

they gotten the Nobel Prize for this work. So they cloned this gene and

then they wanted to know, okay so we have around 5 million olfactory sensory neuron in the nose.
[FOREIGN] Sensory neuron [FOREIGN]. So you got neuron,

one neuron expressed many different types of olfactory receptors or one neuron just

express one type of all the receptors. They don't know. So they did experiments actually here, then
they use the use different probes. [FOREIGN]. There's 1000 type of receptors. So each one type of
receptor detect is about 0.1% [FOREIGN] receptor [FOREIGN]. Then the did other experiments to
confirm indeed each receptor neuron or sensory neuron only express one type of odor receptor.
[FOREIGN]. 5 million and 1,000. How many? 5,000, right. [FOREIGN]. [FOREIGN]. It's quite a
challenge actually for, if

you want to study those sensory neurons. [FOREIGN]. If you want to find a specific
type of receptor neuron for the recording is quite challenging. [FOREIGN] olfaction [FOREIGN]. So if
you want to study this neuron, olfactory sensory neuron, do the then you need to identify them,

right? [FOREIGN]

Like a receptor. [FOREIGN] Like a stimulation, just put on a chemical. [FOREIGN]

Chemical [FOREIGN]. So for this kind of study actually

is quite difficult even if you have 5,000 neurons,

express one type of receptor. You can express GFP under that

promoter of this receptor. But still, you can only find or one or few of these kinds of receptor
neurons,

during the recording if we isolate them. This is kind of a difficult study. So in any case,

the principle is one sensory neuron only express one type of odor receptor. Let's take a look. This is,
actually is receptor gene is the main protein here. Is typical. And then this one is quite cross one
southern type of odor receptor, this actually maybe features for the. And this black one, actually
quite different across different receptors. So what do you think? This different than. So they are
different because the key

features, the common features maybe for signalling is binding to the g protein,

right? Those should be similar, but

if they are different then in most case may be related to the recognition

of different chemicals. For example the. So here then actually is the [FOREIGN] odor receptors only
enriched in the olfactory [FOREIGN], this is some information. And take a look here, this one. In
human, we have in total

it's about 800 odorant gene. But they are,

about 400 odorant gene are pseudo-gene. Function, almost half. No function. It is quite surprising
right? And you can take a look actually here. Like a rat, [FOREIGN] function odor. In the mouse,
[FOREIGN] pseudogene, [FOREIGN] function odor. >> [INAUDIBLE]

>> [INAUDIBLE] >> About what? [FOREIGN]. [FOREIGN] Why in the human actually we have much
fewer odor receptors compared with the lower order animals. >> [INAUDIBLE]

>> Okay, yeah this actually evolution or

the kind of selective pressure. So then has a lot of those

pseudogene happened, actually selected out. That's good. So, indeed, people believe within

the field is, why in the human the olfactory system are not comparable to the mouse, the dogs.
That's because human actually

rely on the color vision. [FOREIGN]. The color vision is so powerful for

human to recognize the food, in the jungle, not human, for monkey. Human we are fine right now,
right. We don't rely on olfaction. You have a coat, you are fine. [FOREIGN]

Not such a critical thing. But as I said, for human,

the olfactory system is mainly for those long term memory and control your

emotion and it's the other things. We know one sensory neuron only

expresses one type of receptors. They select one type of receptor

from 1000 types of receptors. Only express one. This is really quite interesting topic. How the cell
can do this thing. Make the decision,

select only particular one. Indeed it is like really

a fundamental question in the field. A lot of really good labs

actively study this topic. Yeah it does include a lot famous labs. Even Richard Axel. Also interested is
one like and

also some other labs. So to answer, I guess a lot of important studies suggest that

system works is because there is some mechanism within the cell. When the cell expresses

one type of receptor, and then that receptor can inhibit

the other receptor expression, there's a kind of

dis-controlling mechanism. This is quite interesting, right? But most important is,

how did that cell convert in the first place to express the OR gene? That's the key. [FOREIGN]
Control. >> [FOREIGN]

>> Yeah. >> [FOREIGN]

>> Okay. >> [FOREIGN] >> Yeah >> [FOREIGN] >> [FOREIGN]

>> [FOREIGN] >> Okay, [FOREIGN].

3.1.6

One cell express one receptor. And then, how would this cell,

the connection to the brain? And then,

there's another very important topic. And that, we have this different

models about the organization. For example, the same color indicate they should express the same
receptor. Then the organization of the system can be any of these three A, B, C. The first one, A,

is actually the receptor, those neurons express the same receptor. They cluster in your nose.
[FOREIGN] Okay? And then, also they're targeted to

the brain, to the same location. And then, from the brain,

there is one type of a neuron selectively

connect to that region. This is kind of a specific,

just like a telephone line, right? The second one is actually, okay,

it's a different situation. The second proposal is,

in the, in the nose, olfactory epithellium,

those cells express different receptors. Actually, they're intermingled. [FOREIGN] Some magic will
happen when these axons enter the brain. The magic is actually the same type

of receptor-expressing neuron. They kind of find their own way to

converge into the same location. [FOREIGN] This is a second hypothesis. Now the second one will be,

okay, is that B. That means the cell expressed,

even the receptors, they intermingled. But the targeting also is kind

of intermingled together. The there is no kind of sorting happen. Yeah, to determine this thing

actually is also quite, actually, so from Reacher Access lab. [FOREIGN]. Let's take a look. First, you
want to actually look

at actually the cell express, the same type of receptor,

can cluster in your nose. Now, these, why we propose this kind

of study, like in the visual system, as we said, and also in the auditory

system, there's a map map. Do you remember? Like in the visual system

there is a spatial map there. [FOREIGN]

Brain region, right, it's a map, a spatial map. In the auditory system,

there is a frequency map, all right? So apparently here,

what kind of a map will they have? But here,

this challenge to determine the map, because it's a chemical,

what kind of features do they share? It's quite different from the sound,

quite different from the light. Now, but

people still kind of interested in this topic because based on the vision

studies and the other studies. So if you want to determine this tissue

then what you can do, quite simple. Here is like a,digestor uses

an in situ hybridization. Use different approach for

what, for different receptors. For example, here there are three

types of receptor probe. And then what you can see? This is Drosophila. [FOREIGN] Drosophila

are quite interesting. [FOREIGN] Now you can see the different receptor expression cluster.
[FOREIGN] Although, [FOREIGN]. It's not so clear, okay? [FOREIGN] The pattern or image, you can't,
[FOREIGN]

But this is actually in the olfactory epithelium. You can check the distribution

of these different cells and then the results is actually

quite distributed, intermingled. Different receptor neuron, okay? How does the brain, how can you
use, what kind of method to determine

the brain, the connection? >> [INAUDIBLE]

>> [FOREIGN] How you do it? You adjust the [INAUDIBLE]

in one kind of olfactory neuron [INAUDIBLE] it's

a map of this kind of receptor in [INAUDIBLE] area like that. You need another kind of

[INAUDIBLE] to express [INAUDIBLE]. >> Good, okay, okay. Is it easy or

difficult to do the experiments? >> It's difficult. >> Difficult. What's the difficulty actually,

I don't know. Why is difficult, which part is difficult? >> [INAUDIBLE]

>> [FOREIGN] >> [INAUDIBLE] >> [FOREIGN] Okay. >> [INAUDIBLE] >> [FOREIGN] >> [INAUDIBLE] >>
[FOREIGN] >> [FOREIGN] That's actually from Reacher Access Lab. [FOREIGN] P2 receptor, the
promoter. [FOREIGN]

So you see the promoter, receptor P2, to make a receptor P2. [FOREIGN] This is in the notes, okay,
epithelial. [FOREIGN] We talk about it, the same homing, right. [FOREIGN] [FOREIGN] One site, there
are about 2000 of these Glomerulus. [FOREIGN] Very interesting. These axons go to the brain. They
are targeted to your sights. One it just decide to get median. [FOREIGN] Side lateral. [FOREIGN]
3.1.7

Okay, so this is actually the b panel that uses the final

map of the system. The receptor expression in the olfactory

is distributed different scent. But in the brain, actually,

it's a magic happened to then, they can find a specific location for

the targeting, okay? Okay, so

this is organization of the system. So in this system, then although the

signaling in the nose actually is not so clear-cut, because the receptor

neuron is distributed. But in the brain, and the olfactory bulb, organized [FOREIGN] receptors
[FOREIGN]. If we have a chemical coming from outside, [FOREIGN] we talk about, actually, in this
neuron that express the receptors,

right? And also Richard Axel and Linda Buck

in 1991, they cloned the receptor gene. [FOREIGN] How can you

demo straight that one? That receptor gene is really

a olfactory function gene. [FOREIGN] The clone have three assumption. The three assumption, first
actually,

this is GPCR, should be a GPCR, okay. The second is actually, they should expressed in the nose. The
certain ones, which one, do you? [FOREIGN] [FOREIGN] Okay. [FOREIGN] [FOREIGN] functionally,
you've got protein to detect a chemical. [FOREIGN] detect a chemical. [FOREIGN] receptor gene.
[FOREIGN] But unfortunately this receptor gene is very difficult to be expressed in the X casual sale.
[FOREIGN]

That's because this receptor's expression [FOREIGN] They need some maybe chaperone protein.
[FOREIGN] What can you do? [FOREIGN] This is a key question and a burning question in the field.
[FOREIGN] >> [INAUDIBLE] >> Okay. >> [INAUDIBLE]

>> Okay. This is how to read. [FOREIGN] Odor receptor I7. [FOREIGN] Receptor, okay? [FOREIGN]
Now you have the expression for this receptor, how can you check their function? [FOREIGN] O
expression, you expressing more protein, right? So again,

[FOREIGN] This one A is from wildcat okay? B is from this animal. And then you use the chemical to

challenge to stimulate different animals. [FOREIGN]

Or expression. I7 protein. Like a receptor. And then you got this extra response. [FOREIGN]

17 receptor, okay. [FOREIGN] That's a receptor gene. [FOREIGN]

In the mouth, there are about 1,000 gene there. [FOREIGN] Impossible, right? [FOREIGN] These
experiments

only tell you those receptor gene indeed can

bind to the chemical, can signal in the chemical, okay? But we don't know at all
how they're signaling. The 1,000 olfactory receptor genes. [FOREIGN] To create such a odor
perception with mechanism. We know the receptor is

a receptor right now, okay. So there's another milestone work

from Linda Buck's group in 1999. It's a sale paper. So what they did is they isolate

those neuron in the nodes. [FOREIGN] Calcium sensitive dye. [FOREIGN]

Okay. [FOREIGN] Chemical. [FOREIGN] To do response. [FOREIGN] Okay? And then, if you find one
neuron can

respond to you, some type of chemicals. That's good, you know this neuron

responds to those chemicals. But you still don't know

the receptor gene, right? And then you can take up, pick up the

single cell to do the single cell RT-PCR. Then you can find which

receptor expressed. That's what they did. What is the deal? I mean,

this is stuff they are finding, okay. So the clone, they found,

actually about 14 types of receptors, that means actually, for

many, many cells actually, they found actually in total,

they have 14. Even the type of receptors. And this is chemical stimulation. You see, one receptor can
be

activated by different chemicals. And one chemical can activate

different receptors. This is what you talk about. [FOREIGN] So the chemical is recognized by a
different compilation of the receptor neurons. Correspondently in the brain,

actually it's a converter. [FOREIGN]

And then glomerulus one, two, three, [FOREIGN]

3.2.1

Last week we talked about the olfaction. So which group clone

the olfactory receptor chain? [FOREIGN] Okay, it's a Nobel Prize, okay, right? [FOREIGN] Who knows
which group cloned

the olfactory receptor gene? >> [INAUDIBLE]

>> Good, yeah. In the back, in the rich axial, right? The clone is a receptor gene from the rat. And
that's quite important work. They've found about 1,000 receptor gene in the rat. So there's almost
about

a 5% of the genome. So it's really a big family. Okay? And we didn't talk about actually

their olfactory construction right? The receptor is a DPCR, and after all the binding how the receptor
neuron generates signal, electric signal >> [INAUDIBLE] >> The activation with d protein, right? >>
[INAUDIBLE] >> What is [FOREIGN]? [FOREIGN] Times three. It is three, right? And then what will
happen? >> [INAUDIBLE] >> Dnnp, right. >> [INAUDIBLE] >> What channel will open? >> [INAUDIBLE]

>> Sodium channel. So, the channel is a CNG channel,

CNG channel, cyclic nucleotide-gated channel, right? And the CNG channel open, then what's the
following steps in the [INAUDIBLE] cascade? >> [INAUDIBLE]

>> Okay. The seed of depolarized

>> [INAUDIBLE] >> Okay. >> [INAUDIBLE]

[INAUDIBLE] >> No, we talk about actually, a very important feature

in the olfactory system. There is a nozzle amplification step. The acceptor for the GPCR, cascade.
Assuming, what's the next step

after the CNG channel open? Sodium and calcium were coming into

the cell, depolarizes the cell, right? Anything? >> [INAUDIBLE]

>> Yes, yes. Okay. >> [INAUDIBLE] >> Okay. >> [INAUDIBLE]

>> Yes, yes, okay the after transduction work, but it's transduction,

is actually not finished yet. A CNG channel opened, and

sodium will come in, calcium will come in. And then, very important step,

we talk about a lot actually. >> [INAUDIBLE]

>> Exactly, right. That calcium will activate

a correct channel. That's actually needed to further

depolarization with the cell, all right? We talk about actually, why we need

this second amplification step. That's because in the olfactory

in the fresh water animals, maybe their sodium

concentration would be low. And then you need the CNG

channel that step maybe only carry a little of

this depolarizing current. Then you find out better

how calcium comes in. The calcium then will

activate the correct channel. The correct channel open and

the correct will influx, will go out and

the cell depolarize, right? This we talk about a lot. Okay, so

then after the second amplification, and the cell, really maybe a huge

depolarization on the thing. Fire action potential and then the actual potential will propagate

through the axiom to the brain. That's what I'm talking about. For the olfactory organization,

we talked about it actually from the OSN, olfactory sensory neuron,

to the brain, the targeting, right? So what's the key feature there? [FOREIGN] >> [INAUDIBLE]

>> Yep. >> [INAUDIBLE] >> Okay, so the key features is a first actually, one neuron,

only express one type of receptors, right? Okay. And that those neurons express

the same type of receptors. They will converge into

the brain only one or two spot. That spot called glomerulus, right. That's good, okay. So in the nose,

in the olfactory epithelium, how's those neurons distributed? So those neurons express the same

receptors where they cluster together or actually distribute or

intermingle with different OSNs. >> [INAUDIBLE]

>> Distributed, right? So here, actually,

is a very important coding scheme, that is actually the information

at the peripheral, in the nose, is distributed, but in the brain,

then you have really discrete. The coding in one spot and one spot, okay. There's a map, right?
Because they have a different glomerulus. Then what's glomerulus the structure? What kind of
neuro process

happen as a glomerulus? Okay, so we know that's actually

olfactory sense that and it goes to the brain and

the brain, of course, will form a synapse way to

the second order neuron that right? So it's a glomerulus actually

is a synapse region, okay? It's the axil terminal from the OS end,

and the projection you're on, or

downstream you're on, the. There's actually a specific region for

the synapse formation. So we then talk about, actually,

the cloning of the receptor. Just the cloning, right? How you determine the receptor function. We
talked about a few experiments, right? The typical way people will do is,

actually, then you express those gene. In the and then see what will happen to the cell

if you challenge it with chemicals. But unfortunately,

the olfactory receptor is very difficult to be expressed in the. So people, some researchers then use

a very smart way to handle this situation. So what's the experiment

that people did to verify those gene are indeed the olfactory receptor gene for the detection of
odors? [FOREIGN]

>> [INAUDIBLE] >> Okay. Hm?

>> [INAUDIBLE] >> Good, good, you can simply over express some gene in the native

tissue in the mouth, right? The reason, actually, why people have the difficulty to express the OR

gene in the cell. That is mainly because, maybe those receptors need

a [INAUDIBLE] chaperone protein. Some other proteins to help

them to target to the membrane. But in the contracell maybe

those are factors missing, okay? But in the native tissue,

then you don't have the problem, right? [FOREIGN], right? So it's a, they expressed as a over
expressed

receptor gene in the mouth. And then, used a ERG, did some recording. And compared these
animals

with another wild type animal. You will see,

the actual response to [INAUDIBLE] then is the ORG in function, right? This is actually important to
work. And then later, we talk about, because that OSN expression experiments is quite time
consuming okay? In the mouse, you have about 1,000 gene,

olfactory gene. So if you want to determine,

which gene responsible for detactional for what kind of odor, you need to create

a lot those transgenic animal. That's impossible, right? So for this, Linda Bach's group, they did
experiments in 1999. Very important work. [FOREIGN] >> [INAUDIBLE] >> Okay good yeah, to
determine the strategy of the olfactory system for

the coding of the odor. So then you needed to know which

gene detected which type of odor. And then essentially you needed to

actually, from this kind of information. Then you need a clue. But [FOREIGN] only did

the full one receptor, okay. But it's actually quite challenging,

right? So Linda Bach's group then

take a different approach. That is actually they isolated the olfactory of sequence
of single neurons, okay? Isolated them,

get in the range of a single neuron, and then put it on the dish,

on the dish and then, load with some calcium sensitive dye.
3.2.2

And then, they use the calcium fluorescent dye to monitor the activity

of this neuron. And then, they challenge these

cells with different chemicals. And they see whether some neurons

can respond to some chemicals. And then, of course, they will get

some response from the neurons. But they didn't stop at this stage, what they have done is

actually remarkable. Then they pickup a responding cell,

single one. And to do a single cell, [FOREIGN], and then they found it which receptor

gene express in this neuron. And then the node, the chemical,

like a stimulation and then they can put this table together and then you can see this is actually

