Hakan Sahin

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BIO 365R
Hakan Sahin

Table of Contents
UNIT ONE.................................................................................................................................................2 06 September 2007................................................................................................................................2 11 September 2007................................................................................................................................5 13 September 2007................................................................................................................................7 18 September 2007................................................................................................................................9 20 September 2007..............................................................................................................................11 25 September 2007..............................................................................................................................13 UNIT TWO..............................................................................................................................................15 02 October 2007..................................................................................................................................15 04 October 2007..................................................................................................................................17 08 October 2007..................................................................................................................................18 11 October 2007..................................................................................................................................20 16 October 2007..................................................................................................................................21 18 October 2007..................................................................................................................................23 23 October 2007..................................................................................................................................24 25 October 2007..................................................................................................................................25 UNIT 3.....................................................................................................................................................27 08 November 2007..............................................................................................................................27 13 November 2007..............................................................................................................................30 15 November 2007..............................................................................................................................31 27 November 2007..............................................................................................................................32 29 November 2007..............................................................................................................................35 04 December 2007...............................................................................................................................37 06 December 2007...............................................................................................................................39

Hakan Sahin

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UNIT ONE
06 September 2007
Neurons have information that flows one way; arrives at receptors in dendrites. Different receptors for the same signal can then respond in different ways. The nature of the start of the axon hillock is the point at which you've made a decision based on all received information whether or not to cause an action potential. The result of stimulus on a neuron is to change its permeability to ions. In general, sodium will enter and if enough sodium enters the axon hillock decides to start an action potential. If you were comparing charge inside/outside cell, inside of cell usually sits at -60mv. If a stimulus occurs, such as sodium coming in, will depolarize the cell. Positive feedback occurs and more Na is let in until the inside of the cell actually becomes more positive than its surroundings. It's all relative; not because an enormous # of ions came in but because so few came in that drastically changed the polarity. There only has to be more + than – inside. Membranes sitting at rest in general are somewhere -60 to -80mv. Bringing in these few more Na+ will depolarizes the membrane (causes it to go closer to zero). The sodium is being allowed to flow down its concentration gradient until it reaches a threshold potential. Threshold is the membrane potential at which voltage-gated Na channels in axon hillock open. Threshhold = vgate cell chan open. As they open, sodium floods in and it goes back down again. All the way down, dips below -60mv and comes back up a little. K+ leaving the neuron resets the membrane potential at this peak. In order for this to be true, there must be more Na outside than inside, and a lot more K+ inside than outside. This could be a result of Na-K pump working in opposite directions. Usually occurs in 2:2 ratio. Membrane is permeable to potassium most of the time. Potassium leak channels are always permeable to K, meaning that all neurons are permanently permeable to K+. Takes a drug or special event to close these leak channels. Sodium has two reasons to go in to cell: Electrical gradient and [gradient]. After a few have gone in, its going to be relatively positive inside the cell and K+ will have two reasons to leave: electrical gradient and [gradient] as well. Above 0mv, Na+ still enters because [gradient] outweighs electrical gradient. If membrane is permeable to K+, how does it ever reach more K+ inside than outside? Prior to sodium entering, let's just have a pump that pumps Na+ out of the cell. In order to have a negative resting potential, cell is impermeable to sodium. All else being equal (concentrations), K+ will run in because of electrical gradient. At some point, enough potassium will flow in to make it a little less negative. The membrane potential of a resting neuron is dependent upon the flow of potassium across that membrane. The flow of K+ across that membrane is dependent upon the relative values of the electrical gradient and [K+]gradient. There are other ions in the body, but for the most part only potassium sets that.

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At Huntsville, we execute prisoners. We knock them out with phenobarbital. They are killed with a nonlethal, nonregulated substance. They increase the amount of [potassium] default in the cell so that neurons fire perpetually. Why do ions flow? They are Na, K, Cl, and Ca. And Mg too. Something to memorize: Cl, K+, and Na+ usually at dendrites; at synaptic end it's almost always calcium. Channels in the membranes imbue cells with these possibilities. Channels have variable permeabilities; signal dictates whether it can open and the matter of gradients dictates whether or not an ion will flow. For our purposes the NaK pump rids the cell of sodium. That's the #1 function. The fact that K+ is brought into cell is trivial. At rest, just as much K+ is leaving as is coming in (flow of K+ due to pump and membrane potential coming in, flow due to [gradient] moving out). Voltage-gates channels: Na+, Ca2+, K+, Cl. Ligand-gated channels: Neurotransmitter receptor; Glutamate-gated Na+, Ca2+-activated K+, cyclic nucleotide-gated channel. Relative Ionic concentratons In Out K+ 140 5 Na+ 12 145 Cl15 120 Ca++ .0001 2 Ca++ has a huge gradient. If you were to open up most cells to chloride, very little would flow. Calcium inside ER of the cell is topologically outside the cell (vesicled!). One of the contributions making cells negative is that membrane proteins often have + charged portions outside the cell and – charged portions inside. Electrical gradients drive both K+ and Na+ into cell. Walmart neurons often rest at -70mV. Resting potential esablished by K+ *Z IS THE CHARGE. THIS WILL BE ON THE TEST. Nernst equation calculates equilibrium potential for an ion based on relative concentrations inside and outside cell. E = (RT/zF)ln([K+]out/[K+]in)

Emphasize one more time: If K+ is the only ion that can flow at rest, its the ONLY thing that is responsible for the resting potential; that membrane's resting potential will be the equilibrium potential for potassium. If an ion cannot flow through a membrane, there is no equilibrium potential for that ion. Establishing equilibrium Separation of charges creates an electrical gradient across the membrane, the membrane potential Vm. The equilibrium potential for a specific ion is the Vm at which there is no net flow of ions across the membrane (assuming they can cross the membrane). When you calculate resting potential you have to bring in permeability. Not a good equation for calculating resting potential of an ion.

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Goldman-Hodgkin-Katz Equation

In establishing the resting potential of a membrane, brings conductance (permeability). Designed to calculate resting potential of a neuron. Takes into consideration relative concentrations AND permeability to ions. How do you change permeability of a membrane to an ion? You can add more channels or use neurotransmitters to open more channels. Through this course, we'll describe the function of this neurons based on whether or not their channels are affected by disease, toxin, or a drug. Some neuropathic diseases: Liddel's syndrome (Na+), deafness and epilepsy (K+), cystic fibrosis (Cl-). Some drugs: Tetrodotoxin (TTX) is the stripped hydroxyl group that sticks inside a Na+ channel and blocks it. A picomolar amount could poison >100people. Permeability: Increasing permeability is the fact that the neurotransmitter has bound and has oepened the ion channel; doesn't guarantee conductance. Every ion upon increase in permeability will have a flow/conductance that tries to drive a cell membrane toward its own equilibrium potential.