14 types of receptor gene to clone and then this is the chemicals

they have used in their study. Then what you can see is for

one receptor gene, and you have many different chemicals

can stimulate it activate it. And also,

if you look at the one chemical here, and then you can be coded by

many different receptors. They really have evidence for this kind of

coding scheme, in the olfactory system. That is actually, one old one is not

specifically coded by one single receptor. That's not true. You need actually one chemical,

actually is encoded by different

combination of different sets of odor receptor gene,

the activation. This is a very important finding. This different combination. Let's take a look. If you
have this information

sent to the brain. What can you imagine,

what happen in the brain those going to. So in the nose, maybe because

there are different receptors that are going to distribute it, and

they intermingle with each other. Then you cannot see any clear pattern. But if you go to the brain, if
you

use one chemical stimulant the mouth. You look at the brain [INAUDIBLE]. From there, then you will
know exactly

which Like a spot was activated. And then based on that information, you don't need to know
actually

which chemical you stimulated. You can base on that location,

the spot activation, then you will know which

chemical to experimental is used. A group of neurons. The [INAUDIBLE] spot

corresponding to one receptor. So you [INAUDIBLE] summarize, this kind of coding and
transformation is a line receptor neuron, YOR gene, and the [INAUDIBLE]. So this information right
now

is coded by the receptor gene. Different receptor compilation and then you can represent

the mechanical stimulation, so let's take a look how this

information profligates to the brain. So this is a cartoon. Take a look. This one uses an olfactory
receptor

neuron the same thing as I mentioned as olfactory sensory neuron. They're the same thing. ORN or
OSN. And then, these neurons,

as we talk about actually, they only express one type of receptors. And then, for those neurons that

express the same type of receptor, they will converge into the brain,

the glomerulus. Making it one spot here. And then in the brain,

in the this is in the brain. There was another neuron

called a mitrocell. And then, this mitrocell will perform a to form the synapse with these axons over
the front ORN. There was a synapse here. It is quite interesting. For this mitral cell. They have a
secondary dendrite. This also is a mitral cells dendrite. So the mitral cell has two dendrites. One is
the side to form synapse with OSM. And there was a secondary dendrite here. We'll talk about how
this works. So the information,

of course, this ORN when you have a chemical binding,

the ORN fires action potential. And the action potential with

propagate to the axon terminal, and then releases Neurotransmitter

to activate this mitral cell. This is how it works. The information right now go to the brain. But it is
quite interesting. In the brain, in the olfactory bulb, there are some other type of cells,

except for these mitral cell. For example, there was one cell

here that don't have the long axon. They only form horizontal or

lateral connection. You can take a look here. This cell can receive

the input from the OSN. Or they can receive the input

from this applicable dendrite. But importantly, they will have a also

synapse on the applicable dendrite. So this is called mutual synapse. [FOREIGN] Bi-directional. Now,
this synapses mainly this

feeds back to the apical dendrites. They release a GABA. GABA is an inhibitory

neurotransmitter in the brain. And then, these actually receive

excitation from the ORN or from the actual dendrite

of the mitral cell. But we have an inactive feedback through

the GABA release to the actual dendrite. And also, this cell will also release GABA to

a neighboring mitral cell. That is actually, you'll see. For the information,

this is kind of one unit. The information will front to

the converters to the mitral cell. And the mitral cell,

they are actually independent. So one mitral cell only receive, for

example, only from one glomerulus. And then, this one, this mitral cell receives

the input from another glomerulus. So actually,

they are kind of independent channel. And these here thing connect these two. Uses negative
feedback for

the GABA release. Also, there is another step of

the information processing. This is called sale [FOREIGN]. And that they receive

the input from the microcell, the dendrite, the dendrite and also feed it back to GABA,

feed it back to the secondary dendrite. Again, this cell will

make the connections of propagation between different channels. As we discussed in the eye

the retina also have very important to produce the sensors around

those receptor fields. Imported from the horizontal

cell interaction. You see, quite similar. Skin as the neurosector. In this case,

horizontal corresponded to this cell and the current cell

corresponding to this cell. And you know that redundancy is so important in the visual

information processing. The around and

later in the brain the light a bar or our face cells originally

from the horizontal cell contribution to the receptive field. So into the olfactory system. This kind of
connections. And also, we know this cell, it feeds the back through GABA

to connect to each other. But actually, it's not so clear. They will have similar

centers receptive field. As this horizontal cell for the signal for the horizontal cell is quite clear,

because of the spatial stimulation. And the thing [INAUDIBLE] the center and

the surround receptor field. But in this case, in this cell,

in the olfactory system, there's not so directed connect

with the spacial information, because those cells in the nose, those olfactory sensory neurons,

they intermingle with each other. There's no map there. So what is the function
of these connections? People are still trying to

find the true answer and that means it's still in progress. So if you are interested,

you can study these kind of topics. Here, I guess also it's

important actually the synapse. This is a dendrite. First we have this synapse actually

uses the axiom to the dendrite. Now, you can see synapse. And also, axiom to the synapse. The
dendrite here. But we still have another type of synapse here that's actually from the apical

dendrite to the dendrite of this cell. And then, this cell also releases

the GABA to this dendrite. So synapse is not only formed

between axon and dendrite. You can still form some special

synapse between the and the dendrite, axon and the cell body.
3.2.3

Here is a, Study about this structure. The dendrite and the dendrite synapse. So this is a cranial cell
right? This is a mitral cell. They also have the dendrite and

a dendrite synapse. Take a look here. This is a cranial cell, this structure and

the then this is a mitral cell. I guess actually you don't

mention the synapse to you. Can you recognize where

is the granule cell presynaptic region, and the four mitral cells corresponding

in the post synaptic region? For a presynaptic region,

you need what kind of thing? >> Vesicles. >> You need a lot of vesicle right? Indeed, you see here,

a lot of vesicle here. And actually,

this is actually corresponding to a presynaptic region for the granule cell. And then this is a post
synaptic

region for the mitral cell. And then from granule

cell to the mitral cell. Many use what,

GABA right is a feedback signal. And then from mitral cell, you also have, you see here,

a lot of this kind of vesicle, okay? And then this is a cranial cell receive

the information from mitral cell. And then this cell, cranial cell will

feed it back to the mitral cell. How this cell release neurotransmitter? If you use that dendrite

to form a synapse we talk about actually

neurotransmitter this you need action potential coming

down to the axon terminal, and then you need the calcium channel. Once you get the calcium

channel activated and the calcium going in and

trigger the vesicle fusion, right? And it sends the release,

but in this region, how can you trigger

the neurotransmitter release? [FOREIGN] >> [INAUDIBLE] >> Okay. Calcium independently released
right? So what kind of process in the calcium independent of release? >> [INAUDIBLE] >> [FOREIGN]
>> [INAUDIBLE]

>> Okay. This is a quite interesting topic, right? So, how these cells can release

the neurotransmitter from the dendrite. So, it's a recording. So, if you want to study

this this process. Actually it's quite challenging. You cannot do the patch for example. Just from a
patch can recording from

this kind of dendrite membrane. So, you then have some special way for
this study. As I mentioned, this guy somehow you see this is endocrine cell. They release the
neurotransmitter

from the dendrite. From that study, people found actually the endocrine cell express

those empire receptor. For example, the receiver with the glutamate

stimulation from the bipolar cell. And then those empire receptor

take in less calcium go in, okay? And it's those calcium

from the empire receptor, and it trigger the release, okay? And the olfactory system I guess may be

similar mechanism can be responsible for the neurotransmitter release. And so we mentioned that
at

the first lectures about this chemo reception we talked about actually

the olfaction is very profound, has profound effect on a human being,

right? That's actually for the,

sometimes the long term memory and also sometimes for the emotion. Let's take a look how the
olfactory

information propagate in the brain. So this is the olfactory epithelium. This in our notes, okay? And
then the information will

propagate to the olfactory bulb. Olfactory bulb, and then is mainly used

those glumernis right [FOREIGN] okay. And the information will process

from the olfactory bulb and this olfactory system is really unique. In most the sensory system that

information actually before going to the cortex,

you'll need relate by the sentiments. [FOREIGN] the sentiments okay? But this guy, actually does not

relate by the [FOREIGN] sentiments. Directly from this olfactory bulb,

packaged with the olfactory cortex. It has is red direct. [FOREIGN] Let's take a look what

kind of region to target row in. For example from this olfactory bulb

they can target the TC information. Sending the information to this region. This region of cortex

then is like a [FOREIGN], mainly for the emotion okay. [FOREIGN] that you'll feel, [FOREIGN] and also
this information can directly go to this region, pure form cortex and [FOREIGN], okay? And also
project to this region, redirect. So the cortex, again,

it stores the information from the nodes. It's really direct,

only about two synapse away. One synapse here and

then another synapse here. In the visual system, you need to go

to photo receptor to bipolar cell one, bipolar to ganglion cell one,

ganglion cell to LGN one. LGN then go to the brain,

the delay of four. And then you need a fourth synapse. Okay. So let's take a further

look at the information processing or

representation of this effect or signal. Okay. So we mentioned

the the olfactory information. In the olfactory epithelium

is distributed right? And then you go to the brain,

the olfactory bulb, then you have, really, the map there. It's really discreet. [FOREIGN] Okay how
about in the cortex? So for this coding, for

your information coding, it looks actually,

it's quite simple right now. For the decoding, because your information already code

into these individual map cells right? So for a brain, like for us, we just need to take microscope,

open this area. I don't need to know, actually,

what kind of chemical you are using. I just need to read how many these

what kind of pattern of this glomerulus activated then I would know. Which chemical you're using,
right? But the problem is actually, in the brain there was a no microscope,

and for this guy, for this brain cortex to

decode this information, then need to use this neuro receptor. So how this map represented

in this cortex region? That's really an important

questions in the field. People try to understand the system,

right? What kind of strategy will you

use to study this problem? The question is how this

map information from the olfactory bulb is

represented in this cortex. It's in the map there or actually

something what happened differently. So, to study this question. What kind of strategy will you use?
3.2.4

Okay, we checked, for example, some virus or something here. We get to chemicals and

then trace down their region. >> [INAUDIBLE]

>> Okay, yeah. Good.

Good, good. Indeed actually, this actually. People did a similar study. The first thing actually they use
these the imaging studiy. The cancer imaging of actually,

let me take a look. Maybe this is not a cancer imaging,

maybe this is a intrinsic imaging. It doesn't matter. You can use the cancer imaging for

example, you express those kind of

calcium sensitive fluorescence protein like or in the brain. Olfactory context, and then you

stimulate the nose with chemicals. Then you see the specific odorant coming. For example,

you use this kind of chemical. Then you check what kind of cells

actually was activated in the context? Do those cells actually kind

of spread the whole cortex, or actually really cluster. Then you would get some kind of clue. Indeed
as they did in these

experiments you'll see. For this chemical stimulation in this

brain region, you have actually very wide range of the cells actually responding and

for different chemicals as I said. This tells you already. In the cortex,

olfactory cortex, right now, the information spread again, distributed. In the nose, your information
is quite distributed but in a factor about,

actually it's a discrete. It should be one spot, one spot. Clustered. Body in the context, spread again.
What's the advantage of a decision? Why you needed to use this kind of

strategy for the information processing? Like in the it should be

a little bit different. It kind of your extract those important information from the spot

to the centers around and then to the bar and

then to maybe the shape of the face and this kind of more abstract

information process but here is things you just [LAUGH] go back to

the original situation the distributed and discrete and

then distribute again the information. [SOUND]. That it means if you really do a fine job,

you will find actually for a single cell in the brain,

in this brain region, maybe they can respond to

different chemical stimulation. Many different. [SOUND]. That means actually in

the brain in the visual cortex, one neuron may be received a lot of

input from different glomerulus. That means the information

is mixed again in the brain. What's the advantage to do this? I guess you can think about

this [INAUDIBLE] a laser. There was another strategy actually to reveal this kind of processing in
brain. That is actually, as Tanya mentioned,

you can do some labeling but here actually it uses the wire is

actually is not inject to this bulb. They inject into the cortex,

one brain region and then, those axons actually from this

bulb neuron the mitral cell. They will take up this guy and

then they [INAUDIBLE] neuron. What they found is [INAUDIBLE]. There's three region for the
injection. Why is in this region inject,

for example, the green thing? And then this is purple and

also orange here. And then see what happened. They found, actually, for

this kind of injection, I labeled these neurons actually here. For the purple and orange. Actually,
almost equally

distributed in the olfactory bulb. That means the neurons in this

region received all the inputs or mixed the inputs from a lot of those,

from the mitral cell. But for this one, for this green one,

actually is more they clean. [LAUGH] More localized to the total side. Lasers are actually found, this
doses, why this doses site is

special because in the bulb? This actually responsible for the detection of the some kind

of an innate behavior chemicals. For example, the fox urine. For the mouse and, also, maybe rat
urine. Those actually rat or

fox is the predator for this mouse. [FOREIGN] fear to those animals. The structure. Again, this is the
current

understanding of the system. Maybe in the future,

most study can reveal, most subtle different skill but

this is our raw maybe is the principle is right. And then in this kind of region,

then you receive most specifically input. But in this Piriform Cortex, and then it's more kind of a
mixed

information input into the brain. [FOREIGN] which axle [FOREIGN]. This for the olfactory system.
Next we should finish

the topics about the taste.

3.2.5

The understanding about this taste system, is actually not as advanced

as the olfactory system. [FOREIGN]

Let's take a look at how the taste system works. Taste, of course, we mentioned,

what's the difference? The key difference between the chemicals between the olfactory system and

the taste system? The detection of the chemicals,

what's the difference? Why you need two systems? [FOREIGN]

>> [INAUDIBLE] >> Good. >> [INAUDIBLE]

>> Does not need a direct contact. It's kind of remote, right? Good, thanks, yep. So, the olfactory
system actually

detected maybe some long range. [FOREIGN] Chemicals. Sometimes maybe alert to you. [FOREIGN]

Or the taste on food. But for this taste system there is direct contact [FOREIGN]. Contact with your
tongue, especially the taste bud on the tongue. A taste bud here. [FOREIGN] This is a unit of taste
bus. [FOREIGN] What kind of function

do think they let us to have? Why we need taste? Such for food, okay, good, and also? >>
[INAUDIBLE]

>> Okay, a wart is some toxic, right? Yeah, that's good. So, the answer would be actually,

first, actually, let's ask to you,

find the nutrition, right? And then you also avoid some toxin, because some dangerous

thing actually in the wild. For the nutrition, in most cases, actually, the sweet stuff [FOREIGN]
nutrition. [FOREIGN] But the beta stuff,

in most cases, associated with some kind of a toxin. [FOREIGN] During, I guess, during the evolution,
[FOREIGN] so in Spanish. It doesn't matter [INAUDIBLE] for

any animals or humans. They are the same, humans are [INAUDIBLE]

they have the same taste, these kind of modality. They avoid the stuff, and then they really like the
sweet stuff. Now, the taste. Of course, begins with your tongue, and then on the tongue these spots
here,

called, the taste bud. Each one. Each taste bud, we can take a look. It's like this structure. The
structure is actually,

there is a pore. [FOREIGN] And waiting,

one of these taste buds, there are about 100 sometimes. The taste receptor cells, okay? These taste
receptor cells

are not the neurons, they are different from

the olfactory system. The sensitive cells, here,

these cells actually derive from the cell. [FOREIGN] Okay? And then for these cells, actually,

you can take a little bit, each in the individual cells, actually. They will have this kind of shape,

a long shape. This is a nuclear cell body. And then we have a very long

process going to this pore. And then at the top of this process, there is a lot of [INAUDIBLE]
[FOREIGN] those are responsible for taste detection. It's this region, the tip. Those taste [FOREIGN]
they are soluble, right? [FOREIGN] Those things actually

will access to this port. [FOREIGN]

And then, the tip of these cells then

can detect if the chemicals. Take a look at the G structure, then you will think actually this

structure is quite a danger, right? Why? It's because this cells

directly every time, every day they contact

with the chemical direct, it's really dangerous because [FOREIGN]. Really dangerous for this cell,

because they 24 hours [FOREIGN]. And they are the same for

the olfactory system in the nose. Those cells also, every day,

are contact with those chemicals directly. So, these cells will die quickly, okay? In the olfactory
system,

and also this taste system, those sensory cells, they will die,

maybe around one month. They will die, and

we actually experience it quite stable, the taste perception, and also olfactory. A function, right?
That's because, actually,

those cells can regenerate. Okay, some new cells were regenerated, and we then replace those bad
cells. Okay, this is some kind of key features

for this chemo receptor system. And of course, how these cells,

they should regenerating. And I should use especially for

example for the olfactory system, we have so precise connection,

to the brain, right? If one cell die, another cell appear. How that cell can find the connections

to the glomerulus again. And also, I don't know. The cell dying, maybe but actually, in your lifetime,
maybe you have not so often experienced some kind of

lost over some special smell. Detection, right? So, that means, actually, there may be

some mechanism actually, to control. If one cell died, maybe it's some kind

of particular type of receptors, and it's in maybe another cell regenerates. And then we'll express
similar type

of receptors to replace that cell. But this, I guess,

is just some kind of guest cell, okay? You can do some study to find this answer. Okay, so, although
this cell can be

regenerated, that is fine, right? But it's still. These structures has some

special features to protect. The protection is actually,

you can see there's a pore here, and a cavity here, right? And actually, these cells, actually,

under the tip of these cells. There's a tight junction,

this is your special, your membrane,

connected by how many [FOREIGN]. Contact junction. Now, those type of

junction should prevent, those taste sensations to further

go down to these cells, okay? This so that you have the from the cells, okay, to innervate this
neuron. And then you want to protect those

[FOREIGN] damage these cells, okay? I guess, actually, everybody knows, we have a map in the
tongue. [FOREIGN]

What's the map? The distribution for

the sweet, bitter, and the salt, and the sour detection,

what's the there? [FOREIGN] After the cloning of those receptors, they're sweet. So, what kind of
modality, the quality of the taste do we have? Five, right?

[FOREIGN] [LAUGH] >> [INAUDIBLE] >> Sweet, bitter. >> Sour. >> Sour. >> Salty. >> Salty, right? >>
[INAUDIBLE]

>> [FOREIGN] Okay, good. [FOREIGN] Right. This is the five basic taste modalities. And of course,
people talk about some kind of fat detector. [FOREIGN] [FOREIGN] This modality, I don't know,
actually. The receptor maybe have not been cloned,

right? Still, people still trying to find those

receptors for that effect detection. But those five you mentioned

are the classic one.

3.2.6

So and for those study, for those fine basic taste of modalities. Mainly over then, [INAUDIBLE]

receptors held being cloned and then based on those molecular study and

then you can check. You examine how those receptors

is distributed in the tongue. Okay and this is actually a review paper. So that you see essentially,

every receptor, essentially, they kind of are Bitter,

salty, sweet, umami,

sour are in the front of the tongue. And they quite evenly distributed. This, From this molecular
distribution

in the sense actually there's no map. But maybe some mechanism or

some other mechanization can people have with a preference and

some special spot. Okay, that is possible. Okay so from the tongue then, let's take a look then how
the nerves

sexually we're responsible for the taste. So this is a taste receptor cells TRC. And. And then there is a
gastric ganglion. [FOREIGN] [INAUDIBLE] region [FOREIGN]. They send a axon to this top
[INAUDIBLE]. Okay, they will receive information from these [INAUDIBLE] receptors and then they
will relay this [INAUDIBLE] Information to the brain stem, [FOREIGN] Nucleus of the NST, okay?
[FOREIGN] And then,

this information will be further related to you the sedimous,

the tune up. And then [INAUDIBLE], this information

will relate to the gastrula cortex. [FOREIGN] You see, here there are different olfactory systems.
Olfactory system does not emote in

this step the sediments, right? The taste system,

also kind of studied quite a long time. The understanding of the taste

system actually quite limited, okay. For this sensory mortality right now I

guess we talk about it at the beginning. Is down the okay? And they follow the. There are factor and

then this taste system pretty much we don't, what we know

has only happened in the tongue. Okay, in the brain yeah, this quite limited study. But still we can
take a look step by step,

okay. So in the tongue of course how you

understand the taste excuse me in the tongue is actually and then you

wanted to know is clones also receptors. And we talk about actually cloning of the

olfactory receptor gene is in 1991 right? Now it's by Linda Bach and Richard Axle. They cloned those
receptors about
the wine cells and in the tongue. And then mainly actually by this group. Of course has another
collaboratory lab research found the ARH grade bar. Also these two groups

actually did a lot of. Those beautiful study in the taste

system different receptors. For example they cloned

the sweet receptors. And actually there was kind of a animal. The mouse actually, there was AK
Milton. Okay, ask AK Milton if you use

the sucroses and you kind of switch stuff. [FOREIGN] Sucrose water and this is actually the
consumption,

[FOREIGN]. You can take a look, in the wild type

animal you can have these animals, if you put a little bit of

sugar they drink a lot, okay. That means they can detect. They know this is kind of sweet water,

right? Then they drink a lot. But when you have this SAC mutant, and then they cannot detect in this
region about the sweetness of the water. And the and the they cloned the receptor for the sweet
receptor. That is T1 R3, and if you put the T1 R3, that change in back into this then you can their
phenotype. Data tells you this

T1 R3 indeed Is the SAK in animals that gene actually

lost these because of disease. And then, as we mentioned,

if you want to study some kind of genes function,

the protein function. What you can do is actually is express

sent in the hexcell, conscious cell. Now, the deed that the experiment are key. The sweet receptor
expressed

in the conscious cell and then, is the catch imaging to

check the activity of this cell. And if you put a sucrose to [INAUDIBLE]

cell, you see a lot of cells. Actually make an activated, okay. That means these receptors you put into
the cell is responsible for the detection of the citrus. And also in this study they found

it's actually quite interesting, if we just express the sweet

receptor in the cancer cell you may not be able to get this

activation by the sucrose. You need actually to

coexpress with a protein. Data tells you already, that means that receptor maybe is

a GPCR you need the actually the down stream signalling also coexpressed in the

cell then you can make a detection right. And then they did

a further study also from. This one actually is quite famous. This chemical, PTC, this one actually is
quite bitter stuff. But actually among different people, some of them maybe can taste

this really bitter stuff. But some people actually cannot taste
the bitterness from this chemical. They don't,

maybe just nothing to them, okay. It's quite interesting. And then that means actually

among the human being, for the receptor, the bitter receptor maybe

has some mutations. Okay, among people. And indeed people later found actually for those people
cannot

detect these chemicals. They have a mutation in the bitter gene. And for they clone that

the receptors are quite surprising. The bitter receptor actually

is more than 30 types, okay? By the way for the sweet receptor

,they are just like a or two

3.2.7

And this is their study. Let's take a look. The bitter receptors is a big family. That family is called T2R,
and this assembles types 3 and

7, maybe 1 to 30. Okay, so then the tract you see here are hybridization in

the tongue into most tongue. You can see this is T2R3. Label this this cell,

this cell, this cell. If you also label this

T2R7 in the same section, you'll find actually, the co-express. The right there in the green,

the co-express. What it tells you? It tells you those bitter receptors,

actually, it's a co-express in the same sale. This quite kind a full interesting. Why your co-express?
That means, if your co-express

defender receptors in the same sale, then you have a trouble you cannot be

venture the different signalling, right? Let's take a further look at here. If you express, the use of the
probe

the CTU probe mix the T2R, that means all the bitter receptors

you can't stand, it's the red one. And then you see TR13. The sweet receptor. Label it as green, you
can see. Red and green separate. That means the sweet neuron and

the bitter neuron, they are separate. Okay. Sweet neuron only detects sweet. Beta only detects beta.
But here there is a problem, actually. The bitter cell actually expressed that,

so many bitter receptors, and that we know. Even the receptors,

even the bitter stuff, so it tells you, we can actually cannot differentiate

the different type of bitters maybe, use this kind of a system. Does it help you, or

what's the problem of this co-expression? If you cannot differentiate the bitter

stuff, will bring you some trouble or not. Maybe not, right? Bitter case, in any case,

you don't want, actually, to, so, either then you won't

actually reject those stuff, right? It doesn't matter what kind of bitter,

okay? So, things still may be okay. They co-express it within the same URL,

okay? Castazuka really did a lot for make a lot of progress in the field. Dunka actually, before joining
the Columbia University, actually, he was a faculty in the UCSD. And also, into Howard Hughes and

also a national academy. So, his research is quite profound. At the beginning, Dunka studied the
photoreceptor, okay? Mainly studied the softer, photoreceptor, lead detection. After, he also
contributed to those kind of mechanical reception in the. But later,

you can believe the kind not completely. But he worked a lot for
effort to study the remaining [INAUDIBLE], and then make profound discoveries about these
receptors like sweet, bitter, and also some others, for example, Umami. So, this is actually kind of a
summary

of the taste receptors, okay? Take a look. This is for the umami. [FOREIGN]

Umami, they need receptors, why is it T1R1? Another one is T1R3, okay? And also, for the sweet you
need a two

receptors, T1R2, T1R3, but if a bitter, then you just will have a T2Rs, about 30. And for the sour, and
there is pkdl12 or pkd1l3, and for the sodium taste, they use this orange channel. So.

For these receptors, there are two major groups. Y is actually the first three. These umami's, sweet,
and the bitter. Those are the, you can take a look,

what's the features they have? It's a transform member

in the domain protein. [FOREIGN] And we mentioned that. For the sweet, you need protein. But for
this guy, they're different. This actually may be six. And these three, these are our channels.
[FOREIGN] Right? [FOREIGN] And these studies,

I guess is also important for understanding of the GPCR. Yeah, most of the case,

actually, in the photoreceptor, we're talking about the rhodopsin, there's only one genes, yeah,
right? It is just a rhodopsin, and the waste at that time we think mainly, actually. Rhodopsin is a
monomer. [FOREIGN]

Okay, but clearly this study suggests the GPCR can be dimer. [FOREIGN] At least you need a tube
subunit to form a function of GPCR. Okay, take a look. What is the common feature

between this sweet and Umami? Most of this happens with this guy.. TYR3, right? >> Yeah. >> Okay.
This is the common sub-unit. And at T1R1,

there is the specific for umami. T1R2, specific for sweet, okay? [FOREIGN] Yeah, that would be,

you can make a lot of money. [FOREIGN] Receptor express [FOREIGN]. [FOREIGN]

He founded a company also, especially for this kind of thing. [FOREIGN] This science is really great,
and also, this kind of study is kind of also applied study [FOREIGN]. You combine very well this
research and the application. Since other taste. What kind of taste? >> [INAUDIBLE] >> [INAUDIBLE]
>> Okay. So, that maybe you relate to a topic actually, it is a taste,

we have five basic taste modality, right? Sweet, bitter and salty, sour, umami. This are five basic. But
maybe you are talking about flavor. Flavor thing is a different

from this just taste. It's not just taste. Flavor combined with olfaction and

the taste. And it should be happening in the brain. >> [INAUDIBLE] >> No, so, the flavor still
produced by this kind of fine modality of taste,

combined with the olfactory system. Does it, somehow happening in the brain, the integration over
this taste and

the olfactory system. Then you'll have the flavor. Flavor then is more identified, okay? The flavor,
then you will have
some problem, the detection. If you lost, for example,

if you catch a cold, then the flavor is actually not as good. It's. Okay, just call it flavor. From study I
guess,

It's very important thought, right? But actually, to study again,

just like the taste system, it's still quite limited, okay? Yeah, if you'd like,

you will study in the future. >> Professor? >> Yeah? >> Okay. Right, right, right. So, we will talk about
that later. Let me see how I can, okay? So, for these two guys, actually,

this is the tiger, right? Quite interesting, okay? They don't have the T1R2. Okay? And for the panda,

they don't have the T1R1. That means tigers, and also cats, they are

the same [INAUDIBLE] are actually young, and the tiger, they don't have the T1R2. That means they
cannot differentiate

the sweet stuff, okay? [FOREIGN] And for the panda, they don't have a T1R1, that means they don't
have the [FOREIGN] [LAUGH] [FOREIGN] that don't have the sweet receptor. [FOREIGN] But why?
During the evolution,

you have this kind of outcome. [FOREIGN]

They carry some mutations, and they lose their kind of gene. And then later they changed

the habit of their food, right? Either way, these are fine. [LAUGH]
3.2.8

Let's take a look. How those taste [INAUDIBLE] actually

was transduced into electric signal. As we mentioned,

these three modalities, sweet, bitter and umami, they are GPCRs. And [FOREIGN]. Now they need to
couple to the G protein,

okay? Couple to the G protein and the G

protein will couple to another enzyme. Called PLC beta two. PLC is, first of all, lipid C. This is
different, okay? First of all lipid C is very

different from adding the cycles or one of the cycles in the visual system,

olfactory system. This one will hydrolyze PIP2, the lipid in the membrane, and produce the IP3 and
or the AG. This is kind of a second messenger. And then IP3 will open the IP3 receptors in the
Membrane. Then the calcium will come out from the. And this calcium, the channel for this taste
receptor cells is [INAUDIBLE]

is TRP channel. Okay? [FOREIGN]

And then the sodium will come in and

depolarize the cell. This is kind of for

the transduction of the signal. Now, [INAUDIBLE]. This step is not really finalized yet

to understanding, okay? Still kind of make some kind of links. How from this PLC beta tube leads

to the activity of this channel. The process, still a lot of study

works on this research, okay? And actually, this kind of general

thing in the field is from the TIP channels are [INAUDIBLE] TIP channel

is changing the receptor potential. This channel is your first, it's cloned

from the [INAUDIBLE] In the eye. Is it because there's some mutation and then the receptor
potential

actually was changed. [INAUDIBLE] Detection. And then, from there, later people found

so important over these TRP channels. Essentially, participate in

every aspect of our sensations. Like the temperature, mechanical,

and observation, and the taste. And other, actually in the brain, we also

have a lot of TIP channels in the brain. They are quite important, okay. So, this field, actually, the
problem is, actually,

how these channels can be gated by this. People still don't know the answer. There maybe about a
few decades of study for this research, but

the answer is not clear yet. Some people claim it may be some kind

of lipid directly inhibit the chain. Then If you hydrolyse the lipid,
then the chain open. And also there's some kind of

the second messenger pathway. And the some actually propose actually

even in the visual tissue in the fly, maybe some kind of mechanical

sensation from this TRP channel. Okay, so for the sour and salty taste,

then it's more straightforward. Just ion channel there, okay? They have the ion channel in the
membrane. And then the acid can

directly go into the cell. Can cause the cell, that's it. Okay. The taste the receptor cells. We talked
about that [INAUDIBLE]. They trace cells that take the signals,

and it then, they need relate the signal or

transmit the signal to the brain right. How can transmit to the brain? These is quite complicated
okay. This systems is I guess actually

is why it takes actually the understanding is so limited. And this actually is quite,

one of the main reasons, actually make the system actually not so

easy to study, for example. The taste receptor cells in the taste bud. One taste bud can up to

about 100 taste receptors. And then those taste receptors

based on morphology and they can be categorized into

three types of receptor cells. Of course there another one

type is not matured one. Because as we mentioned, these cells

regenerate, being regenerated, all right? And some cells may be at

the very early stage, not mature. And then that's called type four, okay? But for these three types,

they are mature neurons, receptive cells. For this one,

this type one receptor cells. And then, they're quite special, okay? What's special for them? They
have a [INAUDIBLE]. This is what [INAUDIBLE] transporter. And also they have NTP. The ace 2. This is
for the transport of the ADP. And then, also they have like an ADT,

for the neurotransmitter NT uptick. So So we know actually in the brain, when you have this lot for

neurotransmitter transporter, then most likely they're [INAUDIBLE]

cell, right. [FOREIGN]

What? Right. Now, for these types of ones, most likely they are [FOREIGN]. Okay? But they actually
may be responsible

also for the salty taste. Okay, quite strange already, okay? Take a look at type two cells,

this is type two cell. Type two cell, the can't express the Z

protein and also the [INAUDIBLE] Five. [INAUDIBLE] what kind of

channel is responsible for the detection of the sweet, umami, sugar. Right? So, these type 2 cells is
responsible for

this detection. [INAUDIBLE]

And that they have this kind of a signaling

molecule expressed within the cell, like receptors, right. They also have the G protein,

PLC-beta-2, and the 3-amino-5. And this is the type III cell. Type III cell is quite interesting. Within the
taster part,

only these cell can have a direct synaptic contact with the axial

from the ganglion cells. So, there was a ganglion cell,

same as the axon too. And only these type of cells can really have a synopsis with. The is actually
[INAUDIBLE]. The thesis the only synapse came before between the receptor cells and fingernail,
process
3.2.9

And these cell are responsible for

the sour taste. And they release. That's a neurotransmitter. And this guy, for the type two cells, they
don't have direct

synapse formations there. But actually, those axons around the ganglion will wrap that quite closely.
[FOREIGN]

synapse. And for these cell propose that they

also release neurotransmitter, ATP. But if they don't have a synapse. So the ATP release,

then you have some trouble. You release all, it don't have a synapse. Then the ATP will diffuse

to here to type 3 cells. And also maybe will act

on these bundles or have some kind of effect on itself. Okay, so take a look. If some company came
to

a signal transmission, how can you study that system, so clearly like it's a vision system or

olfactory system? It's really challenging. For example, we know this cell

responding to the sour taste. But if you stimulate the tongue

with the sweet stuff, this cell maybe also can detect, have

the similar response to the sweet stuff. Because this cell releases ATP. We have some effect on the
other cell. Yet these actually cause the big trouble,

okay? About the taste of the coding. Let's take a look about

the taste of coding. Okay, so we know this is a taste

receptor cell seated here on the tongue. And then you have those ganglion

sends axons in the way to the tongue, but only synapse onto the type 3,

the sour taste cell. And then they will further send

the information to the brain stem. We talk about NST. This is the brain stem. And then we'll further

send to the PPM here. And then to the thalamus with PPM. And then to the cortex. This is a signal
process

along this neurocircuitry. We talk about here is

already quite complicated. The information transmission. If you recall these cells. These taste
receptor cells. Then you will have maybe

each cell will respond to, see it is sodium chloride

then uses it salty taste. And then, this is the [INAUDIBLE]

of the sour taste, right? And the sucrose. So essentially,

if you recall from these axons. These axons from the axons. This is the gastric ganglion cells axon.
And then, if you cut from this one, and then they have detect the salt and sour, and in from this
neuron, also similar. And this neuron then is a sucrose. The history in the field is actually

when people record from these bundles, these axons use the single-unit recording. Or extracellular
recording. [FOREIGN]. They found actually,

these axons actually not only detect one single modality,

that is the bottom line. They detect a lot of chemical

given the modalities. So then, what it tells you. The taste system actually is

not like olfactory system. Those specific line go to the brain. They are mixed signals. They're already
mixed

actually at this region. And then this is actually some kind

of theory about the taste coding. This is kind of three models,

actually two. One is actually they call it

actually [INAUDIBLE] model. That means actually one cell each

offer the taste receptor cell, only detect one type of modalities,

sweet things sweet, bitter's bitter. And sour then sour. And also, the neuro-connection, the ganglion
cell, that axon,

only in the specific to each type of cell. And then this you see

there is label the line. One signal directly go to the brain. But then these two, then it's different.
These two, one is like this. One cell can detect all

kinds of modalities. You'll see these five they can detect. Of course, then the axons,

the signal was mixed. And then another version will be each individual one still

detect only one modality. But because over the synaptic connection,

they mix again the signal. Okay so there are two types of coding. One is to labelled line,

one is actually cross fiber. This cross fiber actually

is similar as maybe in the brain you need to detect that

information, whether it's sweet or bitter. Then you really need to compare

many different kind of axons. The signal not based on single one. Signal one based on this one is fine.
You'll know this is sweet or

bitter, right? Okay, so this is,

we finished this slide, the last one. They did a beautiful study. So we know in the human, we have
this receptor, hT2R16. This is a bitter receptor. T2 family. And then this receptor is supposed

to detect this bitter stuff. Okay, this human receptor, taste receptor. But actually in the mouth
actually
this bitter stuff mouth does not care. [FOREIGN]. Okay did a beautiful work, is actually, they express
this receptor in the mouth. Use the promoter of the T1 and 2 promoter. [FOREIGN] and

also to express use T2R promoter. [FOREIGN]

Beautiful. Now this one is actually the bitter

stuff you put in the water, let the mouth to drink. Of course if the mouth don't like

the water, they will reject, they will not drink okay. Now this is actually

a consumption of the water. And this one, if you express,

this is control, control animal. They don't care about this bitter stuff. But if you express this bitter
receptor in the sweet neuron,

receptor cell not neuron. And then this mouth actually

drink a lot of this bitter water. Why? And then if you put this

receptor into the bitter receptor cell then

the mouth reject the water. Okay, think about how this system works. And based on these results
group believe

this is actually a labelled line. That means, actually the taste system,

the coding of the taste signal, really actually they

are kind of hard wired. That means, actually, this sweet neuron

carries information direct to the brain. Tell the mouth this is sweet stuff. You need to drink a lot. It
does not matter you express

a bitter receptor or sweet receptor. This is a key message. But still, you can argue this

may not be the only explanation. This is a nature paper,

actually conclusion. Yeah, so the taste coding

still a lot of debating there. As we mentioned, when people did the recording they

found the signals mixed together. And the data from this genetic

study looks very clear. Is it labeled or not? But the people argue, this interpretation,

it's not the only one. You can have different explanation

with the same results. Yeah, you can think

about some explanation. Okay, that's it, yep.

Week 4

4.1.1

So in those conditions,

actually, that don't have much assistance to help them to

navigate to [FOREIGN] input. So actually to rely heavily

on the touch sensation. [FOREIGN] A mouse, rat, to navigate without visual input. [FOREIGN]

Okay. Whisker, right? Actually it's a whisker provide actually very

important information for this kind of explore this space. For example, maybe, there is a wall,

or something actually in the front. The risk thinking make it a gentle touch,

and then the animal will know

actually there's something there. [INAUDIBLE] That thing, right? Okay, so today we will talk about

actually the somatosensation. As we discuss, somatosensation

actually include a lot of sense, okay? Including temperature,

pain, touch, of course and some other chemical sensation for example the proton to the exit, to the
detection. And this happens actually on the skin. The skin, of course, actually is

the largest sensory organ in our body. Also maybe internal organ. For example, the heart, the
beating. And also maybe some other, also happen in the brain. Some kind of temperature sensing.
So for this actually, the start is

actually not so advanced, okay? But actually, the main two sensations,

for example the touch and pain, then I represent more at the rate status. So today we're focusing on
the touch and

the pain. As we mentioned, on the touch, we use quite often daily the daily life. For example, these
kinds of surfaces. It's very easy for you to tell which is the glass surface,

which is the stone wall right? Or this kind of surface just

a gentle touch then you can differentiate these three. Also the touch sometimes

actually quite powerful, right. So for the animal, for example, for

the cat, you just touch the head and it then will enjoy actually your touch,

this animal. And of course, this kind of thing Is related to the affection or

the emotion of this animal. It's a very gentle touch representing

maybe the care to this animal. Right. So your care would be

appreciated by the receiver. So underlying this mechanism of course. There bi-directional signaling.
Why especially from your hand? Your touch the animal, the hair and the, sensation from our, and
also from the animal and he will enjoy your touch,
also through the touch sensation. Through this, the hair,

the skin underlies the hair. So, let's take a look. What kind of neurostructure is

responsible for this kind of sensation. This is a cartoon to show all kinds of somatosensory system,
okay? Let's take a look at this one. Of course, this is a hairy skin. Your skin has this hair. And here we
have,

once something like this, this is the hair, and then there this called a hair follicle, and then there is
some

kind of full neuroaxial terminal, here surrounded this hair. And then, this actually will go to the
neuron cell body

located quite far away in this. Those are root ganglia, [FOREIGN]. And then this neuron actually

is send one process out. This is the process. And then we go two directions. Why is go to the
peripheral. In the weight of the hair, yeah? And at the other end of the axiom,

where it goes to a CNS, for example, the spinal cord. For this one, let's take a look. The purple one,
this one. We call a beta fiber. This fiber has the properties,

it's heavily myelated. So the outside actually surrounded by a. [FOREIGN]

And let's take a look at another one. This one,

this one is a little bit different. Also called a beta fiber but I should

say the notation pattern are different. Actually, this one through

the width in the hair follicle. This one then we knows it's

two different structure these structure is called micro cell. This micro cell actually require

special it's just a some flat cells. Here and this flex cell is for the neuron. Very special and

this micro cell actually later people found actually

between this micro cell and this axon fiber there may be

some significant structure. Okay? Very special. And we, maybe we talk about it later. So for this one
is quite obvious, right? So maybe you have a mechanical force. Remove the hair, and then the
sensory input is from this guy,

from this exoterminal. That means in this exoterminal

there is some kind of mechanical state of channel,

so you have the whole move. Maybe a course,

the change of this member and structure. And then the channel. Then we are open. And the end
sewed in and

calcium may be where going to the cell, the cell And

then the fire action potential. And they send it to the CNS. What happens for this region,

[FOREIGN] is the micro cell. They're quite special. People at the beginning think I should
only the axial terminal, the neuron fiber. Actually sends the mechanical force but later people found
actually

maybe this is a micro cell. Also can sense a mechanical force and when they sense the mechanical

force then they will release neurotransmitter and

then to excite these fibers. Okay, this another way of this signaling. And this, a beta fiber, actually
carry the touch inflammation to the CN,

to the spinal cord. For the spinal cord. Then they are the why to the to,

this is called both part. This is the side. And then this is the gray

matter inside here. Like a butterfly. And we called this one,

this is a [FOREIGN]. Of course there are two, a pair. One here and the other one here. And for this, of
course,

there is a range of. This is a.