Hakan Sahin

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11 September 2007
Understanding the basis of a membrane potential. In order for ions to flow, they have to be controlled by a gradient (concentration or electrical). What we'll be tested on: If this happens to this ion, this will happen to the membrane. We;re only interested in Na, K, Ca, and Cl. Interested only in communication between neurons. Ca enters, signal transduction occurs through neurotransmitters. If there's enough of a stimulus at the soma of the postsynaptic neuron, it will trigger the start of an action potential. Moon has a neuron that's sitting there. Some stimulus will cause Na+ to flow into the cell, so the membrane potential becomes a little less negative, closer to zero. That event is making the cell not so polarized, depolarizing the cell! That event is the equivalent to some stimulus, in particular this event happening at the soma/dendrites isn't enough to cause something to happen to the axon. The amount of sodium that entered the cell is proportional to the stimulus. A graded potential change != an action potential. The sum of enough graded potential changes (temporally and magnitudinally) causes an action potential. The change in the membrane potential of the cell is proportional to the stimulus. The receptors in the axon hillock are note the same as the soma receptors. The soma receptors are ligand-gated to neurotransmitters, the axon-hillock channels are voltage-gated. The voltage-gate-opening-potential of these channels is the treshhold potential for the neuron. As sodium enters downstream, K+ leaves upstream to “recock” the gun. Why do ions flow the way they do, what forces act on them, how do we describe with an equation, what exactly happens at the synaptic end, how do we know this happens? Membranes are going to develop gradients due to pumps, electrical potential differences, and concentrations. For instance, potassium wants to leave the cell due to concentration gradient but enter due to electrical potential. The potential at which the electrical and concentration gradients cancel each other, or are balanced resulting in no net flow. The relative [K+] inside and out will pretty much remain the same. There will be only a small amount of flow with a dramatic change on the electrical membrane potential. The relationship between the [ ] and the membrane potential is what we're interested in. If at -86mV K+ doesn't flow; if the membrane is at some other potential (-60, -100) potassium will flow. The Nernst equation calculates the equilibrium potential which is important to know at what concentrations K+ will flow. Ek = (58/z) log ([K+out]/[K+in]) ; z=1. The membrane potential sets the relative concentrations. Ions flow because membrane potential differs from equilibrium potential. For all intents and purposes, Na+ always flows in. We're interested at the rate in which it flows. To change the rate in which it flows, control channels.

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A stimulus is going to affect how fast sodium can flow across that membrane. However, the cell at -70mV is sitting a lot closer to -86mV than it is to the +55mV of sodium. K+, in order to have a greater effect, K+ has a greater conductance. At rest, the cell always has a great permeability to K+ than Na. The resting potential is established by the difference in relative conductances. The GHK equation takes this into account. Once you reach treshhold, you WILL have an action potential. It will always have the same magnitude. Two kinds of graded stimuli: Constructive interference of stimuli waves summing to reach threshold (spatial summation). Alternatively, temporal summation occurs when three stimuli occur close enough together. If the summations depolarize the membrane sufficiently it will open the voltage-gated Na+ channels in the axon hillock, creating a cascade that is an action potential. The equilibrium potential of sodium is +55. It will never reach +55 because potassiumis flowing out. Involved are gradients, counterflow of ions, and channels opening. Before treshold, only stimulus-gated Na+ channels are open. Then voltage-gated Na+ channels open. At the peak of the ap, voltage-gated Na+ channels close. Suddenly, K+ is now following both is [ ] and electrical gradients and exiting. There are two gates to a voltage-gated sodium ion channel: a pinchy-voltage-gate channel and a balland-chain. Both are open ascending, ball-and-chain closed descending. Past the action potential, both gates are closed. During the undershoot (hyperpolarization), the ball-andchain opens again.

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13 September 2007
MS attacks the schwann cells of the axons found in the brain and the long motor neurons. Shows up as a loss of motor control. Much of what we cover today has to do with why schwann cells are critical in sending a signal down an axon. The signal that goes down an axon is an action potential, a transient dramatic change in membrane potential. Typically, a cell itself does not have an action potential. How is it possible that there is no backflow of potential through the axon? Walking through an action potential: During the rising phases under the graded potentials, you have an Na channel that's open. Most typically the Na channels are not voltage-gated ion channels. Just something that received a sitmulus and that channel increases permeability of sodium at that point. The back-and-forth is because you get further and further from Poktassiums E, we're also getting closer to Na's E. Prior to major depolarization taking us up, a voltage-gated sodium channel with 2 gates (activation gate pinches, inactivation gate-ballandchain). At subtrshhold levels, the sactivation gate is closed. The point at which activation gate opens is the treshold. As you rise up, the interior (activation gate) opens. The difference in conductance is staggeringly different, 1000x greater than non-voltagegated channels. At the peak, the inactivation gate for Na closes. Somewhere along the the peaking, a voltagegated K+ channel opens right about the same time that the ap starts. The closing of the inactivation gate is the key to one-way propagation down the axon. Dropping below threshold closes the voltage-gated Na+ channels, and undershooting opens the inactivation gates again. To narrow the action potential, allow more sodium channels. Have potassium channels open faster. Not all K+ channels are alike. Some guys took a demand amplifier, capable of creating more current if it's needed. You have an electrode stuck inside an axon to insert a current to change membrane potential. You have a detector to measure the potential difference. As potassium flows out to try to reach E. This is a way of measuring current that's flowing across the membrane. Measures current by knowing how much it has to add to compensate for current leaving. The bucket question: You have a bucket is leaking water onto the ground. How much is it leaking? The leaking water is a current, to know how much is leaving the bucket you need to know how much you have to add to keep it at that line. V = IR, membrane resistance doesn't change. They treated a neuron with TTX to block sodium flowing. Na channels open quickly, K+ channels open slowly. Na channels close more slowly than they open. Signal has to go from A to B in an axon with high fidelity. Myelinated axons are faster because the signal enters at one spot and moves with saltatory conduction. There is a tougher issue with Unmyelinated axons: The goal is to get the signal from one spot to another. Ions are attracted to oneanother, like ion-sex. The fact that the ions are stuck on each side of the membrane unable to move is

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called capacitance. It means that as sodiums enter, instead of traveling down the axon it takes a turn towards the negatives on the side of the membrane (radial flow of ions). Additionally, negative ions move towards the +s inside and the +s outside leave. Capacitance currents look like swirls; they dont go in the direction we want them to go. Thats why we insulate the axons with schwann cells. Leak channels, ligand-gated channels, voltage-gated channels, other stimuli. Lots of reasons for channels to open; channels have kinetics. Delayed rectifier: Doesn't all open at the same time (start has some curve). These are the channels that stay open. Repolarization-opens channels.

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18 September 2007
We have an axon with ball-and-chain-gated Na chanels that spreads in both directions; it comes in and it nudges all the internal sodiums over, if the positive charges inside have a reason to shift any way other than down the membrane to trigger the next voltage-gated channel. That shift gets smaller and smaller, so we may not make it down the membrane to trigger the next guy. There are 2 reasons we wouldn't make it here: The sodium coming in is coming into a high density of sodium, any high collection of nexagtive charges inside the axon would reduce its axial current. Capacitance is ions stuck in place by mutual attraction to oppositely charged ions across a membrane. An axial current, heading in the right direction is part of the signal, nudging the next ions down. If it goes in any other direction, that is a capacitance current (I resulting from presence of capacitance). The actions of a neuron can be described using RC circuit equations V = IR. If Na heads toward the wall its the equivalent of a countercurrent to the axial flow. The fatter you get the nerve, the more ions you have that will push through capacitance. You solve it by increasing the capacitance of an axon. Terrestrial animals need fast small axons; We want some signals to transmit slowly. Myelinating an axon breaks capacitance by insulating axon, preventing impact on outside ions by charges on the inside and vice versa. What are the biophysics of an axon? Basically our fast axons are as fast as they can get; we've optimized #nodes as gaps between them. V=IR, voltage across membrane is dependent on current and resistance (how well channels open as well as whether or not you have a conductance across the membrane). Schwann cells increase membrane resistance radially but decrease axial resistance). Soma have action potentials too. There is back propagation from axon hillock to the soma. However traveling axially, by the time sodium reaches the next channel the previous one has not hyperpolarized The period in which the H gate is closed, no Na will flow (refractory period). Synapses: The neuro-muscular junctions single axon synapses onto a single fiber; they are controlled one fiber at a time. We start at the end of a signal: The neuromuscular junction ● releases acetylcholine into synaspe ● acetyl cho is manufactures in axon terminal ● receptors for Ach on post-synaptic membrane's ● Ach binds in a concentration-dependent manner ● Ach is cleared by enzyme action (acythlcholinesterase) ● choline is taken up visa transporter into the terminal ● more Ach is manufactured ● loaded into vesicle via Ach transporter Each item varies from synapse to synapse. Bernard Katz: God of neuroscience. Said two things:

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Quantal nature of neurotransmitter release. Why discrete quantities? How are they packaged. Ca++ dependent release of neurotransmitters. Why is second ion required? What is the link between Ca++ and vesicles. Looked at EPP (post-synaptic membrane potential) increasing and then action potential in neuron. Muscles have very similar properties to neurons. EPP saw that even in no stimulation, there were still some firing in absense of a signal. Mini-end-plate-potentials are all the same size. Neurotransmitters are packaged in same density and same volume anywhere in the cell. A mini-MEPP is the response of a muscle to 1 vesicles worth of neurotransmitters. As opposed to pancreatic cells, leaving insulin released slowly and quickly. Synapsin: vesicle-loading proteins SNAPs – priming/docking, lining up SNAREs – cause fusion to wall, time to release Synaptotagmin -comes off vesicle, is a vSNARE, Synaptobrevin – also a vSNARE Syntaxin – is a terminal tSNARE, in the terminal SNAP25 – is also a tSNARE, just these four can be reponsible for causing vesicle fusion. Calcium comes and opens up a VGCC, the tiniest amount of calcium enter a cell will cause vesicular release. The calcium binds in some way to synaptotagmin. Clostridium: Botulinum toxin and tetanus. Botulinum kills synaptotagmin. Tetanus break synaptobrevins, botox is paralyzing kills synaptotagmin Tetanus causes you to have maximum exertion. SNAPs line up vesicles, synaptotagmin responds to tagmin causes release.

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20 September 2007
Synapse: Electrical/chemical, excitatory/inhibitory. ACh and glutamate. The vast majority of interactions between neurons occur when a neurotransmitter is released from preSM and post-SM. Axonal properties: how fast, how reliably it fires. Synaptic properties: What's released, what's being listened to. Small molecule neurotransmitters Acetylcholine (+/-) Glutamate (+/-) Are the most prevalent in body. Ach is the major neuromuscular junction transmitter. Half the synapses in the brain use glutamate. The other half use GABA and Glycine. GABA is inhibitory (-) Glycine (-) Dopamine Norephinephrine/epinephrine Serotonin Histamine Endocannabinoids Neuropeptides are peptides produced by neurons to communicate to other neurons. Almost not worth talking about. One source of Na comes into cell: Constant Na current while recycling neurotransmitters. Acetylcholinesterase cleaves Ach, on the PostSM you have receptors. SMNT can be grouped in a few ways. In NMJs ach is excitatory. Glutamate is excitatory almost always. Aspartate Bloodbrain barrier regulates amount of everything going into the brain. Glutamate is profoundly basic. Ubiquitous and excitatory, glutamine is its precursor. Loaded in vesicles by VGLUTs and cleared by transporters. Once you release glutamate post-sm will fire until glial cells transport them back. Glial cells modulate the cells that they're wrapped around. Glial cells support a lot of the functions of neurons. ligand-gated channels where NTs bind to one or more units of these channels. If you are a receptor for glutamate with 5 subunits and 1 binding site. Onotropic Glutamate Receptors NMDA binds to some glutamate receptors and opens them. Ampa binds to some receptors as well as Kainate. This is one of the ways in which the brain regulatory function occurs on the post-SM (control

Hakan Sahin of the receptors).

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Glycine is an allosteric excitatory binding. Glutmate receptors can pass many different ions. When glutamate binds, a gate opens which allows Na and Ca and K ions, but will never let Mg through. NMDA receptors receive glutamate signal and nothing happens. These channels have a Mg plug in them. However, if AMPA receptors elsewhere polarize enough to polarize the entire membrane, the Mg block leaves. If you coincidentally have glutamate coming at the same time, calcium enters the cell and bind to proteins to change the nature of the cell. The binding of glutamate increases permeability to Na, Ca and K. Mg enters because its attracted to – cell environment. Zinc could also function like Mg. You run ATP and pump protons into the vesicle, its getting acetic. Protons flow down their gradient and glutamate is pumped against its gradient into the vesicle. VGLUT is an H+/glutamate pump. Glutamate is loaded into vesicles regulated by amount of H+ is in there. A single neurotransmiter binding to a receptor, you can increase the complexity of the receptor. Metabotropic receptors can affect more than 1 kind of G protein, each of which affects a different cellular pathway. An example: NT binds, G-protein binds adenylate cyclase, it produces cyclic AMP, it affects protein kinase which phosporalates K+ channels which shuts them down. Agonist vs Antagonist: Agonist: Biochemistry, a substance that initates a physiological response when combined with a receptor. Antagonist: Bch, a substance that hinders the effect of agonists Inhibitory synapses: GABA and Glycine. It can take many excitatory stimuli to cause an action potential in a PostSM. Quite often though it only takes a few inhibitory to shut it down. Inhibitory NTs affect chlorine, leaving Cl- channels open. Clamps the cell at the Equilibrium potential for chlorine, compensating for positive charges opening/leaving the cell by going in our out. This is why you need fewer inhibitory synapses. 10% question: Both GABA and Glycine are effectively interchangable. Glutamate is only one enzyme away from GABA. Theme for remainder of course: Both are manufactured/sequestered from the Krebs cycle, packaged by VIATTs (inh ) monitored by glial cells transported by glutamine transporters. The important one: As you open this site, chloride leaves the cell. Chloride acts as a demand aplifier. This is the target for a lot fo steorids and the primary target for barbiturates.

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25 September 2007
Different properties of synapses give neuron communications their nuances. With ACh , it's cleared from the synapse through constant enzymatic action. You release it in discrete amounts as far as we can tell. If an action potential exists in a motor neuron, it will depolarize the cell. If a neuron spritzes neurotransmitter, it will only respond if the post-SM is listening. There's a predominant excitatory transmitter in the brain. Nicotinic agonist for Ach acting on an ionotropic receptor; if it spritzed onto the heart it would be a muscle metabotropic receptor. Glutamate is not broken down, its reshuffled back into the glial cells to clear it from a synapse. Glial cells convert it to glutamine before pouring it back out. When AMPA and Kainate receive glutamate they become perm to Na and K at the same time. NMDAs are the same with the magesium block to leave. Glycine, normally an inhibitory transmitter, acts allosterically in an excitatory fashion. In fact, the synapses with a lot of NMDA receptors are bathed in glycine. NMDA specific synapses tend to be silent, they dont regularly tramsit signals. Only if there is a coincidence of signals entering (polarizing at one end, glutamate at the other). NMDA channels are the target site of PCP. Once calcium enters, it invokes lots of metabotropic responses. There are many synapses that have only NMDA receptors, no Kainate or AMPA receptors. Should the cell depolarize enough for calcium to enter, the synapse will recruit AMPA receptors to the synapse. Long-term potentiation: This is one of the basis we believe for learning and memory. One glutamatergic synapse varies greatly from another before of the sweep of receptors on the synapse. Ionotropic receptors are “channels”, whereas there are glutamate receptors that dont allow ions to pass that work through a G-protein process. GABA, Glycine: Glutamate is the precursor for GABA (one decarboxylation). Failure to inhibit is often a way of exciting. Both glycine and gaba increase perm post-SM to chloride. Ionotropic: GABAa,GABAc. Metabotropic: GABAb. These receptors have such a powerful influence on post-SM; exciting an inhibitory receptor can have a total blockade on that receptor. A lot of barbiturates, steroids, picrotoxin (excitatory). Allosteric binding site for benzodiazepines, allosteric associations allow yo not only to act as an agonist but allow you to accentuate access the channel. There's a difference between us having a molecule that works as te same site doing the same thing and working at a different site if GABA is present. There are nasty benzodiazzepines that are like valium and rohypnol. Biogenic Amines: Dopamine: Coordination of movements, reward-motivation reinforcement, and anxiety. When you activate these circuits, you relieve yourself of anxiety. Low levels of dopamine = high anxiety. Drugs