4.1.2

So for this spinal cord,

for the dorsal part, mainly receive the sensory input, okay? The ventral part, then actually,

there are a lot of those motor neuron. Actually, this is a output neuron,

to control the muscle. Okay, so this one, there are some kind of axon come out from these motor
neuron cell bud [FOREIGN]

to control the muscle. These fibers, these purple are beta fiber. They will in the way to you,

the dorsal horn, okay? This is sensory input and the dorsal

horn actually divided to five layers. [FOREIGN] very clear and then this a beta fiber coming to the
dorsal horn, mainly the layer four and the layer five. And then of course There'll be some, there will
be a lot neurons

actually inside here. We'll make the synapse with this guy and then those neurons will further relay
that sensory information to the brain, okay? And there is a special branch here,

take a look here, this purple neuron going

to the dorsal horn. At the same time, there was, there

are some bright directly go to the brain. They're quite special. So this touch information,

we go to the dorsal horn. And in the same time,

this touch will directly go to the brain. For example, maybe some touch signal from your toe and

they will directly go to your brain. Actually, result any other synapse,

okay, very direct. Of course, from here then they make

a synapse with this dorsal horn neuron. And then, they will relay this

information to the brain, okay? There are two pathways. Take a look another one,

for example, this one. This blue one, okay, let me. So for the skin,

actually there are different layers, okay. It's called, this is a epidermis. This [FOREIGN] and

this bottom wire is damaged, [FOREIGN] and you can take a look. This blue one, [FOREIGN], okay?
But they don't have some other structure. Is it just free ending okay? Unlike these,

they have this structure here, right? But for this, no. Actually, the ending actually

just free in the dermis. And this one may need to, for the temperature sensing, okay? And then, this
information

will relay by those route, ganglion cell to the layer one and

the layer five. Yeah, layer five, one and

five of the dorsal horn. There's another one. Actually, this green one. This green one then
a little bit different. Also is kind of free ending, okay? It's a nerve but this called C fiber. The C fiber
actually is very special. [FOREIGN], okay, and they are very small. Take a look, you can see it

is the rarest thing on fiber. And this fiber carry mostly

the pain information, okay? And the pain information mainly

into the layer one and two. Okay, this is how to, the screen tells you what kind of signal to receive.
And for this one, we also talk about the, we can sense the muscle contraction by this fiber. This is
called a alpha fiber, okay. This one, owning into those muscles. And for this one, The axon quite
large. This is the largest axon among this group. And also, they have the [FOREIGN], but the
projection is quite different, okay. Take a look at their projection,

their projection should be directed into

the middle of the spinal cord or the range of of the spinal cord. As I mentioned,

this region they are not for motor neuron, will control the muscle. So that means actually you have
muscles, the changing of the muscle contraction. And this one, we are relating

information to the motor neuron, here. And those motor neurons

control the muscle. To adjust the muscle contraction, and then that means these pathways quite
fast,

quite direct. That's important because actually

you want to maintain your composure. [FOREIGN], right, and also,

because this fiber is so large, the speed of the action potential traveling along this axle will be fast.
And also,

because it's a high water [FOREIGN]. So their speed is the fastest

among this group, okay? Some of these fiber endings will kind

of surrounded this hair follicle. Some of them actually will go parallel,

like this parallel of this hair follicle. And those actually are fibers actually, maybe are responsible to
[FOREIGN] those information. And then, make your reflex [FOREIGN].
4.1.3

For the skin,

we actually have a two types of skin. Okay, [FOREIGN]. One is actually the hairy skin,

just your [FOREIGN] and the other one, glabrous skin, [FOREIGN] is opaque, something to see the.
Okay, they, for this to type of skin,

of course, actually, the sensory system

are a little bit different. All right. [FOREIGN] Let's take a look,

actually, at the structure, as I mention for the skin,

the wider to the epidermis. This is p. And then, this is damaged. [FOREIGN] For

most of those types, sensation. Mechanical neuron. Actually, it's a way to the [INAUDIBLE]. The
largest one is this one. This [INAUDIBLE]. [FOREIGN] This guy. This one actually [FOREIGN]. The
meter. [FOREIGN],

okay. This guy [FOREIGN] is some

kind of special cells. Actually, it's kind of wrapped many,

many times, and they make the structure. And this fiber,

this is actually the neural fiber, okay? The neural fiber actually is going to

the middle, wrapped by those structure. And this guy, actually kind of located quite deep in the
dermis. And this one, actually, is responsible for

the high frequency vibration of your skin. [FOREIGN]

Detect the information okay. [FOREIGN]

We'll talk about the properties of this cell. And this one is smaller than this guy, there are ending,
here, they are smaller, but actually they are

quite large compared to the other guys. And also, for this one, this structure is quite special, okay?
[INAUDIBLE]

For this guy, actually, take a look. They kind of,

on the surface of this dermis, right? And they actually, they are on this kind of reach [FOREIGN].
Okay. For this one, we talked about actually the hair follicle

receptor surrounding the hair, right? This is the nerve ending. And then, for this axon fiber, as we
mentioned,

there are quite a few different types. And actually, for this structure. There are two types, okay? One
is actually is into this scheme,

from the scheme, then the [INAUDIBLE] actually,

is the frown. Alpha beta then the delta,

then the C fiber, okay? But, for those actual in

the way to choose a muscle, they have a different name,

corresponding it to group one, two, four. They have fiber, actually, quite large. We mentioned it,
right? It's the largest one, the fiber. [FOREIGN] Fiber axle. And the outside is [FOREIGN]. So among
this,

only the c fiber actually [FOREIGN]. And the c fiber, also,

is the smallest one. For the c fiber, we mentioned, actually, mainly responsible for

the pain sensation. And also, the temperature and the each. Also, can be sensed by the C fiber. C
fiber has the free ending in the skin. And for this fiber, and

then they are responsible for the pain. And the temperature sensation. And for a beta fiber, and

then they're mainly for the mechanosensation of the skin. A alpha then is mainly responsible for

the muscle. [FOREIGN] Because the fiber,

the diameter and also the outside surrounded by or not. So, their speed for the spike propagation.
They're different. So, what kind of relation

between the diameter and the cephalic propagation speed? [FOREIGN]

>> [INAUDIBLE] >> [FOREIGN] >> [FOREIGN] >> [FOREIGN] >> [INAUDIBLE] >> Okay. >> [FOREIGN]

>> The simple way would be the larger the diameter, and

the fast the traveling, right? So, for the c fiber, take a look here. C fiber, this bit uses the slowest one,

of course, and then there is about

0.52 to meter per second. [FOREIGN]

Okay? [FOREIGN]

So, based on this information, then you will know. There are two kinds of pain there. Because a beta
carries a pain sensation. And the c fiber also

carries a pain sensation. But their speed are different. Link to your experience. Whether you have
this kind of experience about the given pain. [FOREIGN] So, those are related to the of the action
potential propagation. So, this table then summarize,

actually, the whole information here. And we have a beta It's responsible for

the mechanical and the [INAUDIBLE]

joints. And the beta, this one, is for the mechano sensation,

mainly for touch, okay? And also for

the temperature on the c fiber. And for this actually, it's not like the other system where you really
understand a lot. But for this study, basically,

people study for quite long, okay? It's just actually too much

details inside for this study. And for example, for this site,

for example the fibers, also for the response for this,
they have specialties. Some of these touch, for example, you will have very fast adaptation. Now,
you got [FOREIGN]. That's called adaptation. Here, I guess, actually, for this mechano

touch, we have two kinds of neurons. One is for rapid adaptation. One is for slow adaptation. Let me
show you what I am talking about. There are two waves of pain,

so, if you have a stimulation, and then you will feel basically,

two kinds of pain. The first one, actually,

is a sharp pain, okay? And this carried by

the A delta fiber in your skin. And again, this pain finish,

then you will follow a more slowly developed

[INAUDIBLE] sharp pain [FOREIGN] dedicate the second [INAUDIBLE]

carried by the c fiber, okay?

4.1.4

So, let's take a look about

the [INAUDIBLE] in the fiber's response properties, okay. So for this one, let's take a look, okay? So,
for the touch sensation, they are some of those fibers actually responds to very low threshold this
mechano receptor. That means actually,

you just need a gentle touch and then they can detect it, okay. So this called low threshold

mechano receptor LTMR. And among them this is

actually the mucous cell. The LTMR and also they are slowly adapted SAI that means slowly adapted

take look the list of bones. If you recall from these axiom okay? You'll actually recall the file and then
you give the scheme a push like here. And then you'll record,

recording will show his dead cell. Actually at the beginning of the stimulus

[INAUDIBLE] of an action potential. And then,

maybe gradually decrease the frequency. There is a response stimulus. That [INAUDIBLE] actually,

slowly adapting LTMR, okay? This response stimuli and interpretation and also for this roughly, this
one. For this ,roughly, the ending. They also are similar slowly adapted. But take a look at the other
one,

like this guy. This is with this one. It's this one. [FOREIGN] This line so special, take a look. If you have
stimulus and the at the

beginning and at the end of the stimulus. So during this stimulus actually,

they don't care. This is called rapidly adapted. So, at the beginning you have response. And then the
cell, just quickly adapted

to the stimulation, no response at all. But the way you release stimulation,

again, responding to you, right? These two type of cell of course then,

will response for those kind of gentle touch, okay? But for this cell, then mainly response to the high
frequency of the stimulation,

right? Because they don't care about it's

actually how long you pushed the skin. Because there is a time that don't do

the push, they were not responding to you. Okay, there is another one. This is type one, rapid
adapting,

low threshold mechanical receptor. There's another one,

this is type two for this one. They're also similar. Just as it was responding to the onset and

the offset of the stimulation, okay? For this one actually they

responded to as I mentioned because it is sitting there in

the deep of this damage. They're responding to really high

frequency of the stimulation, okay? And that this one, relatively low frequency of the stimulation,
because

they sit on the top of this ridge here. There is another type of cells called

high threshold mechanoreceptors. That's corresponding to the free ending,

like this green one, green fiber. This guy actually, they need really high, strong stimulation, then they
can respond. If you use this kind of

low intensity stimulation, those neurons will not

give you the response. And also, this neuron actually

not much adaptation to it, right? What's this? Of for pain right? Because under this situation quite
strong stimulation might be

dangerous or would damage your skin. And then this guy will

report to the brain. This is a painful situation you need

to work to protect yourself right? Indeed, this is mainly the fiber. It's [INAUDIBLE] free node ending.
It's correspondent to high threshold,

receptor. It's quite interesting, right? For these three types

of different response properties what correspondent

to make this adaptation. What kind of mechanism responsible for

the adaptation? [FOREIGN] Take a look here. If you recall from this one,

this is the Pacinian corpuscle here. And then if you use a stimulation,

push down and the cell will respond, okay? But during this push the cell

actually will not give any response. But when you release this stimulation,

the cell responds again. Does this property belong to the neuron or

to the surrounding structure? People did a clever experiment. Dissect out this new ending and then
give the stimulation directly

then you can take a look. If we use this push this new ending and the cell that gives the response
during

this push so deal gives it a response. And the thing it release, no response. So what it tells you then,

is this kind of structure, the surrounding structure,

has those kind of properties for adaptation and also for the release

response or for response, okay? But of course that response is

produced by the network fiber. Only the network fiber can

give you the response. But because this structure somehow telling you this stimulation pattern,
okay? Is it a [INAUDIBLE], okay. So this is kind of [INAUDIBLE] cell neuron response properties. As so
we've discussed before,

for a sensory neuron, especially another important

feature is the receptor field. I'll show you how to determine

a neuron's receptive field. For example, in the you when one and then how you would deepen the
stimuli

to the map to the receptive field. >> [INAUDIBLE]

>> The question is actually how to determine a sensory neuron's

receptive field, receptive field. We can take one example

to discuss this issue. For example if you recall from a. And we know center surround

receptor field, right? So, but

at the beginning maybe you don't know center surround receptor field. How you doing the
experiment, how you probe this kind of a profile? >> [INAUDIBLE] in the surrounding area. >> Yeah
good, good so

just actually you try to deliver different kind of the stimulation. Maybe at different wavelengths and

also maybe intensity, around some certain area, and

they check the cell's response. Either the cell will be excited, and

then that's called an on response. If the cell was inhibited

by the stimulation, that also considered a receptive

field of this neuron, right? So this way, we've found actually for

the ganglion cell we have the send us around sometimes in

the center, maybe excitation. They're surrounding, maybe inhibition or

sometimes maybe the opposite way, okay? So to determine the receptive field of

these kind of neurons similar strategy. That's what people did,

actually, from a human subject. And then you can from those fibers, okay? For example,

one fiber actually running into your palm. And then you just actually

use some kind of sharp needle to probe the surface of the skin. And to see whether this neuron can
keep

the action potential firing or not. And by this,

then people found the Meissner's corpuscles If this neuron

is corresponding to this kind of a neuron type and

the receptive field is quite small. What you see is just those tiny spot. But if that fiber is
corresponding
to these is very different. The receptive field is really large and

sometimes covers the whole finger, okay? So that means there should be

different types of neurons. The detection,

spacial detection are quite different. For the kind of quite subtle detection, you need actually quite

some more receptive field. [FOREIGN] Then you need to redefine the

receptive field for the detection, right? If you use this kind of strategy to determine, even the skin,
the region of the receptive field. Then you will have a map about, or actually it's the receptive field,

across the whole body, okay? So you can have a guess on which region

actually has the smallest receptive field. >> [INAUDIBLE]

>> Face. >> Face.

>> [INAUDIBLE] >> Okay, face is still too large. We need to go to the more definite region. The face
that you have is a tongue. You have your lips, you have your nose. You have all those areas, right?
Lips, right, would be quite actually

a small receptive field, right? And also? >> Fingertip. >> The fingertip, right. Yeah, this is what people
did, okay. The [INAUDIBLE] actually, you see okay? So this is actually it's

how [INAUDIBLE] regions. Okay, so

if you have very small receptive field, that means that actually you

can read it differentially. The two points actually are how

far away the two points? Actually, then you can judge, okay? So, for this one,

[FOREIGN] our index finger, they are quite small receptive field,

okay? And also for this kind of region [FOREIGN]

okay? [FOREIGN] These neurons actually, the stimulation is a kind of mechanical stimulation, right?
So then you will think, okay, so how does

this neuron detect this mechanical force? The answer will be,

it's a mechanical sensitive ion channel. They don't just use

the DPKR calcium right? Maybe a mechano gated channel. For this study actually unfortunately

the progress is quiet slow, okay? To identify what kind of [INAUDIBLE]

receptors responsible for transfuse this mechanical force.

4.1.5

The progress is really slow. In the insects, or for

example, in the Drosophila or in people found a lot of channels. But somehow there are no similar

homologue in many system. And then, for

the mammalian mechanical sensory channel. People searched for a long time. And the thing is
actually only one family maybe is really important for the mechanotransduction. So far, people
found this piezos. This quite interesting actually. How you will search for this channel. What kind of
strategy you will use to

find a channel for the mechanosensation? >> [INAUDIBLE]

>> [FOREIGN] You can find a you can recall from one cell. Then you give a mechanostimuli and

you get a response. But you still don't know the receptor, what I mean is you need to

identify the receptor, or the ion channel responsible for

the mechanotransduction. [FOREIGN] If you want to make a bigger discovery, then you need find
some

way to solve this issue. >> You say it's an ion channel, right? >> Yeah, ion channel, right. >> Maybe
we can [INAUDIBLE]. >> Okay. >> [INAUDIBLE]

>> Yeah. >> [FOREIGN] >> Okay. >> [INAUDIBLE] >> [FOREIGN] Okay. [FOREIGN]

Yeah? >> [FOREIGN] >> [FOREIGN] >> [FOREIGN] >> Good, good, good. >> [FOREIGN]

>> Right, right, right. [FOREIGN]. >> [FOREIGN] >> Okay. >> [FOREIGN]

>> This is hard strategy, good. [FOREIGN] Membrane and protein. [FOREIGN] Responsive for the
mechanosensation. [FOREIGN] make the discovery. [FOREIGN]

you could see all nine in there. [FOREIGN] Okay? [FOREIGN] reasoning [FOREIGN]. [FOREIGN] This is
a membrane protein. [FOREIGN] Yeah? >> [FOREIGN] >> [FOREIGN] just detail [FOREIGN] If we lock
down that protein. [FOREIGN]
4.1.6

If you express that gene in the hex cell, [FOREIGN] channel properties. [FOREIGN]

This work is really important, okay? [FOREIGN]

So if you found this [INAUDIBLE] is important channel but here's they are only in their [INAUDIBLE]
does not relates to physiology, right? So you still need actually

examine whether this channel is responsible for

your detection of the touch. So what can you do,

then you need to do to knock out, right? Indeed, actually this group the Piezo2 Is responsible for

the light touch. Just a gentle touch this is actually,

we talk about actually, okay? A light touch could be found

a megacell that could be found, right? Just like you can, [FOREIGN] you get axon as you connect with
that. [FOREIGN]

Now what they did, [FOREIGN]. [FOREIGN] This neuron gives a action potential but when the
[FOREIGN] condition [FOREIGN]. A mucous cell [FOREIGN]

okay? They found actually you can tell this

wild type and this condition in north up. The responses are different, right? This kind of continuous
response here but there's still some

transient response here. So it tells you that actually, light touch can detect by both

the neutral cell and the neuron. [FOREIGN] This is the experiments

of information so for this make a note are channel are mainly in the mammalian system. Right now,
this family Piezo Is

the most studied channels, okay? So for the somatosensation, as we mentioned, we still have

the temperature sensation, right? And for the temperature, and actually, there is another

family called the TRP channel. The TRP Channel. The TRP channel is quite a unique family. You see
they are six transmembering domain protein and

the NC terminal. Both inside the cellular site, this is a channel, okay? So the discovery of this channel,
also as Tanya mentioned. [FOREIGN] Those root ganglion cell, [FOREIGN] mechanical capsizing
[FOREIGN]. [FOREIGN] then they use the cast imaging

to detect whether you apply the sizing. You will get some response, okay? If you found, and

then you can narrow down that data pool. That pool and then you say, [FOREIGN] you will have a
more efficient transaction,

right? [FOREIGN] channel [FOREIGN] capsizing,

okay? [FOREIGN] If they express the [FOREIGN]

channel in the [FOREIGN]. What they found is actually

you use capsizing stimulation, you'll get huge results. At the same time,

if you increase the temperature by 43 degrees,

then you also get a huge response. Now, from here, the data tells you this

TRP E1 channel has dual functions. It can sense the chemical of capsaicin,

it also can sense the temperature stimulation. And through a similar strategy they found

actually another channel called trip M8. Trip M8 is a different channel, okay? They responded to the
constant stimulation [FOREIGN] and

also responded to the main cell. The main cell, [FOREIGN] okay? So, the triple m 8 channel
responded

to code and the main sub, okay? If you express this two together

then you will respond to auto stimulation, so

the temperature sensation. Mainly through the TRP channel family,

okay? So again,

if these two channels doesn't mean they really detect the temperature

of your skin, right? And then the knockout, okay? They knock out for

example when the [FOREIGN] channel here is this is the wild type respondent to the 45 degree.
[FOREIGN] now and then if you have TRPM8 knockout the animal's still able to respond to the 45
degree stimulation. That means TRPM8 not responsible for the sensation but TRPU1 knockout

they lost a huge response, okay? Majority was the response a lot due

to the triple one knock out,also for the count stimulation now [FOREIGN]. Considers coat stimulation
for

the sale and the while type is okay, so we are supposed to

22 degrees stimulation. But not to the triple M8 knock out, so the triple M8 is responsible for

the [INAUDIBLE] .okay? Of course this is in the mouse but

it's quite interesting, okay. There are so

other channels are not discovered yet because, in this radio they have, like only 12 degrees
stimulation. [FOREIGN] You see, all this actually essentially similar, the same. [FOREIGN] That means
there must be

some other channels responsible for detection of these that got

really low temperature. And also, again actually,

for the high temperatures, we still have some here left,

that means maybe some other channels. So people are still current

activity to look for this temperature sensing channel, okay?

4.1.7

We talked about actually as a peripheral. The touch sensation. The mechanical sensory channel,

and also the temperature. Channel. The trip channel. So, with those information,

connect to the peripheral. This is a signal to again,

to send to the brain, okay? The pass way will be from the, there's

no ending to the aorta neuron right? And then will go to the spinal column. Spinal cord,

then you will have two pathways. One is through the second

autoneuron in the spinal cord, then they relay

the information to the brain. But actually, the route,

there is another branch, result in a way to the spine

goes directly to the brain. Right? Okay. So, when those information

go to the brain, let's see, this is the pathway for

the tough. Okay. Very simple. Take a look. This is the spinal cord. This is the DRG, the cell body,
right? It gets the information from the skin, and then it will go to the dorsal home [FOREIGN] then
they relate the information to the medulla, [FOREIGN] nuclear, [FOREIGN] okay? [FOREIGN] Columns
nuclear. [FOREIGN]

Then the information will relate to the somatosensory cortex. [FOREIGN]

So, as we discussed before, so

what are the other kinds? There's an auditory system.

Go to the brain, it will be relayed by the. By.

[FOREIGN] Okay, so these pathway is actually quite straightforward, right? For the pain pathways,

it's a little bit different. Take a look here. This is a pain pathway. Now, the pain information

connected by the neuron. And then, they will again,

enter through the dorsal horn. So [FOREIGN]. But then the information, the neuron will cross.
[FOREIGN]

Spinal cord [FOREIGN] does propagate to [FOREIGN]

[FOREIGN] this too, pass away, keep separate. So, these too pass away had different,

right? Why is actually below this medulla, [FOREIGN] you can touch the sensation, [FOREIGN] spinal
cord [FOREIGN] okay? [FOREIGN]

The doctors can use this information to [FOREIGN]

the patient. Which side the spinal cord [FOREIGN] for example [FOREIGN] [FOREIGN] okay? This is
the pathway to the cortex,

let's take a look at this cortex. Of course, the information,

when they propagate from the DRG to each relay center, the signal already different, okay? They are
different. Already have been processed. [FOREIGN] But

the most complicated processing [FOREIGN] let's take a look at the cortex. This cortex, actually, is of
course,

we talk about actually, the somatosensory cortex [FOREIGN],

okay? [FOREIGN] A cortex. [FOREIGN]

3B. [FOREIGN] 3B [FOREIGN] Primary somatosensory cortex [FOREIGN]. Why? It's because within
this layer of 3b to receive most intense

input from the sediment. Okay?

[FOREIGN] A somatosensory cortex, right? For this cortex,

we talked about it before. How many layers? I'll show you. Cortex [FOREIGN] [FOREIGN]

Six layers, right? [FOREIGN] The cortex. [FOREIGN] Cortex. [FOREIGN] LGN [INAUDIBLE] exactly,
good. So, [FOREIGN]

okay? Good. [INAUDIBLE] Three piece layout to further send the information to this,

region one, and the two, because this is the somatosensory cortex,

right? They send the information to one,

region one, it means the texture of the stimulus,

okay? And the size and the shape, then send it to region two. [FOREIGN] 3a also receives some input
from. We talked about, actually,

the cortex organization before. Six layers, and also,

we talked about actually. [FOREIGN] Okay, so here, similar thing happen. [FOREIGN] Principle. This is
the cortex organization, okay? The principle is actually. Here, take a look. This somatosensory cortex.
[FOREIGN] Colon information. That is actually, for a small region, that is responsible for

similar future stimulation. For example [FOREIGN]. [FOREIGN]

Okay? In the vision system,

we talking about another issue, especially there are some nerves there. A map in the cortex,
actually,

corresponding to the map you see in the retina, that kind of map. [FOREIGN] Cortex [FOREIGN]. We
talk about that, also,

in the auditory system. It's the frequency map. [FOREIGN]

There was a map this one again similar. This one actually the old days actually is the [FOREIGN] a
very famous one. Penfield. [FOREIGN] They need operation. [FOREIGN]
4.1.8

[FOREIGN]

Okay let's take a look, this map, is quite interesting. [FOREIGN] Responsible [FOREIGN] the relation
essentially in the peripheral if you have a lot of receptors [INAUDIBLE]. [FOREIGN]

Representation in the brain [INAUDIBLE] for the most important parts, actually the brain devote a lot
of space, computation, for the function, okay? This reasonable, right? Okay, so this is actually for

the human being, let's take a look about the mouse. The mouse, at the beginning,

we talked about In the dark, the mouse needed to navigate the space,

they rely on their whiskers. [FOREIGN] Now, [FOREIGN] we can image that whisker represents a very
important,

actually. The information to the brain, right? We can take a look about this brain targeting the
somatosensory cortex, [FOREIGN] each single whisker here fiber has a representation of one
column. [FOREIGN] You've got whisker [FOREIGN] that means actually, this whisker is really
important to the sensory structure for this mouse. [FOREIGN] Each single dot, called a barrow
[FOREIGN] okay? So this actually is the study, actually, used quite a lot, this preparation. The barrel
cortex, and [FOREIGN] [SOUND], if you recall from corresponding

pair of the neurons. And you give the stimulation, and then

you can get it to respond from there but if you, at some stage of the development. If you cut one,
some of the whiskers,

you cut off these guys and then the corresponding barrel

will occupy by the other whisker. [FOREIGN] There's a bigger plasticity, okay? Okay, so I guess there's
lots of point I want to

talk actually is the pain regulation. Now this is important, okay? So, of course, this is for clinical also. I
guess it's most people Extension everyone maybe has experience, that is usually, [FOREIGN]

>> [INAUDIBLE] >> [FOREIGN] So woman [FOREIGN] like a neuron. That neuron can respond to both
the pain

information and the touch information. Pain is through the C fiber and

the touch is from this alpha or beta axon. Of course, the c fiber carries

the pain information but if you stimulate at the same time,

this a alpha and a beta fiber. Somehow, this information

can be inhibited, how? That actually is a proposed mechanism,

there is an inter neuron here. [FOREIGN] Also receive the input from this touch neuron but

by excitatory synapse. [FOREIGN] And this receives

inhibitory input from the C fiber and this neuron also inhibits

this projection neuron. [FOREIGN] If we only have the C

fiber pain information coming in, the pain C fiber inhibits this neuron, but at the same time excites

the adjacent neuron. And that the information will

actually go to the brain without no inhibition because

you're inhibit this neuron. This inhibition release

the cellular excitation [FOREIGN] but when you have another fiber, this fiber touch fiber, activate it.
But this fiber actually will act and excite this one [FOREIGN] of course there is other pain regulation.
[FOREIGN] If they will inhibit those pain neurons with this glutamate and then you will have the
[FOREIGN]. Now, the important pathway

actually is this guy. [FOREIGN] Spinal chord [FOREIGN] information [FOREIGN]

4.2.1

Today we talk about

actually one of the most fascinating copy, that's sleep. Sleep actually, I guess actually a lot of people
have interest how the sleep happened, and why did it happen? But this is not actually so

advanced, okay? It's difficult for this kind of study

compared with the other sensory system. Actually, for example, for human study,

study sleep is quite easy, right? You just actually use imaging of the brain electro-recording is from
the EEG recording and then studied for quite a long time. Especially the chemical boxer,

studied sleep quite a lot. And that's actually most

of our understanding. About the sleep,

it's coming from those studies. So in the animal model,

the research actually is quite sparse, okay. So not so

many study focus on the animal model. But of course for

the making us understanding. You need to study the animal model. No, it's just a human behavior
study. So for the sleep, as I said, it's a really fascinating topic. But the understanding, right now,

is not so out of range. Therefore, a lot for open discussion we can have, for this lecture. So, I guess,

the first thing is what is sleep? You have your own answer, right,

everybody has interpretation. Xiaoyu. What do you think? What is sleep? >> [INAUDIBLE] >> Okay.
>> [INAUDIBLE] >> Thank you. >> So, imagine it's a state and with less sensitivity, to the sensory
input, right. >> I guess. >> Okay, [FOREIGN]

>> [INAUDIBLE] every night, when we close our eyes and the outside from the outside world.
[INAUDIBLE] condition where you cannot control our body, and [INAUDIBLE] actions in our brain
[INAUDIBLE]

>> Okay, [INAUDIBLE] mentioned there is a state, and then dimension is actually a behavior. It's a
dynamic change

of a serious behavior. I guess this definition actually

is more close to describe sleep. Sleep is actually a behavior, okay. It's actually a very dynamic
process. It's not just one state there. It's a series of states and

it changes among each other, okay Of course then one of the things sensory

input, then the sensitivity's quite low. [FOREIGN] >> [INAUDIBLE] >> I rest, okay. >> It was on the
[INAUDIBLE] of the brain,

they need to rest or they will, or

they're function will be defective. So I think, [INAUDIBLE]

>> So, [INAUDIBLE]

mentioned, sleep is actually is away to let the brain to recover from kind of some states to how I rest
especially and then wake up then can be refreshed. One function maybe related to the sleep. So we
still have a lot

of things to discuss. For example, when to sleep,

how to sleep and why to sleep. How, from this of course it's. But then the thing is

how the neuron control this sleep is what I've meant, okay. So when do you sleep? When you feel
tired you try to sleep. [INAUDIBLE]

>> When I want to sleep and I'm allowed to sleep. >> What? >> [LAUGH]

>> [INAUDIBLE] >> Okay, you're right. So it's good. From this I expected you would mention it. The
thing is that sleep is controlable. Altough you want sleep, it's not allowed. From example, from this
lecture. And then you can fight for

the need to sleep, right? And in most case when you want to have sleep, Of course it's according

to your body reason. And the sleep will not happen anytime,

right? For a particular person, maybe have a special kind of schedule,

everyday schedule. And for that schedule you almost you have kind of fix time for the sleep and also
for the waking is the same. Your sleep will sometime take

will automatically you wake up. Right, okay, so for the sleep, then what's the neuromechanism for

the sleep? Of course, right now you don't know

just based on your imagination, or your knowledge learned

from pure studies. So, how do we sleep? >> [INAUDIBLE] >> [FOREIGN] Right. >> [INAUDIBLE] >>
[FOREIGN] that's a physical, [FOREIGN] neural mechanism. [FOREIGN] Already some chemical? Okay,
feels tired or sleepy right, okay so,there's one way you can have some chemicals produced in the
body and then control your sleep. Okay next one. >> [INAUDIBLE] >> Okay, okay. [FOREIGN]
4.2.2

>> [INAUDIBLE]

>> So, you think that there is some

specific neurons in the brain. They are responsible for your sleep, and those neurons when they
activated

then you will feel sleepy. >> [INAUDIBLE] >> [INAUDIBLE] >> Okay, maybe there is another type of
neuron, they are responsible for

your weakness. But then, when the receiver

inhibitory neurotransmitter or modulator, then the activity disappear. Then you will fall asleep,
okay? >> [FOREIGN] >> [INAUDIBLE] >> Okay, good, so you mention one interesting thing,

actually when you finish your eating,

then you feel sleepy, right? So, that means that actually somehow

sleep relates to your feeding. If you are very hungry,

can you fall asleep? If you're really sleepy,

you won't go to sleep. But then you have not,

you are very hungry. [FOREIGN] What will you do? You sleep or stay awake. Then you said opposite,
right? >> [FOREIGN]

>> [FOREIGN] >> Right, right. >> [FOREIGN]

>> Good. >> [FOREIGN] >> [FOREIGN] >> [FOREIGN] >> [INAUDIBLE] It's achieved by certain
circulation, it's the expression of several proteins, and it's one thing if it's genetic, as genetic can-

>> Yeah. >> Possibly. >> [FOREIGN] >> Okay. >> [FOREIGN] >> Is a internal, for example to a service
rush hour, as well as these things to find some neurons as well, called us to give us information that
we should see at this time

>> So, the carbon dioxide, when you go to sleep, how it can be reduced during the sleep? >> When
you reduce the physical behavior, which will-

>> Activity, you mean. >> [INAUDIBLE] Several

[INAUDIBLE] Maybe it's. >> [INAUDIBLE]

>> Okay, you mean that carbon dioxide is in

your wirement, or in the blood? >> In the blood. >> In the blood, all right. In the blood,

then you reduce your activity. Then, you think actually the carbon

dioxide can be reduced, okay? How about the clock? Circadian reason, how does it relate to the
sleep

you mentioned in the first point? >> It's. [INAUDIBLE] >> Mm-hm. >> [INAUDIBLE] >> Right, right,
right. This is fine. There is a clock we know, circadian clock. >> Yeah, right. >> But
then how the clock relate to the sleep? >> [INAUDIBLE]

>> Okay, then you can have an answer either late,

so how about the next one? >> [INAUDIBLE] >> Okay, [FOREIGN] >> [FOREIGN] >> Okay. >>
[FOREIGN] >> [FOREIGN] >> [INAUDIBLE] >> [FOREIGN] Right, right, right, okay. >> Yes, it's basically
synchronization

of the actual activity of the neurons, [INAUDIBLE] and how this is controlled by

the distribution of different categories, different chemicals, or neurotransmitters. >> Mm-hm. >> I
think there are many categories,

and I [INAUDIBLE]. And A stand for

the activation [INAUDIBLE]. >> Okay.

>> [INAUDIBLE] From each area of your brain. For example, while you're sleep, the motor

activity of the body is totally inhibited. But I mean, the still area of

your brain that is reactive. >> Reactive. >> Reactive when we are awake. >> Okay, okay. So the point
is the sleep is between, it's a balance between two opposite needs. One is actually maybe arousing.
One is maybe sleep. So these two states, you mean activation? What is inhibition, right? >> What are
the different

chemicals that are responsible? >> Okay, okay, so,

you talk about actually, there are a lot of neural transmitters,

ten neural modulator in the brain and when they are they achieve a balance

between the activation and the inhibition, then you will

modulate to the sleep and awake. That's the model you mentioned, right? >> [INAUDIBLE] >> Okay,
okay. Good, okay. Yeah. And the next one.

>> [INAUDIBLE] [INAUDIBLE] [FOREIGN], you are not speak at all. >> Yeah.

>> So I think it actually goes signal or the mechanism that

controls the [INAUDIBLE]. >> Mm-hm. >> Or may it only last for

a certain period. >> Okay, okay. So, the point is actually,

they should related it to neuroactivity. Of course, we mentioned

neuromechanism underlying sleep and awake, shouldn't be controlled

by the neuroactivity. Neuroactivity, of course,

then modulated by the neurotransmitter or neuromodulator. Yep? [FOREIGN] >> Yeah. >>
[FOREIGN]

>> Yeah. >> [FOREIGN] >> [FOREIGN] >> Okay, okay, yeah, that's a good point. Sleep is, as we
mentioned,

is controllable. Yeah, is a behavior controlled

by the nova cistern? Then, of course,

then these kind of behavior, then you can resist for the sleep. Even if you feel sleepy. But actually,
this behavior is difficult

to control under some circumstances. For example, if you can resist to not to eat or drink. That's fine
until someone die. [FOREIGN] >> [FOREIGN] >> Yeah. >> [FOREIGN]

>> Good. [FOREIGN] >> Mm-hm, mm-hm, okay. Yep, so this. In short, sleep is a behavior, okay? It's a
behavior. It's a very thalamic process, okay? And, also,

it's under the control by its brain. There's no doubt, okay? It's quite interesting, right? So, we spend
almost one third of our lifetime in sleep. And what does sleep do for you? What do you gain from
this sleep,

why do you spend so much time? And actually, essentially, every animals sleep, okay? Especially you
consider for human beings. Okay, we sleep. With how we sleep,

there's not much danger for human society. But for animals, some of the animals,

actually, really dangerous. If they fall asleep and

there may be some predator will catch them and then there's a life or

death situation. So, you don't want, actually, stop trying

to sleep, or to risk your life, right? But, it's ideal to sleep.

4.2.3

So what's the function of sleep? So I guess all these kind of quite really interesting questions related
to sleep actually there are many disorders. Because sleep is so important for us. Although, we don't
know

actually what sleep do for us. But it's important, we know. You cannot fight for

the sleep under some conditions. There are a lot of problems

associated with sleep. For example, this one. [FOREIGN] Of course, also there are some kind of
problems associated with sleep. [FOREIGN] >> [LAUGH] >> [FOREIGN] >> [LAUGH] >> [FOREIGN]. >>
[LAUGH]

>> [FOREIGN] >> [FOREIGN] >> [FOREIGN] [FOREIGN] [LAUGH] [FOREIGN] Let's take about the
animal kingdom. Some kind of quite

interesting sleep phenomenon.