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that work on these sites are so powerful in their addiction. Excitatory/modulatory, primarily in corpus striatum, tyrosine, loaded in vesicles by VMATs, bind to g-protein coupled receptors, cleared by transporters, mono-amine oxidases. Dopamine works solely through metabotropic receptors. Cleared very specifically by transporters. In addition to that, it's destroyed by monoamine oxidases. Expressed in very specific regions of the brain, andhave 2-3 means to clear from the brain. V powerful with longterm effects. When MaOs work too hard, they have a tendency to clear dopamine from synapses too quickly. Nardil and Marplan are 2 of many anti-anxiety drugs that are MAO inhibitors, they prevent the breakdown of dopamine. Parkinsons: The substantia nigra produces the largest amount of dopamine in the brain. We noticed 1 thing: With the onset of parkinsons, One of the late set-ons of Parkinsons is anxiety. When the anxiety gets really bad, one of two things could happen. The dopamine levels drop precibitably with Parkinson's. Michael J Fox is currently taking L-DOPA (precursor to dopamine). Cant give people dopamine to get across the blood-brain barrier. Treatments for physical problems that we try to address have trouble with their specificity. Norepinephrine/epinephrine: Excitatory/modulatory, primarily in brain stem, tyrosine, loaded in vesicles by VMATs, bind to G-protein coupled receptors, cleared by transporters (Na+), MAOs. If you were trying to handle a dominergic issue by taking MAOI, you prevent breakdown of adrenaline. Drugs that attack MAOs can often lead to worse reactions. Know what neurotransmitters are up to norephinephrine. Almost all disease state we're aware of are not a problem with neurons themselves but receptors or ability to make neurotransmitters. Side note: Peptide neurotransmitters are sometimes way outside of our realm of understanding. Enephalins are part of the most powerful painkillers in the body. Cocaine is such a good dopamine-releasing drug it would be a good treatment for Parkinson's. SSRI's are similar to cocain, LSD (ergot) is is an amazing SSRI.

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UNIT TWO
02 October 2007
We're going to talk about sensory reception. Your nervous system is made up of a lot o fneurons, you sense things! The action of moving is a product of the motor systems in the body. Motor systems are pretty basic with the exception of control of the heart. The CNS is the processing center for all incoming information. Sensory-motor information: Can travel this in three possible loops: The first one is a reflex loop, comes up sensory neuron, goes into spinal cord, and then synapses to an interneuron(s) then down to motor neurons (eferrent). That same sensation goes up the spine and informs you of what's going on. This is the cerebellar loop. This is something that manipulates your behavior. The hangy-down part in the back of the brain. The last pathway is the slowest of the bunch, the lemniscal pathway. Almost everybody knows there is a right and left side of the brain. They are connected by the corpus collosum. Females have a bigger corpus collosum. Men have a more densely packed corpus collosum. The right brain controls and recieves information from the lefthand side of the body. One of the themes for the next exam is to keep this in mind for remainder of course. At what point does information cross to the other side? What point does it decussate and synapse onto the other side of the brain. The sides of the brain handle different chores. The left side handles speech perception and formation. Music appreciation and concept is on the right side. Dolphins sleep one half of their brain at a time. You really can use one half at a time. Ducks, when they are in a row In radical cases of epilepsy, there is a procedure known as a lobectomy. The prefrontal cortex is an incredible part of the brain we're just learning about. We want to take a tour of the brain and get into the sensory systems. CNS consists of cerebrum, cerebellum, brainstem, and spinal cord. Your sensors are truly just dendrites and they come together and form an axon but processing occurs at a ganglia, knots of cell bodies on either side of the spinal cord. A good deal of of what you process does not make it to the cerebrum. The cerebrum is incapable of doing what your cerebellum can do. Cerebellum is running most of the time. We have an entire system registering with the cerebellum at all times Then everything goes to the motor components: The Visceral Motor System and Somatic Motor system. These act on the effectors (smooth muscles, cardiac muscles, glands, and skeletal muscles). Brain divided in 3 groups: Hindbrain, Midbrain, and Forebrain Hindbrain is everything above spinal cord: Medula Oblungata (autonomic function, breating and digestion), Pons and Cerebellum (motor learning, motor control and cognitive functions). The midbrai

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is all by itself, handles the most innate motor control in the body (control of eye moments). Forebrain (Prosencephalon) consists of the Thalamus and Hypothalamus (Thalamus: Gateway to cortex, major connection point of all infoprmation coming from the body. Hypothalamus regulates endocrine control) and the cerebral hemispheres (Perception, thoughts, cognition, and language). Pons is the thing that is attached to the cerebellum. The diencephalon is the medschool version of the thalamus. Basal ganglia (Huntington's/Parkinsons), the source of almost all of our dopaminergic pathways. The midbrain is whre most norepinephrine/epinephrine in the brain. When you talk about brain lobes, you're limiting to surface of brain. Frontal lobe, Parietal Lobe, Temporal Lobe, and occipital Lobe. Your vision starts at temporal lobe, processes es through thalamus, goes to occipital lobe. Sensory channels: reflex,cerebellar, lemniscal, --dorsal column medial - proprioception: The ability to sense joint angles, flex on muscles, orientation in space --anterolateral systems -pain/temperature: A stretchreceptor is a sodium channel that is gated because of distorted membrane. Different sensations are determined by how the nerves are wrapped up. Pacinian corpuscles are wrapped up in layers of lipids they detect pressure. Ruffini's corpuscles detect the stretch. Somatic-sensory motor system.

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04 October 2007
What we taled about before were somato-sensory channels, reflex cerebellar and lemniscal. This is sense of touch, pressure, temperature, body awareness and three-dimensional orientation. The reflex step goes through the spinal cord and triggers a motor response immediately. Moon wants us to know that the chili-peppers near the spine are basal ganglia and all the information comin gin is very discrete, if you were damage the spinal cord anywhere the damage done is localized to a portion of the body. Reflexes try to keep things the same. Reflexes compensate for things. When you pull on the muscle, the afferent neurons sens If you are holding onto something and you're trying to lift it, a sensor checks your golgi tendon. The brain talks to the interneurons and spinal cord to control all this activity. An awful lotof what we need to do to have conscious activity is to inhibit reflexes. As a side note, PCP has this same effect (horse tranquilizer). Inhibits inhibitory circuits. Mechanosensory touch has nothing to do with reflexes. Two-point discrimination threshhold in mm is used to figure out how sensitive nerves are. Dermatome: Skin-mapping onto the spine. Nociception: Pain and temperature information from the upper body, follow the anterolateral system, come in on the anterolateral side entering through the dorsal horn and decussates immediately and travels up the other side. Nociception is detecting the orientation of the body, form of reflex (don't want to lose that). A fibers are almost always excitatory, C fibers are unmyelinated are slow and delayed. Temperature receptors in the body are capcaicin receptors. The next step is the cerebellar system. We should know that reflex happens without us thinking about it. Vision versus visual perception One of the most heavily studied systems is the visual system. Brain interprets by contrast.