4.2.4

For example, some animals can sleep

when they don't need lying down. They can stand and then sleep [FOREIGN] zebra. [FOREIGN] So
these two zebra actually they are sleeping. [FOREIGN]

Okay, now why they need to do this? [FOREIGN]

Sleep for the animals. Sometimes, actually is

a really dangerous timing for them because if you fall asleep, and then your sensory input and

the sensitivity is really low. You don't know what happen in

the environment maybe some animals will attack then, right? So for this, if the then maybe easier for
them o run away when they

suddenly realize something. [FOREIGN] For the sleep there was another quite interesting animal, it is
the dolphin. What's special about dolphins' sleep? [FOREIGN]

Dolphin sleep is quite interesting. [FOREIGN] dolphin [FOREIGN] Now anyway [FOREIGN] approach.
[FOREIGN]

These are actually maybe face actually upside and the [FOREIGN] okay. Keeps the eye open and
receive the eye, the input the visual input and

also control the body to float there. [FOREIGN] There's another

quite interesting one. [FOREIGN]

[LAUGH] The most interesting animals, I guess it is a migrating bird [FOREIGN] that means they can
eat and sleep in the air. [FOREIGN] Okay? Yeah [FOREIGN] [FOREIGN] You cannot differentiate it's a
sleep problem or actually over activity [FOREIGN] okay? [FOREIGN] Find a way to

sleep [FOREIGN] okay? [FOREIGN]

4.2.5

What controls the sleep? [FOREIGN] Okay, that's the circadian clock, can control your sleep.
[SOUND] There is another factor to sleep. [FOREIGN]

You have found the second day sleep will last longer. [FOREIGN]

back to normal. [FOREIGN] This is a process [FOREIGN] circadian clock. [FOREIGN] This curve alerts
[FOREIGN] circadian clock. The circadian clock control

your body temperature. [FOREIGN] This is why the circadian clock is a 24-hour. [FOREIGN] biological
clock. [FOREIGN] circadian clock synchronizes. [FOREIGN] circadian clock. [FOREIGN] clock, reset,
synchronize. [FOREIGN] This one is just like the circadian clock. [FOREIGN] circadian clock. [FOREIGN]

Another one that we talk about, actually, sleep. [FOREIGN] body temperature, body hormone.
[FOREIGN] We'll talk about, actually, the stages of the sleep. [FOREIGN] Sleep is a rather

dynamic process of behavior. Now, a series of steps, stages, okay? [FOREIGN] This one, where you,
Just prolong the most

important sleep stage, okay? [FOREIGN] Let's take a look

at the circadian rhythm. Now, circadian rhythm, this is the time, six. [FOREIGN]

Now this vertical axis. [FOREIGN] This one is temperature. [FOREIGN] [FOREIGN] The body
temperature. [FOREIGN] Circadian rhythm. [FOREIGN] Important physiology function,

okay? How can you execute this kind of control? We don't know yet, okay? [FOREIGN] Now
circadian. [FOREIGN] This one [FOREIGN] body temperature, the [FOREIGN]

okay? [FOREIGN] Okay. [FOREIGN] So that tells you the circadian rhythm really can control the sleep,
okay?
4.2.6

Now circadian rhythm in the memos happens in this region [FOREIGN]

okay? [FOREIGN] In individual neuron, there is individual neuron is a clock. [FOREIGN] That clock is
controlled by those clock [INAUDIBLE], that clock [FOREIGN] oscillation. Then oscillation is about 24
hours, okay? But, these cells actually,

you also receive the visual input. Later, we talk about this,

it's a ganglion cell [FOREIGN] ganglion cell,

send the input to the brain, okay? So data input can also go to SCN,

especially those ganglion cell are expressing that. [FOREIGN] Neuron [FOREIGN] synchronizes them.
[FOREIGN] This one, SCN, is the core clock in the body [FOREIGN] it's a neural mechanism.
Synchronized, all these clocks [FOREIGN] comes from the retinal input [FOREIGN]. Of course, there's
some other mechanism, for example [FOREIGN] there is a communication. [FOREIGN] For the sleep
study the most frequently used is this one, it's the EEG. [FOREIGN] The two parameters, that one is
the frequency [FOREIGN] frequency. The second way, why is the amplitude, [FOREIGN] new activity
under the scar, in the neuron [FOREIGN] neural activity. [FOREIGN] [FOREIGN] High frequency
[FOREIGN] just a [FOREIGN] [FOREIGN] Yeah, that's the interpretation of this signal. Let's take a look,
if you use this strategy [FOREIGN] that's quite impressive, okay? [FOREIGN] There are two kind of
patterns, right? [FOREIGN] reason [FOREIGN]

reason should be [FOREIGN] okay? [FOREIGN]

From the transition from the awake to sleep, you will enter the stage one, [FOREIGN]

so that's the reason [FOREIGN]

okay? And if the doctor makes a noise [FOREIGN] okay? [FOREIGN] Okay, then the TI stage,
[FOREIGN] the activity at different [FOREIGN] complex [FOREIGN]. Okay, now, [FOREIGN] deep sleep.
Deep sleep [FOREIGN]
4.2.7

[FOREIGN] Slow wave speed, SWS [FOREIGN]. Okay? [FOREIGN]. Restless legs syndrome [FOREIGN]
[LAUGH] [FOREIGN]. Stage 2 [FOREIGN] sleep [FOREIGN] stage [FOREIGN], okay? [FOREIGN] This
cycle from long range sleep one, two, three, four, two to the REM sleep. Takes about 19 minutes
[FOREIGN]. Now [FOREIGN]. The important things are this slow-wave stage sleep. [FOREIGN] REM
sleep.

[FOREIGN] EEG monitor, the stage of the subject when they enter to the brain sleep stage, then
you're waking up [FOREIGN] REM sleep [FOREIGN], okay. [FOREIGN] The same

compensation will happen. [FOREIGN] Okay. [FOREIGN]

Slow wait with sleep and the drain sleep's critical

component in the sleep. Only this EEG,

the information it's difficult to relate to the individual

neuron activity. But actually this assay is quite powerful. [FOREIGN]. So, people try to relate this kind

of EEG to the single neuron level. [FOREIGN]. Now, this is one of the study. [FOREIGN]. This is neuron
activity, okay. If you see a line here, that means,

actually, one action potential. [FOREIGN] activity excitation. So in [FOREIGN] downstate [FOREIGN].
This is a summary of

the study about the sleep. And as you can see this is the wake stage, the behavior one. These a wake
stage [FOREIGN]. Now this is long REM sleep,

there are four steps, right? One, two, three, four. [FOREIGN] Now take a look, this is the EEG
[FOREIGN] wake state. What's the pattern? Alpha and beta right? And if you go to this rings slow
wave state then there is a [FOREIGN]. Rem sleep. [FOREIGN]. >> [INAUDIBLE]

>> Very close to the wake state, right. [FOREIGN]. Neuron activity in the brain, quite active. Now let's
take a look at the sensation. [FOREIGN]. During the sleep stage, [FOREIGN]. How their attention,

is sensitivity, [FOREIGN]. Okay, [FOREIGN] REM sleep, [FOREIGN] sleepless [FOREIGN] Okay?
Paralyzing them. [FOREIGN] That's I guess, that makes sense, right? Because actually during the REM
sleep,

actually there is a lot of dreaming. [FOREIGN]. Because you can paralyze

[FOREIGN] [LAUGH] [FOREIGN]. Okay, these use EEG. We can read the sound to dissect the sleep
stage. Let's take a look. We mentioned actually the Dolphin

can sleep on one half of the head right one hemisphere. Lets take a look this

is the dolphin sleep. This actually is right side and left side of the EEG recording and then this is the
wake

state [FOREIGN] okay? Now then you can take a look at this one. It's during the sleep. The left right
now is awake, right? [FOREIGN] [FOREIGN], right? So the EEG can really tell you

something about the sleep, okay? Now [FOREIGN] at this stage [FOREIGN] This is the sleep cycle.
[FOREIGN]. During seven to eight hours sleep you
maybe have a four to five sleep cycle. Each cycle lasts about 90 minutes, okay. Now [FOREIGN] long
wave sleep, REM sleep [FOREIGN]. During the first cycle, [FOREIGN]. We needed to know what's the
real neural mechanism for this sleep. And actually there are a lot of studies
4.2.8

So this is actually one summary

of all those studies okay? So let's take a look, so. The studies suggest actually

that two controlling systems. One is a waking, [FOREIGN] arousing [FOREIGN] okay? There is another
sleep center pass way [FOREIGN] [FOREIGN] Ascending arousal system. [FOREIGN] sleep promoting
area of anterior hypothalamus [FOREIGN] okay? [FOREIGN] There are many, we talk about
[FOREIGN] many neurotransmitter in what would the, in the sleep control, okay? Now this includes
the [FOREIGN] serotonin [INAUDIBLE] promoting neuron [FOREIGN]. Okay, now, close look at the
brain stem [FOREIGN] neurons which side to go TMN. [FOREIGN]

Around the neuron, the neurotransmitter, where you chief [FOREIGN]

okay? [FOREIGN] Control the sleep [ [FOREIGN] You feel kin of drowsy, kind of sleepy. [FOREIGN]
Sleep [FOREIGN] there are two states, one is awake, one is sleep, right? [FOREIGN] a mutual
inhibition [FOREIGN] neuron [FOREIGN] [FOREIGN] Free tongue, get used to that, okay? Now, in the
early days what

you can do is actually quite challenging to do

this kind of research. [FOREIGN] You may actually put that in that actual here [FOREIGN] slow weight
within a sleep, the pattern. [FOREIGN] Okay?

[FOREIGN] Your brain sleep [FOREIGN], slow wake state [FOREIGN] this early study actually used this
kind of strategy or uses addition, [FOREIGN]. These actually are not clean method, okay? If we use an
electron simulator here [FOREIGN] now, at this stage there's some really cool tools available. For
example, channel [INAUDIBLE] genetics [FOREIGN] you can specifically express for example
[INAUDIBLE] neuron. [FOREIGN]

These tools are much cleaner [FOREIGN] and at this stage we can make a lot of progress in
understanding this system, okay? [FOREIGN] Indeed a lot

of exciting research actually devoted to this kind of study. There is another [INAUDIBLE] this is
FOREIGN] activate this neuron [FOREIGN] yeah. >> [INAUDIBLE]

>> Okay, there are different tools available for probing this kind of

neural section mechanism. You can either excite this neuron by

a light or inhibit this neuron by a light

4.2.9

There was a model, actually,

summary about those studies. That is a, we have two systems, right? One is actually sleep

promoting region vlPOA. Those neurons expressing GABA. And we also have a brain stem or

forebrain arousal system. Those neurons actually

promote the wake stage. [FOREIGN] many neurotransmitter,

for example, acetylcholine. [FOREIGN] We talk about actually to have mutual inhibition, right?
[FOREIGN] You can see, with this process, you have the cross inhibition,

mutual inhibition. [FOREIGN]

If this GABA neuron is very excited [FOREIGN] right? [FOREIGN]. So this one is really good, actually,
for deep sleep and waking switch. So you'll remember

[FOREIGN] Flip-flop model. [FOREIGN] What's the problem? [FOREIGN] Model. [FOREIGN]

Sleep and waking. What's the problem for this model? [FOREIGN] [FOREIGN] [FOREIGN] go in the
dark. [FOREIGN] Orexin. How do you get orexin? [FOREIGN] Sometimes a neurotransmitter or

a neuromodulator trigger receptor. [FOREIGN]. Okay, that's good. Next, put all these together,

then new ways link all those kind over duration experience,

actually have a nice explanation. [FOREIGN] So we have this sleep and waking flip and flop, right?
And this one vlPOA is a sleep

promoting SWS-on region. And this arousal system,

of course, for arousal. So there is another one, it's this one,

another group of neurons. It's just a hypothalamus [FOREIGN] okay? These are orexinergic neurons.
[FOREIGN] You got neurotransmitters. [FOREIGN]

Trigger arousal system. Right [FOREIGN] arousal system. [FOREIGN] Trigger arousal system.
[FOREIGN] neuroactivity [FOREIGN] metabolic activity [FOREIGN]. Okay [FOREIGN] trigger arousal
system. [FOREIGN] orexin system. [FOREIGN] each inhibition. [FOREIGN]

trigger orexinergic neuron. [FOREIGN] circadian clock. [FOREIGN] That's because your hunger signal
activate this orexins neuron. An orexin neuron then

activate this arousal system. [FOREIGN] Right, that makes sense, right? [FOREIGN]

Okay, I guess that's all for the sleep study, yep. [FOREIGN]
Week 8

8.1

So let's get started. So this, I guess, is the last lectures for

the whole course. So today we'll talk about the gene and

the behavior. This is a big topic, okay? Talking about the behavior, it's very complex actions recruit

from the whole body. But then we need to think out actually, what kind of gene you

want in this behavior. This is quite challenging. Because as you remove the behavior's

actually not only involve with one single gene. Actually they need a couple of many,

many different genes, all right? Let's take a look the behavior. This photos actually for the left. For
this side,

there is a dog hunting for a bird. Okay? This is in the dark. Actually the dog carries because

this is kind of an experiment. Actually carry that fluorescence

actually device and then you can track how the dogs

actually move in the dark. Then this is the dog and this is a bird. There you can see the dog

actually knew this attack. Follow this trace of the odorant or chemicals from this bird. We know
actually that dogs

have a very acute sensitive olfactory system to detect

these kinds of cues. In comparison, a human,

actually, we don't have so sharp olfactory system,

compared with these dogs. One reason is actually because it's a dog. So actually, always, the nose is
so

close to the to the ground, and the most chemicals,

actually, are the source. It's actually from the ground,

okay, right? So [LAUGH] then this one,

there is actually a, A person, So the vision was blocked. And just to mimic the dogs behavior. And
very close to the ground

is the nose and then also there is a kind of odorant choice. This white line. You can see actually,
quite interesting, the movement of this person

actually is also kind of zig zag. Why?

Why are they moving in this kind of direction? So, the task is actually

to maybe use this cue guide is a person actually

to find a target here. But the point is why you should

follow this kind of zigzag movement. The dog's of course

actually is much larger. Any reason for this one,

for this kind of behavior? >> As a close data [INAUDIBLE] and the smell is stronger. >> Yes >>
[INAUDIBLE]

>> Aha >> [INAUDIBLE] the smell is stronger. >> Yep. This is a very good point. So because actually
these

kind of direction cue. So the direction cue is actually, you

need to follow the highest concentration. Then you know actually the sources

along this line, right? But how can you know? The concentration is highest at

the particular location, you don't know. You need to make a comparison. So you need to move
around and

you find an area. This direction is actually

the strongest one, right. Then you will follow this direction. So that means you need, actually you

make a comparison during the tracking. Clear, right? Okay. Apparently, it doesn't matter human or

dogs. They use similar strategy. To detect the chemical cue. I guess this also is quite familiar

maybe behavior to everyone here. This actually is the quite

interesting right? For the ducks,

when they hatch out from the eggs, people found actually,

it's the first moving target, it's their parents, okay? [LAUGH] What's that mean? It's actually, These
ducks actually just hatched out, and then if they saw a moving target, it doesn't matter it's a dog,

or cat or duck, most likely they will believe

that target is the parent, okay. So of course in the most of case. Is it is actually the true

biological parent. Up hear actually update alright. So they follow all the time. And that. People do
the experiments is

actually you see a person, actually the ducks just

follow him to everywhere. Just actually follow the parent. Because actually before they hatch,

this person actually sit in front of those eggs and

when they hatch will solve the puzzle. What kind of gene or nuerocircuitry controls this kind of
behavior? This kind of behavior actually

It's quite interesting right? So they do not need to learn, okay. Actually, when they were born and

they have this kind of behavior that means this behavior is kind of genetically

determined or programmed. Already when they're born and

it is neurocircuitry. Wild is just specifically for

that kind of function, right? We also maybe mentioned

in our lectures before, some animals actually can

sleep with half brain. They can one half for

the brain's sleep and the other half is awake and that for biological significance is that they need to
be a well of the danger okay. So for example, like this kind of

behavior, actually for this duck. They can sometimes, if you notice, they

can one eye open and the other eye closed. Another thing, actually,

one half of the brain is resting. The other one, of course, is actually

alerting, looking for the dangers. And also we mentioned actually last time,

actually the dolphin is similar. Dolphin because they actually

need to breathe and then they will actually when they sleep

they will open one eye and also, Looking for the dangers and

also floating on the water. And then, the other eye closed. Of course, in this case, the brain,

actually, this is the opposite. The open eye, the opposite brain,

actually, to this side, okay? This is, if this is the left eye, then the right brain is alerting, okay? It's
awake. And then this side, the open eye

side of the brain, they're in rest. So this kind of behavior of

course we still don't know what's the gene determining this function.
8.2

Determine dysfunction. Let's take a look at another one. There was a called Bruce Effect. It's a very
famous effect. What's Bruce Effect? Actually, it's this lady. That is actually in 1959, she noticed that
pregnant mice will abort if they're exposed to

another unfamiliar male. What's this mean? It's actually, if one mouse, actually female mouse

already carried a baby, and then if there was a another intruder, went in to this colony by a male
mouse,

and then, there was a program actually

built in the newer system. And then will trigger the abortion of these pregnant female mouse. This is
called the Bruce Effect. And then, people found later actually that Bruce Effect actually is cost to buy
the olfactory cues, his chemical cues. That means actually another intruder

male carries some kind of a smell and chemicals, and

then this female detected and then will go through the olfactory

signaling, and then detect that signal, and will go to the brain, and

then control that behavior. Is actually is controlled

by the animal you serve. It's the female controls

this behavior by herself. Later, people found actually also the Bruce Effect in the monkey. It's is a
trove, a science paper. Over there they should be in the colony, in the monarchy of course

it's a hierarchy, a dominant. [FOREIGN] The dominant male in this colony actually has all the power
to mate with a female in the colony. And there is a observation

if this male is weak and there was intruder,

another male coming into this colony and the previously dominant male, actually, if you cannot win
the fight

with another male, then there was trouble. And that means actually he

will give up this colony, and then the other one would take over. And when the other male monkey
take over this colony, and all those pregnant female monkey will, how is it, abortion, okay? This is
quite interesting. Why they needed to do this? It's not actually did a mayor

force to do these thing. Again, those actually are behavior

controlled by the female. Of course this one, he could argue that's because for this one they can
save the energy to not waste any energies for breathing those kind of young baby from the
previously father. Because actually you and those baby monkey grew up. And then, the new father
will kill

all those other young animals. So in this case, and you waste a lot

of energy or resource from the female. Because you kind of maybe have a long time

pregnancy and then the baby come out. And then, was killed by the new father. Then, it's just a
waste. So in this case,
as you do in the evolution, the monkey developed

a program called Bruce Effect to control this fate by then served,

by the female, by the mother. I forgot some quite while

your touching behaviors, for example, for the elephant, if they found, actually, a dead one, they will
stop there for

quite a long time. And sometimes you can see

the tears maybe come out. This is really called emotional goodbye. So what controls this kind of
behavior? It's quite interesting, I just show

a couple of these kind of behaviors and then we still don't know

actually most of the genes and [INAUDIBLE] to control

these kind of behavior. So talk about this one,

then what's the behavior? What's the definition of the behavior?

8.3

[FOREIGN] >> [INAUDIBLE] >> Stimulus. >> Okay. So, the cause is internal or

external stimuli. Right. >> Okay.