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08 October 2007
The retina works like a film, recieves the light (comes through series of cell bodies hitting rods and cones). Rods are long, sort of symmetrical. Cones outer membrane is invaginated whereas cones have discs inside. There are bipolar cells (directly receiving input from rods/cones). Neither rods nor receptors nor cells have action potentials, they are all graded potential. Next in line are retinal ganglial cells. Sets of horizontal cells mediate interactions between rods and cones. Amacrine cells regulate interaction between bipolar cells and ganglial cells. Most basic: Receptor -> Biopolar -> Retinal Ganglial cell. Your body is largely concerned in making distinction based on contrasts. The circuit will consistently try to decide the difference in the amount of light between neighboring rods and cones. In rods whenn in the dark, sodium flows through a channel and the rods depolarize. In the dark, when nothing's happening, these cells are firing and when you see light these guys shut off. Non-selective cation channels (ca and Na) go quiet when they see light. In the rod there are pancake-stacked discs. Stuff happens in these discs that communicate with the ion channels in outer membrane of rod. Photoreceptors are in the discs of a rod. There are 2 proponents to the receptor, the receptor is rhodopsin. The protein is called opsin with a cofactor of Retinal. Retinol has 2 forms: cis (kinked) and trans (straight). Upon exposure to light, retinal conformation changes from cis to trans, this changes the rhodopsin that will undergo a subcellular process. Active rhodopsin effects transducin which is a g-protein. Transducin activates PDE which breaks down cyclic GMP out in the cytoplasm which then binds to ligand-gated cation channels. Upon exposure to light, this rod cell is going to hyperpolarize. In the dark, you release glutamate onto bipolar cells and in light you do not. You hyperpolarize in the light and release less glutamate. Arrestin: A strange protein that does 3 things simultaneously: Reassembles g-protein complex trabsdycub (turns off PDE which breaks down cGMP to GMP), pushes out trans-retinal from receptor by interracting directly with the receptor and removing trans-retinal, In the back of your eye where retinol is, in the center of the back of the eye you have the optic disc. The cones are centered right around the center of the back of your eye (the fovea). You have incredible density of rods 20degrees off-center either direction from the fovea. Retinal ganglial cells report cell-per-cell to the back of the brain. There is a stop-over at the thalamus on the way, this includes vision. Then it goes to the back of your head. A single receptor reports to a pair of ganglial cells; for every single point of light this happens. The receptive field is a chunk of your visual field, ganglial cells only respond as light enters and exits a receptive field. In episodes of greater contrast, the neuron will fire faster. This is what defines the two areas of a receptive field: the center and the surround. If there is high contrast here, the neuron will fire faster.

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Ganglial cells have a behavior that they're interested in. A receptive field has a center and a surround.What is the circuit that causes one ganglial cell to be on-center and the other to be off-center? Highest contrast exists when one of these ganglia is firing fast and the other is not at all. This center cone is hyperpolarized, it is not releasing glutamate. One bipolar cell is inhibited upon exposure to glutamate and the other is excitatory in response to glutamate. It gets worse. The horizontal cells accentuate this process. If the surround is dark, then these two cones are releasing glutamate to the horizontal cells. Horizontal cells have dendrites in both directions, and will trigger faster hyperpolarization and cause center cells to go quiet faster by allowing information to go from the surround to the center.

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11 October 2007
In the retina, you process regions of contrast. What the retina reports, cell by cell, is the part thast I am looking at is either all one color (on) or all dark (off) or its reporting contrast. Anything other than optimal contrast condition will fire at an intermediate rate. The neurons, as they report to the back are not reporting anything in between. This is different from what books will tell you. Horizontal cells talk between rod cells, however they also synapse onto bipolar cells (they are being documented). A neighboring horizontal cell inhibits. All retinal circuitry, we're interested in contrasts (extremes). thalamus, brain porn on tuesday. All information goes through the

The lateral geniculate nucleus LGN The connection of all the ganglial cells axons is the optic nerve. They chross over in the optic chiasm. In reality, what's going to the right side of the brain is everything in the left visual field. And vice versa. The optic chiasm is a site of frequent traumas, the pretectum controls blinking and the superior colliculus has to do with tracking in the eyes. The ability to follow is not a conscious thing. Ipsalateral information is stuff that stays on the same side, contra-lateral is everything that crosses over to the other side. As the LGN feeds info into the midbrain. The LGN has six layers. You have a left and a right LGN, the info coming in from your eye gets split (gets replicated here). Each layer is mapped just like the retinas, two magnacellular and 4 parvacellular layer, and one conacellular (the interlayers). Parvocellular layers receive information from retinalgangliar cells that are receiving information from cones. You have six layers, but in the lefthand LGN, we have stained layer six, layer four, and layer one. 6, 4, and 1 receive left-fieldeverything from the 5,3,2 ipsolateral 6,4,1 contralateral. This information in the striate cortex is then processed in groups; you have cells here that receive information from the retina that say “do i see not just 1 dotted light but a row, not only a row, but at one angle, and that is moving in one direction.”

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16 October 2007
Your visual field is divided up into a left zone and a right zone, and in some parts the eyeballs overlap. Each of those left and right visual fields is divided into a series of receptor field, represented by what a pair of ganglial cells responds to. The circuit of the retina set it up so that you fire the most when you have a dot in the center of a surround. Light is really edge detection, major chunk of information into the retina is the outlines of what we're seeing. The enforce this we have lateral inhibition: Your eyes are litterally lying to you to accentuate an edge. If an off-center cell patch. Horizontal cells allow inhibition of neighboring cells to amplify contrast. Ganglial parvocellular cells report color, magnocellular report edges. Red-ON-Green-Off surround. Seeing ren-on and green off is no different from an empty field. The other type is Blue/Yellow. The rule is the Left LGN is going to receive at 1,4,and 6 information from the right eye. The Left LGN always recieves information from the right LGN. Koniocellular cells exist between parvo and magno cells, they are a way of comparing contrast. The K-layers interpret depth of field and because of that, motion. One myth: The LGN is not a one-way street. Some 80% of input to the brain comes back from the primary visual cortex. At the striate cortex is retinotopic, meaning it is mapped according to the retina The info coming from LGN goes to only one layer of visual cortex. The neocortex in the brain is extremely complex and all the neurons from LGN synapse at layer 4C. It basically ends as you get out of V1. Alternate layers of the LGN are comparing two different eyes. What your left-and-right eye see at the same point in space is represented side-by-side. In that cortex, you have many cells but Moon only cares about three. Simple cells, complex cells, and hypercomplex cells. Simple cell circuits largely interpret orientation. They say that a whole row of a ganglial cells are firing at a single rotation. From each of the cells, the cimple cell circuits fire only if a whole horizontal, vertical, or diagonal. Complex cell circuits talks to a series of simple cells and watches the order in which they fire. They are also called end-stop cells. They add up with spacial summation. Hypercomplex cells They determine the size of the bar and the limits of the bar. If it's this big I'll talk, or I won't talk. Leaving end-stopped cells up to us. Information came out of the eye and we had 2 ganglial cells reporting information for the black-andwhite field.

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You have slabs corresponding with the cortex with a hypercolumb in each slap. They're mre concerned about grey, pink, or tye-dye. The “blobs” as they're called will fill in with most dominant color. The whole thing is like one big Seurat painting.