And the response is either a behavior or emotion. So Okay. And do you think this behavior

is controlled by the gene or by the environment. >> [INAUDIBLE] I think it must

have a genetic component. >> Okay. >> But in these African [INAUDIBLE]

and see this [INAUDIBLE]

>> Okay. Naturally to define what's a behavior

actually is quite a challenge. Actually it takes a long time

[INAUDIBLE] in the field naturally. A lot of debating, okay. About [INAUDIBLE] debating. What is
behavior? And Michelle,

you mentioned a couple of points. Those are important points,

okay, Let's take a look. Some of, of course,

this kind of definition. You can find that it's not perfect. There's no any perfect definition for

behavior. But there are a couple of them. Externally visible activity,

of course you can see behavior, right. A coordinate pattern of sensory. You need a sensory because

you detected a stimuli. And of course you need a motor system. You can choose this kind of
movement. And associated neural activity

responds to changing condition. Now the condition The conditions

can be internal or external. And they're [INAUDIBLE] similar. [INAUDIBLE] similar. But behavior has a
genetic basic for

this one. Right. And [INAUDIBLE] to natural selection

because maybe for survival. Right? Be mortified by. You see okay, this is more kind

of elaborate definition, okay. Of course there are some other

things we need to pay attention. So actually,

it's the activity of an organism. And [INAUDIBLE]. So, stimulation. This is [INAUDIBLE]

organism [INAUDIBLE]

body. [INAUDIBLE]

Organism. [FOREIGN] Behavior can be defined as a way an organism [FOREIGN] The simplest one
What animal does. Okay, so this is important. So we talk about it actually uses

a whole organism to the response. Okay, so in a hot summer day [INAUDIBLE] [FOREIGN] Your body
detect those temperatures right. Too high temperature and they trigger your [FOREIGN] this
behavior. You think it's a behavior, right. This is behavior. The behavior definition is
difficult draw in mind. But if we take this kind of thing as the definition for a behavior,

then this wedding is not that behavior. It's just a reflex. [FOREIGN] It's not a behavior, right. Look,
what if we take this seriously. Think about it, okay. Sweat needs to know that behavior,

I called into this definition. It's a man's question of behavior,

not a single if. Choose Hannah you'll find a tree, there's shadow there. Then you move to the
shadow. And then this is a behavior. It's response. It's in the organism, okay, yeah. [INAUDIBLE]

>> Okay good. Just individual,

just a whole organism [INAUDIBLE]. [FOREIGN]

Reflects. I guess this can be debatable. What is behavior. >> [INAUDIBLE]

>> Okay. Good, good. Yep. There would be more strict definition. Yeah, in the brain, those kind of
control. Then actually we will be more elaborate,

the action. [INAUDIBLE] do nothing in our body, [INAUDIBLE] does it

belong to the behavior. >> Do you think so, thinking, is that behavior. >> [INAUDIBLE]

>> Yeah if you a motto system Sensory. Okay of course maybe something

you're thinking okay. What's the modal unit here. New section because of you. I was thinking you
were a circuitry. Okay, so this is UK, find it more elaborate Definition for the behavior. But this
actually is the most actually,

this kind of definition used in the field right

now is kind of common sense, okay? All right, so the behavior

actually has three foundations. Three, Principles,

by natural selection, and also can be learned,

by individuals, and also can be transmitted through

the kind of culture.

8.4

With actually there are two

kinds of behaviors. One is innate behavior. One is learned behavior. Innate behavior that's what we

talk about actually, was born to have that kind of behavior without

any kind of learning or experience. Okay. But if it is learned

behaviour then you need, you moved a lot of things

actually to learning. For innate behavior, most likely, this one like the spider. [FOREIGN]. And then
the bird actually built a nest. [FOREIGN]

They don't need learning. They can build by themselves. And let's make a comparison. You need
behavior things of course. It's genetic determined. And it can inherited from parents. This no
environmental input. No learning [INAUDIBLE]. This is the innate behavior. We compare this with the
learned behavior. Yeah, this is the difference

between these two behaviors. We have sensory, we have motor. We have the neural circuitry. >>
[INAUDIBLE]

>> Yeah, yes, okay. This you cannot control, right? [LAUGH]

>> [INAUDIBLE] >> Yep. >> [INAUDIBLE]

>> Okay, okay. So that is innate behavior, right? >> [INAUDIBLE]

>> Okay. That's a good [INAUDIBLE]. So, actually, I don't know actually

the true answer because it's still, the definition of that

behavior is debatable. How do you think? >> I don't know [INAUDIBLE] But personally I think that it is
possible that it is [INAUDIBLE]

>> Okay. Voluntary movement. I think maybe more unprofitable behavior,

right? Why is it so opposite. >> No, no, no, I didn't say the opposite,

I said that if it's involuntary behavior that it's definitely, it definitely

cannot be the basis for behavior. >> Okay.

>> If it's voluntary then it may or may not be, not necessarily 100%

>> Right, right, right. That is a good point. Yeah, yeah, yeah. Good. Yep. So okay, so let's move on,
let's see so we have a behavior here, okay, and it's in how you study that

behavior in the gene. So if you want to study the,

what kind of a gene can show the behavior? How can you study? Designs or experiments or

any more model for this kind of study? How can you study this kind of relation? Okay, so you make
some mutant. And it is screen the behavior change. And if you found the cell

phenotype then you know, okay, this gene controls the behavior. >> [INAUDIBLE] >> Related to the
behavior, right, okay. >> [INAUDIBLE] Behavior we mentioned
today has many movement involved in [INAUDIBLE] and control based this term

so that behavior may not be [INAUDIBLE]. So maybe the one defined it's

hard really hard to find. >> It's difficult right? >> Yeah. [INAUDIBLE]

>> Okay. Right, I guess this concern,

indeed actually. Very important actually, okay. So, even you found some gene or

changes of behavior. It might not be the direct

actually control of the behavior. Maybe it's just one link changes one

point along the whole process, right? But still you can pinpoint. If you find some gene and

then you locate actually under which neuro section point

actually make the change then you still can study the effects,

right? So okay, ofcourse we can maybe use some other more conditions, for example if the two
brothers and sisters. Even if they are twins, and

then maybe, in some case, actually it's a gene actually

is 100% actually identical. And then maybe we have

different behaviors, right? Under those case, actually you know, actually maybe there's not

gene control the difference. Maybe it's the environment. And sometimes maybe you

can study the issue okay. And the in between actually maybe

they only show 50% of the gene and then they have very different behavior. And for this kind of
behavior

genetics you can also make some study about the gene that

controls the behavior, right? But actually the most

straightforward is not those study. Actually it's this kind of study,

okay, so from Seymour Benzer. Seymour Benzer actually is

a very clever scientist. And you see [FOREIGN]. And then molecular biologist and

then also he studied kind of the DNA, those kind of related things. Molecular biology. And later,
about late 1960s and then his school started to study the behavior, the gene and the behavior
relation, okay? Is called neurogenetics. And what he used, actually, is [FOREIGN]. [FOREIGN] you can
make a lot of mutations. And at that time nobody

will think about actually, yeah this is that kind of behavior

can control the bio syncl gene. The dominant view at that time,

no it's impossible. One gene you cannot control that behavior

and the gene is under that kind of a they make this. And actually there is quite
an interesting book about Seymour Benzer. It is a writer. And he wrote this book for Seymour
Benzer. After 1971, actually. His group actually studied a lot of genes, and controls of behaviors. For
example, the gene controls

the the circadian rhythm. And then also he studied, actually it's the genes control

the mating of the animals. And also of course they studied

the genes control the memory. Now this book is about Seymour Benzer. A very good book.
8.5

Let's take a look,

what Seymour Benzer did, okay? At that time, there was a strategy to make the mutants off of the
Drosophila. You just used those chemicals, and you excrete to induce

the mutations of this gene. And then you screen, because decent

mutation you cannot control. It's just random. You don't know which gene

affected at first, okay? It's just actually a bunch of mutants. And then you're screw in the phenotype.
So if you are interested in the time,

the circadian, right? When the fly,

the deep waves of the fly awake. So if you check this kind of pattern and

then you can find some genes mutation maybe will

affect this behavior, indeed. This is actually a very

famous paper in 1975. They published in P&S. This study is, okay, so this is the behavior of the
animal. This behavior is called, actually, the monitor the activity of the fly,

or the movement of the fly. What they did is very simple, okay? So you just use a tube,

a plastic tube, transparent. And then you take one fly, put inside. And then put the tube under

the control for the lighting. Sometimes maybe few the light conditions,

sometimes dark, okay? And then you monitor

the activity of the fly. How you monitor the fly activity? You cannot use your eye

just directly of result. Because these take a long time,

days, weeks, you will maybe, even longer amounts. Then what you can is do is,

actually they just used, because he was very clever at the time, he has a very

strong background in physics. Of course, they just used the dy

is the infrared ping, a y-shift. Now and then that infrared beam actually pops the tip. So if the fly
move, breaks the beam,

and then you have a detector, and then you can automatically

record the activity. Then you know when the fly move once, and then they'll record the way,

record fly activity. And the thesis, you can see,

each of these individual line, horizontal line, is one day or

maybe two days, yeah, put together. And then you can see, these thick lines

actually is the activity monitor. That means actually the fly here

is very active, move around, okay? And then for this period actually,
then the fly actually not much activity. Use the genes and

then [INAUDIBLE] you see. This is 24 hours, okay? 24 hours and then, this maybe a 12 hour in the
dark,

12 hour in the light. And then this is actually

in the light condition. This is in the dark. So the fly actually makes a lot

of movement in the light, because you want to show how,

you want activity. And then, in the dark,

actually that's activity, okay. This is kind of you can

see quite interesting. The flies actually maintained about

actually this kind of 24-hour cycle. Because you have the light condition,

your control, these 12 hour light, 12 hour dark. So things 24 hours, the cycle, right? And then, I'm
sorry, here is actually they

change the condition. The first, actually they change

the animal actually in this 24 hour, 12 hour, 12 hour, the cycle. And then the experiment actually is

then you put this fly in complete darkness without any light cue,

24 hours in the dark, okay? And then you see these

animals actually maintained their activity about 24 hour period, okay? So then it means actually this
animal

has intrinsic clock in the brain. They know actually when they should

actually move around, when to rest. This is called circadian rhythm, okay? This rhythm actually,

they don't need the external input. It's intrinsic. Without any cue you can maintain. And then, quite
interestingly,

on this screen, it is a mutant animal. The fly, actually, some animals you

see the purity is much shorter. This is in the wild obviously about

24 hours circadian in the dark, intrinsical clock. But it isn't anymore,

actually only about 19 hours. Apparently, something changed,

right, changed the behavior. And then she also found, some animals, deep in the mutants has a
longer period,

about 29 hours. And of course, some animals actually,

just no any reason, just awake and asleep actually,

quite disrupted. And then later, actually,

they mapped this, okay. So right now you have this mutant. You know the phenotype, because you

have the chemical-induced mutation. And then you know there is some kind
of phenotype deficit for the circadian. And then the next thing is actually

you want to find which gene actually really are responsible for

this kind of behavior, right? Then they did the mapping, okay. How you do the mapping,

actually the chromosome mapping and determine which gene actually was

disrupted in this mutant animal. And what they found,

actually quite interesting, for this one, the map to a protein called. And then there was some amino

acid actually was changed, notated, and then this one again is. But it's different amino acid
mutations. So it tells you,

right now it tells you it's one gene. You change a different

amino acid to different locations it can affect

the behavior differently. One can make this

circadian rhythm shorter. Another one make it longer. So they are very excited, because

this is the first time to demonstrate to you a single gene can

change their behavior, okay? And at that time, as I told you,

nobody believe this is what happened. But it did,

they did demonstrate at this point. Okay, so this is actually the first

clock gene discovered ever. And the later then follow

similar strategy, and the people found more and more clock gene. So for example in the fly, the
Drosophila, is really a good model to

study this kind of gene and the behavior relationship. And later a lot of different

genes actually were discovered, also affect the circadian rhythm. For example, the first one is

the [INAUDIBLE] period, right? We talk about [INAUDIBLE] in 1971. And then there was another one

called a [INAUDIBLE] team. There's another gene, also,

if you mix the mutations, the circadian rhythm will be changed. And also there is another one, the
cycle. Cycle also another gene.
8.6

The cycle. Cycle also another gene

controls that behaviour. These issues all are very important

clock genes to control that behaviour. And that this ready Important work is actually followed

actually in the mammal, in the mouse. Or people found similar thing, okay? This mainly a few labs
for

this Drosophila work. But actually,

in this one in the mouth is actually the main player is a Japanese researcher Joe Takahashi. Right
now, his lab is seen Texas, University of Texas Southwestern. And they found a similar strategy. This
strategy seems actually

impossible to work. That because here,

how can you find the purity gene? Do you just say,

maybe we could make the mutants, and then screen a lot of Drosophila. That's quite easy,

because the Drosophila is so easy to make the mutant, to maintain. And then you have the high
throughput

report, actually, a behavior essay, right? So you see, quite easy to find this gene. How about in the
main insistor the mouse

if you want to make a 1,000 or 10,000 mutants with how many

results you need it to have. But actually Joe Takahashi's lab take the effort and then they indeed
found, actually a homologue of the gene, also a clock gene they

also have [INAUDIBLE], and also they also found. This is a clock gene,

also in the mouth and also the clock gene actually has

a homologue in the [INAUDIBLE]. And of course this is not a single

gene when they found one gene, and later they found more, and more and

make the story more complete okay. So what's this gene doing here to

control the behavior, circadian? What they found is

actually if you make this, I guess it's maybe a Western blot. If you take the animals [INAUDIBLE] and
then at a different time

point The 24 hours period. A different tempo, you take the animals,

okay, and then make it a tissue. And then make a staining

to see the peel rate. You will see actually a sunk conditions

actually is quite low level, right. And then under these conditions, the level

is quite high, and then lower again. So this gene actually turn on
actually at a kind of a oscillation of a 24-hour period, okay? So if you see, it's this. This period gene
expression, it's a cycle. This cycle is 24 hours. And also, the found, actually the adult genes also is
about 24 hours, okay? So your found one gene is

oscillating about 24 hours. It's good. Maybe you found the clock. The clock is it turn about 24 hours
right. But when you find one gene okay then

you wonder okay this is a clock then. Then what controls this gene, because this gene also need
oscillation 24

hours then what control this gene right. So then the question is

still not believe addressed. By the way you put all these gene

together then you form quite interesting. This gene can interfere,

because this gene synthesize a protein. The protein can be a transcription factor. And then they can
control each other. And most importantly, this gene cause

a transcription feedback mechanism. And then for example, there's a period

when they exports their protein, and the period came,

actually go into the nuclear, and bind to this region and the to inhibitor period expression

is neck to feedback loop. And then this one of course then when you have a high level of this

period protein what will happen? Imagine, if we have very high

level of protein that work, and then this will enter the nuclei

will turn off this gene expression. And then you have less and

less, the protein, right. And then you will look down

When the protein lower down and then this inhibition is released. And then you will turn on the
expression. And then you have cycle. Right, and

then later the foundation is used to. Actually, like a period. It's not function by itself. You need a
partner. The partner is called the Tanis. That is actually,

when you have the period synthesized, okay, the protein is there. But this protein cannot be stable.
It will be degraded, made first. Only then you have a pattern to turn this, get this team protein and
then two can combine together and

they can be stable. Okay?

Then when they're stable, then they can assimilate, and then they can enter in the nuclei

to control the transcription. So this is just the cycle's control. And of course this one in

the mammalian system is similar strategy was used. Okay. The most interesting thing

is actually these kind of clock genes,

concentrated actually in one cell. Okay. So in the brain then you can find

some neurons, some particular neuron. That neuron can house all
these components there. That means those genes

in the single neuron. They can oscillate 24 hours. Then if you interpret this kind

of results, then you think, okay. So it's this oscillation in the individual

neuron deal with the timing. And then that means those neurons,

you can define as the clock neuron. There's a clock in your brain, right? So, these are clock gene and

the neuron express all these clock gene, things clock neuron, and then,

where is those clock neuron? How can you find it then

right now you know the gene. You know the phenotype. Then you need make a new circuitry, right?
Of course then quite easy, right? Then you just, yeah, use in-situ to

see well just MIA locate all right? And then people found actually. Later I will show you the results.
Okay, so

this is how the clock system works. Actually by different genes to control

each other, especially the transcription. Feedback is the main,

the core mechanism for the timing of this different

clock coding oscillation.

8.7

Okay, so

I guess the experience is actually, for example, the jet lag. So if you fly from one time

zone to another time zone, then sometimes you have the jet lag. Then the jet lag actually will

cause some problem to you because, for example, you have a circadian rhythm. Maybe right now is
a new time. Yeah, 1 or 2 o'clock. 2 o'çlock in the afternoon,

but actually if you'll fly to the States,

the Eastern side, then right now it is the midnight and

then you have a problem. You will have a problem. Essentially, then you are not comfortable,
because it is not your

circadian noon time. Then there, you need to sleep. And, but actually, in most case,

you only will have this problems for maybe about a few days,

maybe less than one week. And then it's fine. You can get used to that local,

the timing. And then how you can achieve this

is by this circadian mechanism. Let's see, okay. This is the clock, okay? This one black one, of course,

is even is the night. No, yeah, this is sleeping time, this is day time, okay? And then let's take

a look at what happened. As we said those, Circadian gene, they oscillate, okay. The oscillation
there, for example, when you stop. The light off, this timing. Then I attend a case. You actually don't
have much

of those proteins, okay. You have a lot of, MIA,

of this clocked gene. And then, of course, this MRI, then we

are synthesising a lot of proteins, okay? And then when you lighter off and

then a lot of proteins, they should be also synthesized. And the protein at the beginning,

they sit actually in the cyto cell. And again, as we said, the time and

the period, actually it's the combined. They're back to each other and

then they're very stable, okay. When you have a lot of accumulation,

wonder what happened? Then do we enter to the nuclear. And then a lot going to the nuclear. Going
to the nuclear, what would happen? It inhibit transcription and then you have very few the mra.
Because mr you were degraded and

then no since, no transcription happened. Of course then it would get less and less. And then, okay,

this actually takes time to build on, and then almost actually at

this time when the light will be turned on and at that time

a lot of proteins actually get stuck into the nuclear to

inhibit the transcription. Okay, when your light turns on, what will

happen, you see, when your light turns on and there is a light sensor in the cell. A light sensor
detects a light. Then the light sensor,

right now people know it's called okay? The actually will activate

it by the light and then by the sensors with

the great proteins, okay? And then that means actually these

proteins will get less and less, because your light shine on, and

then no inhibition any more, and then you have more and

more mra, right? And then you have mra appear through

the and then accumulate here, and then you can synthesize. This is a cycle, okay, let's take a look.
This is important here. If you get to a time zone, for example, at this time your circadian rhythm,

actually here is actually in the night, right. But if there's still a light appearing,

what will happen? And then, the light that appear here. And then the light will activate

the light sensor [INAUDIBLE]. And it then will degrade this protein. Then you have less,

this protein accumulation, right? And then what will happen? You would take a longer

time actually to build this accumulation of the protein because right

now the light degrades your protein. Then you take a longer time to

synthesis and accumulate, right. So that means at this phase

you have a light shine on. What would happen? You delayed your cycle. It's clear, right? Quite
interesting,

if you turn on the light, just actually before the lights

should be on, their timing. You turn, maybe a few hours earlier,

the light on, what happen? You will see. And then the light on, and

then you degrade these proteins. And then you appear like in this stage. That means actually,

there is a cycle actually, right? So this actually is for adjusting your

time is by this kind of mechanism, actually you can control

your circadian rhythm, okay? This process actually

is quite fascinating. A lot of status, after the 1971 Simon Benson's study,

and a lot of groups actually, wrote for this kind of molecular

control of the circadian clock. And right now, essentially most of those circadian clock genes and

the proteins people are studying. And right now, at this stage,

we know so much details about this clock gene, but the problem is
actually in the circadian field. As we said,

this is just within one single cell. Okay, a single neuron, a clock neuron. But actually, it's a clock
neuron

to the circadian behavior. It's quite far away, okay? You need actually many,

many different clock neurons to act together and actually to control

some kind of neurocircuitry and then to control the physiology

on the behavior. Right now this kind of information is and

the people don't know much, okay. And the more people, right,

get to these kinds of start, including us. Actually, we also try to

understand the neurosector mechanism underlying

this circadian rhythm. Okay, let's take a look. We actually use this model system, use to study the
circadian rhythm. Actually is good for

the genetic study, right? Because we mentioned that. And also, actually it's quite good for the
functions study

because it's the brain. It's small and

those neurons actually individual neurons actually,

you can easily to labor then. Which is GFP, then you'll exactly which is

the clock neuron, okay, individual one. You can find it, then. You can make the function start it. Now,
for us, we do the from those

individual neurons in the brain, and also, you can do imaging. So far, people know,

actually to clock neurons in the brain. Express those clock genes. How many? Only about 150
neurons. Okay, and then the 150 neurons actually

distributed in the whole brain. It's a central cluster. One cluster maybe sometimes may

be a few like eight or nine or sometimes maybe 30 or 40. But in total only about 150 neurons is
considered to be the clock neuron

because they express those clock genes. And then so this clock neuron, how they can form a newer
circuitry

to control the circadian rhythm, right. Although there were some kind of study,

anatomy study, for example this kind of a neuron to make

a connection with the other neuron. But the function, we don't know much. So right now actually we
have

studied the circuitry of connection between different

groups of those clock neuron and to see how they can synchronize

to control the circadian.

8.8

Okay so this is actually

considered the circadian clock, actually this is considered

the most understood behaviours in the whole world of animals. Because of lot of really good studies,
actually, about the gene,

about the cell and about the behavior. This is considered very well understood. But actually there's a
lot

of unknown things there. So, let's switch to another behavior. There's this kind of mating behavior,

okay? Also, the fly is a really good

model to make this study. For example, it's a circadian reason

because it's the first study, first genes cloned in the fly. And then follow up. Actually, the mating
cicada use

exactly the similar mechanism. Okay, very similar. And those genes, very conserved. And then here is
the mating behavior. [LAUGH] We don't know

actually I'm sure actually we know actually human beings diff strategy. But let's take a look,

understand sometime for principles about the gene and

the behavior. This is the two flies. One is actually this is the female fly. And then this is a male fly.
They're quite interesting, okay? So these flies, for this kind of

behavior they don't need to learn. That means if you put two flies,

isolate them and then put them together they immediately

would do this kind of behavior. Okay. This behavior is kind of a fixed pattern. It's just start from here
and

then a cycle. Like this. What's first actually is

the male where face is female, and then this male will later,

will actually follow this female, and then will use the forelegs

to touch the fly, the female fly, and then, if everything is fine,

this female will then sing a song. You see, this wing. The wing vibration makes

a ultrasonic song. Okay? And then this female

will detect this song. If everything is fine,

they will have the mating behaviour. Okay, so how do you study this behavior? Of course, this is. You
can easily, too,

just take a look under the microscope. And then,

there is a quite interesting phenomenon. It's actually, if you have one gene. Called fruitless or fru
gene division. Then the fly will have some trouble. Typically, actually it's
the female mating, right? And if you have this kind of

mutation the fly has problem, and it's actually the male will. We have caught not only female but

also we caught the male. In this case you can see if we put those mutant flies together then

the fly will follow a chain. Follow a chain where is

one maybe male here. Another male here. Another male here. Yes Yeah, it's just strange. This is just
a single gene mutation. Later, people found that this gene,

fruitless gene, is related to, so for the gene actually, in the female that don't have the fruit,

the protein, okay. Only in the male they have. Why? It's because okay,

there's a quite adverse diet system. It's actually this is a female. Female you have with two X
chromosomes and then this is lung. Okay, this is the autosome and then if you have this 2:2:2 that

means that the ratio is one. When you have a ratio of one

this applies to females. When you have a this ratio then

you will turn on a sex gene. And this sex miso gene, as xl gene, you will can choose surprising

of this gene itself. And then,

this also were another gene splicing, that's called a transformer transformer is actually, Tra, okay?
Tra, and

also it's a pattern now called Tra2. And then we can ensure two things, one is actually the double sex
gene. Turn to a female double sex gene. And this one will turn on the other gene expression and
mainly actually for

determination of the female gene. But actually this one will also make this

splice of the fruit in its gene okay? Then the fruit in its gene cannot be the protein cannot be a
functional

when you have this splicing. Now Let's take another look. For this male, then this X and

a ratio is a 0.5. Okay? And this case this gene may not be turned

on and then you don't have this cycle. And then in this case you will have

the fruit initially expression And also this is double six male gene turn on. It's not the female, okay.
Let's take a look. What's the difference between this fru and

it's male and this fru? This is actually the gene

of this fruitless, okay? This is one axon and another axon, and then the female will have

a from happen in this region. And they in this case, it happened there

is a stopped actually happening here. Is actually the translation

to here that is truncated. The protein is not functional. That means that in the female

this protein is nonfunctional. No fruit on these. Okay? But in male,

you can have a full functional protein. Let's take a look. What's this gene doing? Okay, so we also
maybe can take

a look at this expression. We know actually there

is fault in this gene. You have mutation. Then you have to travel,

the male follow the male, right? Okay, so let's first take

a look where is gene expressed. In which neuron? Which cell? So then you have a strategy. Then this
gene and

then you have a strategy. Look on a fly, put a and it is the promoter of the photenis okay? And then
you can use some expression

system called the gail for UAS. Then you can put some other genes into

the system, for example you can put a UAS. So you have to see. Under the control of this GAL4 this

promoter and then you will see, if you see a GFP expression then

you'll know that cell expressed also the Fru okay,

this is the strategy people use. And then people found this

is the Fru expressed neuron. Into olfactory system. Also in the auditory system [INAUDIBLE]. And
also in the eye. Also in the mouth. And also in the legs. The legs, because of the touch,

the female fly, right. And also in this region. Okay so, didn't mean to say should

the [INAUDIBLE] express being multiple, multiple regions, okay? To control that behavior.
8.9

Okay. So we have the problem say should

we look at the protein and then the behavior was changed, okay? And then there is another

kind of experiment you can do okay in the fly is actually

then if you express. So in that case actually,

if you knock out the protein, the cell maybe not function properly. But if you activate specifically
those

neurons, use some other method to activate them, then you will see how

examination, what behavior was changed. This is the experiment people did. This is wild type of fly.
You put two flies and

then the sequence of the mating behavior is quite clear, right, follow and sing a song and

also of tracing and then mating. And for this experiment

actually people use a strategy. So this one, TIPA, is a trip channel. This channel is a temperature

sensitive channel. That means you just need to increase

the temperature a little bit, and then this channel will open,

will activate the cell. Okay, so in this case, you just need

actually to use this fruitless scale for to drive the tRP A1 expression. And that means, actually,

all those fruitless neuron, you will express triple a1 channel. Then you'll increase the temperature
and

then those neuron will be activated. Then you'll see exactly when

you activate certain neuron, that a single fly, a male fly, then show

up this corresponding behavior we can see. We told a female fly there. She just do the mating
behavior. So this means it's actually those

fruitless neuron, expressing neuron. Really important to control

this mating behavior. Okay, so if it's true,

that's quite interesting, right? So people did another experiment here. So let's take a look, first,

actually this one, as we mentioned, the fruitless protein is not

functional in the female, because of suppressing, right? It's only the male can express. You see this is
the control fly,

a male fly, a female. You make staining of the fruit protein,

and you see in the male, you have the protein. But females don't have. Okay, so in this case,

people did again another experiment. The knock out, actually,

that fruitless gene, okay, in both male and the female, and only expressed the female
fruitless gene back to the fly. That means the female will express right

now a male version of the fruit protein. And male of course still

expressed the same male version of the fruit protein, right? And the people found, actually,

in this case that the male is fine, is back to normal, Y type. But the female quite interesting,

you see [LAUGH]. This is a female fly,

transgenic female fly. And this a normal female. You see, this female is doing

the same behavior as a male. So, this result is quite stimulating,

right? Tells you, maybe, yeah, the fruit protein really is important

drive to control the behavior

8.10

Okay, so, We still have some time. We can talk about another behavior. This quite, Important
behavior is eating. This one, actually, then we used

a mouse model as a demonstration, okay? For the eating,

it's related to everyone here. Some kinds of observations in the animal

experiments is quite interesting. So, okay, so if you, Starve the animal, the mouse for example. Okay,
what will happen to them? They will get thinner and thinner. Of course. So but then you, Give the
food, after this treatment, and

then you give back the food to the animal. Let them eat at their own will, okay? What will happen to
them? Well, they gain the body weight again, maintained at the same level as before,

as the healthiest state. Okay, that means actually these kinds

of behavior you can control, right. Another opposite approach. Okay, so right now,

you force the animal to feed a lot. For example, you,

maybe in the food, actually, you have a lot of food,

high calorie food to them. And then, they eat a lot. And then, they grow big, okay? But then, if you,
again, Let the animal eat at their own will, and then the body weight will recover to

the previous healthy state, okay? Just again to show you,

the animals actually, they can control this kind of behavior,

and quite robustly. Okay, so, Which region in the brain controls

this kind of behavior? And the people do the science experiments. What they did actually then,

they disrupt the brain region, okay? Of course, there was a lot, deep in the study actually in early
days,

and the people found actually,

if you destroy the hypothalamus, okay, the animals can grow really big. They cannot control their
eating anymore

if you destroy the hypothalamus. Okay, that means it give you a clue

is the hypothalamus actually is important,

it controls the eating behavior, okay? All right, so then people did

these kind of clever experiments. These experiments actually is you, Take a surgery to link

two individual mouse, link them together. From where? From the [INAUDIBLE]. So this part is
individual. That makes actually

the [INAUDIBLE] correlation, somehow can be shared partially. This is important. When they share
the blood circulation, that means some signals

generated in one animal can go to another animal and

they affect each other, right? These are very clever experiments. Let's see what happened. This is
actually the body weight, and then this is manipulation of

the experiments, let's take a look. This is a normal, single animal, okay. It's about 300 grams. And
then if you destroy

the hypothalamus and what do you found? Actually, this single animal

will get a lot of body weight. [FOREIGN]

Okay? Now let's take a look,

if you linked these two animals together without the surgery for

the hypothalamus. These are fine. They can also maintain

the body weight here. Okay, important these experiments. So when you link them together, actually
you destroy,

one, animals have and they're animals, of course,

will eat a lot and then the body weight really gain a lot. But quite interesting, okay? So the other
animal you see. The body weight should have

lost it a little bit, Okay? Okay, so this is the maybe not so

dramatic. And let's take a look at this data. This data actually is, gets the fat tissue from the mouse,
and then, wait then. See what will happen to

that fat of this animal. And then, most dramatic is this one. Take a look here. So, the animals without
the hypothalamus

get a lot of the fat, all right? And then the other animals

actually not much fat there. Actually get thinner and thinner. What happened? Make a guess here,
what happened to them? So the logic here is actually, okay, so because these animals,

the hypothalamus destroyed, cannot control the eating

behavior anymore. And then the animal will eat a lot. When you eat a lot, that animal

created a [INAUDIBLE] feedback signal. That feedback signal somehow goes through

the blood circulation to another animal. That animal animal,

receive this inhibition signal. Then that animal don't eat any more. Reject to eat, refute to eating.
And it, of course,

then will get thinner and thinner, right? Okay, yep. >> [INAUDIBLE] normal animal. >> Yep. >>
[INAUDIBLE]

>> Good. If in this animal or the animal? In this animal, in this destroyed animal, hypothalamus is
more functional and there was a feedback signal

produced by the hypothalamus. It's thy hypothalamus's detection signal. That's the information from
here. This okay? All right, so if the animal ate a lot and

somehow their eating create a feedback signal,

inhibition signal. But not from the hypothalamus,

maybe from somewhere, some other place. And then that signal actually should go,

act on the hypothalamus. So then it means hypothalamus actually is

the receiver of that information, okay? Yeah, this is quite clever experiments,

right? And then what's the signal? >> [INAUDIBLE]

>> Yes. >> [INAUDIBLE]

>> Okay. >> [INAUDIBLE] >> Okay, so that's a good point. So maybe you also can

monitor change this one to the food assumption, right, consumption. Yes, I guess it's correlated. So
in this case, for

these animals, will eat a lot, and a lot of food consumption, yeah.
8.11

Okay, then in other experiments,

this experiment, the message is they should

tell you what's the feedback inhibition signal is from the fat tissue. Fat tissue,

they will release this leptin, okay? [FOREIGN]

>> [FOREIGN] >> [FOREIGN] okay. This fat tissue are released, this signal. Because you eat a lot, and
then fat tissue

then somehow triggered to release leptin. And this leptin is important signals to

control the food consumption, the eating. Let's take at look how

people found this thing. This is the wild-type animal. The body size is like this. Quite interestingly,

in the Jackson app [FOREIGN], Jackson app [FOREIGN] mouse strain. [FOREIGN], okay. Somehow this
[FOREIGN] mutation [FOREIGN] okay. Obese [FOREIGN] strain [FOREIGN] strain. Also, it's kind of a
huge body. That called DB. DB also is another strain. But actually,

it's different gene mutation, okay? Let's take a look, okay. So wild-type is like this. This is obese
animal, very big. So they did a similar experiment to

try to find what's the mechanism here. To make this wild-type fly and this fly,

link it together and see what happen. This is a change. And if we use Db fly. Also, it's like that this is
the change. Db and Ob together, it's the change. Okay, let's take a look here. First, take a look at
these two fly. Okay, so this is the Db fly when you link to another Db sorry [LAUGH]. I'm so

used to the fly because [LAUGH] everyday in the lab I talk about, okay,

which [FOREIGN] we need to use or which fly we should do the recording,

I'm sorry, okay. Db mouse, okay, Db mouse and

the wild-type mouse linked together, and you see, okay, Db mouse. He grew even larger, right? And
then, this wild-type mouse actually

then get thinner and thinner, okay? And also, here, similar thing. The Db get larger and larger and
then even this Ob/Ob mouse. And gets so similar. It's quite interesting. So from here, then, how you
make the reasoning to explain these results? >> [INAUDIBLE] to of the fat. Lines to the output, which
is to inhibit the nutrition extraction. >> Okay.

>> And maybe the Ob mutant is inhibit [INAUDIBLE] at the input [INAUDIBLE] pathway, which means
maybe the fat sensor is disturbed and the-

>> So Ob, you think Ob this is the same cell or

Ob is a feedback signal. >> I think Ob is the sensor. >> The sensor, okay, why? >> because since it
cause a normal

[INAUDIBLE] mouse to [INAUDIBLE] [FOREIGN] >> Okay, okay, so to get each, to get a repeated signal
in this case

diluted or maybe less inhibition. Then, these mouse can grow larger,
eat more. [FOREIGN] Now that means this Ob is for

what? >> [INAUDIBLE]

>> It's inhibitor signal. It's not the sensor. >> [INAUDIBLE]

>> So you think this one controls

the leptin release. >> Yeah. >> [FOREIGN]. [FOREIGN] Can you explain? Elaborate. >> [INAUDIBLE] >>
Right. >> [INAUDIBLE] >> Shield it, right? >> [INAUDIBLE]

>> Yeah, okay the concentration. For the wild-type right now

would be diluted a little bit. They eat more. Then this wild-type will eat more

food right and gain some weight. [FOREIGN] But for this one is still

actually you would have lost some weight. Because actually, right now, you get the leptin signal from

the wild type, good okay. Makes sense [FOREIGN]. Okay, so in this case, then that means Db

Is the same cell with the leptin receptor. >> So, I made a mistake. I think this-

>> Okay. >> Maybe the fat and not the leptin. >> The fat. >> Yeah. >> Okay, leptin is from the fat. >>
[INAUDIBLE]

>> Yeah, released by the fat tissue. Okay, for this one say, there are anybody volunteer to make a
reasoning here, yeah? >> [INAUDIBLE]

>> Okay, good. >> [INAUDIBLE]

to limit food consumption [INAUDIBLE]

>> Yeah. >> [INAUDIBLE] will in

turn produce more leptin. >> Good, okay. So this guy will release more leptin,

right, okay. >> [INAUDIBLE]

becomes thinner. >> Yeah, so this wild-type,

they have with the receptive intact. >> So you have more inhibitor signal and

then reject to eat, right. Okay, good,

if everybody follow the same page and then I guess we understood

everything here. So Db is the leptin receptor and then Ob is the leptin,

the inhibitor signal. Okay, so indeed,

people later mapped these two locations. And this Ob and the Db, and found actually corresponding

to why is this the leptin? Why is it the leptin receptor? All right, so what's the next step,

if you got all these data in your hands? What will we do next? >> [INAUDIBLE]

>> Okay, the protein leptin is found in

the fat tissue, okay, and then? >> [INAUDIBLE]

>> Yeah, clone the receptor, right? >> Also what others [INAUDIBLE]

>> Okay, good, so

the important thing is that right now, you know all these things then you wanted

to know where this receptor is expressed. Of course, leptin,

where does leptin come from? And then, for the receptor, because we

talk about actually the hypothalamus. If you destroy the hypothalamus and

then there was trouble, like just just so

they could see this Ob mouse, right? And then, indeed, people found

the receptor, the leptin receptor concentrate in the hypothalamus, okay? The hypothalamus actually
just

some neurons actually express. Mainly two types of neurons

express the leptin receptor. For example, there was one group

of neuron called AgRP neuron. And they expressed the leptin receptor,

okay? And people did experiments actually, they used a virus to transfect the brain especially for this
nucleus. For tha AgRP, okay, for this neuron. Express channelrhodopsin. Channelrhodopsin is right
now is

kind of fashion in neuroscience. It's called optical genetics [FOREIGN]. Now, that what's that mean is
actually

this channelrhodopsin is a light sensor. The light sensor itself is a channel. So if you shine light and

then this channel can open and then will excite the neuron

express this protein, okay. So when they express this

channelrhodopsin AgRP neuron and then use a fiber buried in the brain,

a optical fiber. And they use a laser to stimulate

the neuron that means you can excite particularly those

leptin receptor neuron and what they found you can see here. This is the control fly during the
[INAUDIBLE] and this is the, yeah, this is for the consumption, yep. For the consumption,

you can see the wild-type fly is okay. They take some food. But then,

if you have channelrhodopsin expressed in a stimulant then the mouse

will just eat crazy. It doesn't matter,

the mouse is full or not, you're just eating, okay, continuously. That means these neurons really

control the eating, right? All right, so later people found

actually there are two groups of neuron in the hypothalamus actually

express the leptin receptor. That is one POMC neuron and

one is this AgRP neuron. And then, the leptin, okay, the leptin actually will excite this

neuron, activated this POMC neuron. And the POMC unit will

release some peptide. Then a peptide will activate

it at downstream neuron here, express MC4R [INAUDIBLE] receptor,

and to inhibit the eating. Okay, this is this pathway. And for this pathway thing is different. This
AgRP, AgRP then,

apparently when the AgRP neuron excited then the animal

will eat crazy, right. So that means that this AgRP

neuron actually somehow inhibit this POMC pathway, you see? The leptin will inhibit this neuron.
This neuron will inhibit this guy and

then you have some inhibition. That means that HRP neuron

controls the eating. And then, POMC neuron inhibit the eating. This is quite new progress, okay, is
because right now we

are in a stage we have these fancy tools to study, to use for

this kind of behavior study. Okay, I guess this all what I can

say about this gene and behavior.