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18 October 2007
The parvocellular and magnocellular pathways get devided into 2 general pathways: Where (parietal) and What (temporal). Two face-recognizing sections: Familiar faces and ought-to-know faces. We have somehting called a prefrontal cortex. Hit right away by alcohol. Phineas Gage was working on a railroad and a rod went through his cheek and came out of his skull. We rely on these events to gell us something. The rod went right through his prefrontal cortex; after this incident, gives decision-making and consequence-action relations. One of the most profoundly perceptive functions of the brain: anticipation. After this incident, he became an ass who was difficult to work with. This is one of the last parts of the brain to develop, develops later in males. How you distinguish frequencies, origin of sound, how we adapt to changes in sounds. Broca's: A lesion between frontal lobe and centers that allow him to hear what he's saying himself. Wernicke's: Lost aspect of ability to form speech and tie it in. Cochlea is a spiral structure filled with fluid. The meat an potatos: The organ of corti is what attrs. Tectorial membrane covers organ of corti; basilar membrane is pink and smooth with a lot of structure and inner hair cells with afferent axons leading up to the brain. Three rows of outer hair cells and 1 inner hair cell row. Outer hair cells have efferent axons. In the same fashion of the eye, feedback occurs. The spiral ganglia accumulates the information from the inner hair cells. The inner hair cells have a resting potential of roughly -45mV; up in the endolymph there is a high K+ (80mV potential). The scala tympani is also very lo win potassium. On one side of the hair cells you have extremely high concentration of potassium.

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23 October 2007
At one end from the oval window it gets very narrow but thicket. The further from the source listens to lower and lower frequency. We have tonotopically arranged cells in the basillar membrane. We have a roughly 5 hertz discrimination range. There's a concept called phase-locking where we discriminate low frequency sounds better than high-frequency. The neurons can actaully fire somewhere up to 2-3000 hertz. For our purposes we go with 3,000 hertz figure. Bats however can phase-lock 40-45,000 hertz and respond up to 60,000. Because of the nature of this membrane, for most of the membrane we hear very very low tones up to the range of th enormal voices. Phaselocking is the ability of the hair cell to fire as rapidly as the membrane is flickering up and down. We put that down at 3000 hertz for our class. Outer sterocilia are arranged in rigid v-structures which are pushing the membrane up and down. Outer stereocillia amplify sound at lower intensities. In high-intensity sounds they do the opposite. As we hit the maximum range, they will have destructive interference. Somatic electromotility! The cochlear nucleus detects the fact that information has come in. One of the first site it hits is the Nucleus of Lateral lemniscus. Your ability to turn the head and hunt us down is dependent on the ability to hear it. Cerebellum turns head in direction of sound. We never regulate our eyes moving towards something. What we hear gives clues to our eyes on how to move. We sensitize and desensitize sterocilia by Stuff comes in through cochlear nucleus to medula, wanders up NLL to inferior colliculus which allows us to orient things. Superior Olive – Location Detection. Circuitry in the brain that deals with frequency determination. If the input is unequal (3,000 khz>), then one olive significant inhibits the other more. 3 things: Discriminate/amplify frequency. Localize the sound. Pull this together to determine quality of sound. The thalamus does this. Below 3KHz, we're phase-locked. The rate at which they fire and distance from left-to-right ear and medial superior olive Pinna changes the quality of the noise coming from above, behind, beneath you. Vestibular system is responsible for sensing what direction your body is in. The utricle, saccule, ganglion, Somewhere in the canals is an ampulae that pushe

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25 October 2007
Information come sin from cochlear nerve and arrives at cochlear nuclei. You innervate superior olive in the pons and the NLL and th einferior colliculus simultaneously. Inferior colliculus does the left/right and vertical fine-tuning, generating a space-map where sound comes form At the cochlea and spiral ganglia and nucleus you have discriminated frequencies. The superior olive is concerned with frequencies and so is the Inf Col but the NLL is not. NLL recieves stuff and just wants to know where we heard it first. This NLL recieves contralateral monaural input. The IC is receiving information from both sides. The medial geniculate decides whether or not to pass that information to various parts of the brains. There are 3 ampulla, one for each semicircular canal. Two sacky things: Saccule and Utricle. Roughly he same sensors and they tell you that you're moving lateral. They are dependent upon gravity, whereas angular momentum (dependent on mass). The gravitational force affecting the two pads has to do with our sense of proper posture. Vestibular system talks to a lot o fstuff: It come sup through the cranial nerve and part goes to the cerebellum. That is largely responsible for our sense of balance and postural control. Then there is a thalamic nucleus (VP nucleus) that has to do with we'll talk about it later. Our limb motor neurons are being regulated by the vestibular system also, it talks to our legs our arms and our head to keep everyone oriented right. Also extraocular motorneurons (eye control). We have motor control of inhibitory and excitatory strimuly These systems are constantly firing and you have to numb them to eliminate the input. A systems preview: Motor We're not very good at motion control. Cerebellum is the thing that coordinates body attitude and posture as we go through voluntary motions are controlled by cerebellar motions. The cerebellum uses positive control and the basal ganglia use negative control. Ascending pathways: Visual Auditory Vestibular Somato-sensory information Proprioception Mechanosensory Nociception (Pain/temp) Cerebellum is under no control from the rest of the brain. Recieves information from everything but the brain does not tell cerebellum what to do. You train it to take care of the mundane tasks of life. It has peduncles: three of them. Superior, Middle, Peduncle. Peduncle is a big fat nerve. You have the trigeminal nerve coming in. Dorsal Nucleus of Clark is often called the DNC, recieves information coming up and goes to one part.

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Receives sensory information from body and motor responses from the brain and says “yeah it makes sense to do that.” You already know there's vestibular information coming in through vestibular nuclei and inferior olive. Two big waves of info comin ginto cerebellum: motor intent an body action. Devided into two terms: Proprioception Pathways and Magnocellular Pathways. Afferents come in from both frontal/parietal coreces, go through th epons to the middle cerebellar peduncle. Proprioceptie info comes in from the inferior olive, spinal cord, and nucleus. Cerebellar cortex takes in all that info and makes a decision and sends it to the deep cereballar nuclei through the superior peduncle which goes to the VL complex and sends info back to the brain saying “you may take that action and go ahead and stick your lleg out while you're doing it.” This information come sout of Deep cerebellar nuclei, goes back up and fires on motor cortex and says take this action. You learn in your cerebellum. If you blow air onto the eye of a rabit it will blink. This is unconditioned stimulus (innate). Open a can of dog food and open it under the nose of a dog, it will salivate. These are unconditioned stimuli. Howver if you pair another stimulus like a tone, such as preceeding the puff of air with a tone. The circuit gets rewired and so the bunny hears the tone and will start blinking. What's going on is the puff of air come sup and hits a trigeminal nucleus which goes to the inferior olivary nucleus which has an excitatory action on another nucleus which comes down to the red nucleus. The red nucleus is the major nucleus of th emotor area that sends a signal down to a facial nucleus that causes a blink. However, if you hear something you operate your vestibulocochlear nucleus Moon wants us to know: There is a climbing fiber that wraps around the Purkinje cells. These are extremely well-studied. That fiber is a parallel to the mossy fiber that comes up to a granule cell. Every stimulus you can think of comes up and broadcasts in a broad circuitry of parallel fibers, which interact with purkinje cell. There is an attenton center in each of the Parietal lobes. One is dominant to the other. If you lose some of your right parietal attention center, you lose all attention to left visual field. responsible for contralateral neglect. A cone talks to at least 2 bipolar cells. Superior Olive -> Inferior Colliculus -> Turns head towards sound Inferior Olive -> Superior Colliculi -> Turn eyes/head towards visual cue The NLL necessarily goes to the inf col to move the head. The IC all by itself can move the eyes without input from the NLL.

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UNIT 3
08 November 2007
Cerebellum to Basal Ganglia to Limbic System Two pathways come out of basal ganglia: Motor control and other stuff going on in the brain (inc learning and memory and sleep and how you process subtleties of language such as intent). The amygdala is one of the last checkpoints of information in which you process the physiological response to stimuli. It's where you house to a very large extent notions of fear. There's a link between the amygdala and the rest of the body which is very strong and that link is through the hypothalamus. The basal ganglia mediate all motor information adnt they take into considration things like the nucleus accumbens and the VTA (pleasure center) and all of that comes through pontine reticular formation. All the basal ganglia affect the pontine reticular formation. Hippocampus governs learning and memory. In the midbrain we have the red nucleus and the substancia nigra (affected by parkinson's, tremoring is a result that the substancia nigra lead to anxiety disorders and motor control. Weird dual-job of the system. Our activity is a function of how well we handle the situation around us. Goes through midbrain (prebrain and tectum; tectum contains superior colliculus and inforior colliculus). Below that is the reticular formation which goes down to medulla oblongata. Part of a descending pathway; got a VTA coming out of basal ganglia and we're going down from there. Upper motor systems: Motor cortex wants to do things (mediated by basal ganglia) we have a brainstem which takes in information from vestibular system along with cerebellum (through red nucleus). Motor nucleus + Mcortex synapse onto lower motor neurons taking into account sensory input and sensory input and goes to muscles. Junction between upper and lower neurons is very discreet. Youj have the superior colliculus which drives things goeing down. Superior colliculus has signal that comes out and goes to cervical spinal cords that drive motor control of head and eyes. Superior is predominantly as a result of visual, inferior as a result of auditory information. They decussate immediately. They have inhibitory arcs crossing the other direction. The cerebellum is behind all this and it talks to the red nucleus; red nucleus itself comes down and it deals with cerebellar modulation of all these descending pathways. It's not the cerebellum or the basal ganglia but the reticular formation that imbues us withmost of our grace and motion. You can go down from premotor and motor and decussate and go down the reticular formation or you can go through a lateral tract. We're born with the same number of motor neurons that you'll ever have. The somatic motor system: Skeletal, smooth, cardiac muscles and their innervation. Between skeletal, smooth, and cardiac muscles go about contracting in different ways so be sure to notice the DIFFERENCES between these systems and how they are innervated.

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Muscles: You have muscles that come in organizational units. What occurs in the smallest muscle unit (sarcomere). The two proteins involved are actin and myocin. They are contained in each myfibrile; a myofibrile is a sub-cellular structure. The motor neuron comes down and hits the membrane wrapped around many myofibrils and the membrane is a cellular membrane. The membrane has invaginations that come all the way in called t-tubules. The membrane sticks in and allows for increased contact with sarcoplasmic reticulum, wrapped around each myofibril. Input from the neuron will cause a muscle twitch. Continuous input causes increased twitches. It is, to a point, gradational. It is graded response to muscle strimulus. If you continue to fire the muscle will just stay as contracted as it can. The primary receptor is acetylcholine receptors. Muscles rest somewhere around -100 to -90 and when Ach binds, it is highly permeable to sodium but not potassium because we're really close to potassium's Eq potential. As we depolarize, we start to move past potassium's Eq potential. Most depolarization events just get us to the reversal potential for that membrane and then we repolarize. The currents responsible are both sodium and potassium. E(Na) = +65 E(K) = -80\ Reversal potential: -10 You get a motor neuron coming down, it releases Ach on Ach receptors and you depolarize the membrane to such a degree that its effect reaches down T-Tubule. Once we get to sarcoplasmic reticulum, it releases calcium which drives muscle activity. Calcium is effectively working as a secondary messenger here. The t-tubule comes down and lays over the fishnet stockings and brings the depolarization wave as close to sarcoplasmic reticulum as it can. Motor activity is this: You've got something that sits there (myocin) and pulls in actin which lays on either side and passes over it. Calcium binds to Troponin which moves out of the way so the actin head can bind (without energy). It flexes without any energy to bind. The energy being used is a green atp which allows the head to stretch out again. Moon will say this once: We dont need to know about the Magnesium (enzymatic cofactor for ATPase activity of myocin head). Calcium ion nears troponin, binds to troponion and troponin changes configuration. It seems as though the troponin moves out of the way. Magnesium binds myosin, atp is cleaved, and the myosin extends so it can stretch out again. A twitch is the muscle result to a single strimulus. Te temporal summation gives us slow tension and we eventually result in a state of tetanus when you reach full contraction. The two main things we're concerned about: You need ATP to reset the head and you need calcium. General stores: a few contractions. Creatine phosphate: 15 seconds. Creatine phosphate can restore adp to atp. Glycogen (1-60 minutes anaerobic v aerobic). Myoglobin is a unique form of globin in muscles and it has Mg in the center instead of Fe. It's more powerful than hemoglobin so it sucks the oxygen

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Calcium binds to triponin after going through a series of receptors. Di-hydropyridine Receptor (DHPR) is a voltage-gated channel in the t-tutuble. It senses the depolarization of the sarcolema. On the sarcoplasmic reticulum is a Ryanodine receptor (mechanically-gated). In muscles, what happens is that DHPR detects voltage and changes conformation when a voltage gate comes through and it literally has a tether that reaches from t-tube membrane to sarcoplasmic reticulum and it yanks open a ryanodine receptor that lets the calcium through. Tahat calcium comes down and does its thing on troponin. If ever there was a final exam question: Step 1 through 14, this would be it. We have multiple kinds of muscles: Striated (voluntary) muscles (multi-nuclear, organized sarcomeres (end-to-end), and sarcoplasmic reticulum in fishnet). Motor neuron stimulus. Smooth: Monocellular, unorganized sarcomeres, have an endoplasmic reticulum as opposed to a sarcoplasmic reticulum. Don't behave like regular muscles. Autonomic stimulus Cardiac muscles: Mono-cellular, very organized sarcomeres but have sparse sarcoplasmic reticulum. Cardiac muscles bifurcate onto two other cells that allows once cell to attach to multiple cells. It's not a linear path of contraction. Autonomic stimulus and auto-depolarization. Smooth muscle cells have stuff going in every direction and they just get smaller in general. No sense of linearity at all. Moon really wants us to understand this aobut smooth muscles: There are many ways to make a smoth muscle cell fire (if you somehow let calcium in, the calcium binds to Calmodulin and this complex binds to MLCK myocin-light-chain-kinasse. This kinase adds a phosphate group to the myocin heads and a phosphatase is constantly reversing this process. When they're being activated the myocin is getting phosphorolated. Only when its phosphorolated does it reach over and grab the actin. CyclicAMP inhibits this MLCK. We have a description where Calcium can enter the cell (in this case through a gap junction. Norepinephrine binds to a receptor which uses a Gq subunit which drives phospholibase C IP3, Ca++ R/ MLCKwhich) Epinephrine goes and binds to a Gstimulatory subuntit which goes to adenylate cyclase which produces more cAMP and inhibits. In skeletal muscles you need neuron-per-fiber. But in smooth muscles it communicates slowly and rhytmically. A Adrenaline as norephephrine causes excitation but epinephrine shuts down. Cardiac muscle will branch and so a cell will have a muscle fiber which comes up and binds to the next cell The heart respodns to autonomci system but also beats by itself.

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13 November 2007
Recruitment: You have a very careful system that calculates how much force you need to lift, squeeze, which neurons to recruit. It's all cerebellar. You control a heart in two steps: I want you to beat harder. To make a heart work well physiologically, we have to tell it to squeeze out every drop, then you tell it to really relax so it can fill with everything so you have a larger stroke volume. Major theme in heart control is time delay. One node is called the Sinoatrial node, the pacemaker of the heart. Pacemaker cells are only here in the SA node. In fact, if there are pacemaker cells anywhere else that is a diseased state. Cardiac cells depolarize to pacemaker signals. You start at the SA node then a wave (propagated by gap junctions) fire from SA node outward. You do not want atrial systole at the same time as ventricle systole. If the ventricles fire early, they push the blood back into the atrium and the venous system. During atrial systole, ventricular diastole occurs. As the signal propagates from SA node, it hits the AV node which passes the signal through bundle branches (down to the heart apex), Purkinje fibers depolarize the ventricles almost all around There is a sodium leak current in the pace maker cells of the sa node. The size of that current dictates how fast you repolarize your calcium current. One more concept: SA node cells have 60 bpm. AV node is maybe around 45-50 bpm. We don't know why, but if you eliminate the SA node the heart will still beat. There is a backup in the AV node. The Bundles of Hiss and Purkinje fibers by themselves have a 20-30bpm cycle on their own. Probably due to sodium leaks. If they shut off your SA node the heart will still beat. Striated: Motor neuron stimulus / Ach-> Nicotine receptors, Up gNa and gK Smooth: Autonomic stimulus / ach -> muscarinic receptors, up gCa Cardiac: auto-depolsation autonomic stimulus / Ach -> muscarinic receptors up gK down gNa & gCa / NE -> adrenergic receptors down gK up gNa and gCa. Dihydrophyradine channel blockers include nifedipine: Cause calcium current to be reduced. Five types of calcium channels: N, P, T, L, Q. N type: pre-synaptic terminals, strong depolarisation. Down at the end of the presynaptic terminal that allow calcium to come in and allow neurotransmitter release. Blocked by omega-CgTx. P type: Strong depolarisation, slow inactivation. Often called P-Q type. Blocked by atratoxin, obscure toxin from funnel web spider. Number 1 killer of little boys in Australia. T type: Activated by very small depolarizations. The one that gets the heart going. Found in pacemaker cells. L types: Heart cells (along with virtually all other cells). Blockedby verapamil. Exam Question: What are the effects of adrenaline and atropine on the heart? Why use one over the other. CNS-> Motor Neurons-> Internal invironment is the autonomic nervous system.

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There is a sympathetic and parasympathetic system. In general, Ach is transmitter of parasympathetic system. Norephinephrim: Main transmitter of sympathetic system.

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15 November 2007
Cells in AV node unique from atrial cells. SA node is a localization of specialized cells; they effect the bundles of Hith. You can have nonfunctioning atria and still move blood around the body. There is also a barrier between the atria and ventricles in which there are no gap junctions. This has been known to fail. The initial immediate drop in the cardiac myocye membrane potential is because you lose sodium flow. Then it stablizes (stable calcium currents) and As this starts to repolarize, the HERG channels open and you have a very large potassium current which causes rapid descent in later part of the curve. In human pacemaker cells, there is an inward current which is a sodium leak current. Could be a calcium leak current also. Atropine causes dialation of the muscles in the peripheral circulatory system.

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27 November 2007
Learning and memory are functions of the entire limbic system. In addition to that, it's utilizing a part of the brain which half limbic system, half cortical system (medial temporal lobes). This system, which is also responsible for emotions is responsible for learning and memory. From the cerebellum to the basal ganglia to the limbic system to the associative cortex to the hypothalamus to the autonomic system. The basal ganglia are dark areas that are close to the structures of the temporal lobes. The associative cortices are everything that are not primary motor cortices. Quick cerebellar review: Receives input from motor intent and sensory cortices. You also get vestibulular information and the inferior olive brings info from visual/auditory cues and the DNC which brings in proprioceptive information. The function of the cerebellum is to take over as much of that activity as it can. Another issue is the primary motor/premotor cortex. The hippocampus: A structure that recieves information from Thalamus, Amygdala (inhibiroey mostly/excitatory), hypothalamus, and Vental Tegmental Area(nucleus accumbens pleasure center, the pathway that assesses this and leads to a process of reward). The VTA hightens the activity of the hippocampus and says don't forget that. There's a raphe nuclei that's dedicated to fine motor control but also somehow learning and memory. The raphe nuclei synapse for all intents and purposes, everywhere. The cerebellum, cortices, hypocampus, EVERYTHING. Activates the hypocampus for remembering things. If they are working hard, then they mediate motor control so that you're not very good at something. “Watch and pay attention” structures. The hypothalamus sends in information on body state. The wire that comes out of the thalamus is the fornix that touches little bodies (mamillary bodies) that talk to the hypothalamus. The CA1 cells of the hypothalamus are where long-term potentiation and long-term depression take place. The CA1 cells look like perkinje cells. Other cells come in and synapse on them. You receive information and store memories as a result of that. You receive primary sensory information, and you couple that with where you are (place memory), and your emotional state. You remember based on your emotions. Cortical association -> Parahippocampal and rhinal cortical areas -> hippocampus -> back to cortical assocation to say this is worth remembering (most of these are inhibitory) and also through the fornix to the hypothalamus. Memory and learning: You have declarative and nondeclarative memories. Nondeclarative memories include motor skills (reticular formation, basal ganglia, cerebellum), associations and priming cues are usually found in temporal lobe structures. Amnesia: See how it doesn't work. Lots of kinds of amnesia. Retrogradae (often cortical) amnesia (can't remember things in the past). Anterograde (often hippocampal) (not being able to form new

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memories). If you remove some of the medial rhinal cortexas you are definitely going to have retrograde amnesia. You have to be able to call upon your temporal lobes to recall information. If you whipe out the thalamus, it kills the point at which medial structures talk to one-another. Three theories of hippocampus modality: Cognitive map theory (spatial context): Remember things because of where you were or where they are. Configural association theory (logical associations): You figure out what things are because they're logically associated with it. Path integration theory (relational associations): Relational assocations where you relay a lot of different factors and you intergrate it (that's what a memory is). Supported by hippocampal wiring. Striatal cells (caudate and putamen) relational memory: Pretty straightforward: The CA1 cells are really the cells that are changing; their synapses are undergoing long-term potentiation/depresssion. The structure they synaplse onto are just like the parallel fibers in the cerebellum. You have a major output going to cerebral structures. The major incoming pathway is the perforate pathway. There are structures that send this to the associative cortex and determine whether or not something is worth remembering. Immediate memory -> working memory (memory you utilize as i write it down and hear moon say it and 5-30 minutes I recount most of it) -> (consolidation, occurs with repeated exposure or a contextual switch; if we meet anywhere but this room and talk about this again we have ANOTHER spatial context to remember this in, or if we find new words to explain this concept, there's another really good way to consolidate memory: high stress or high pressure) -> long-term memory. Sleep: What cues us to sleep? Light controls circadian rhythm. Hypothalamus has a structure which has a suprachiasmatic nucleus (biological clock) They will maintain a 24hr cycle for a few days. Our clock cycle is dictated by a very short series of proteins such that every 24 hrs you run out of a certain protein. This whole cycle is reset instantly upon exposure to light. The lack of light causes receptors to fire; so the lack of light melanopsin is being produced. Melanopsin is triggered by the loss of light and the paraventricular nucleus and it sends a signal back down the spine again to the SCG which comes back up and ttalks to th epineal gland (ancentral organ). Serotonin levels spike that provides the resources for melatonin to be made. Natural process will convert that to melatonin. You do lots of things in sleep: Alert cycle much higher during the day, body temperature is a lot higher during the day. You grow at night; if you don't sleep, you don't grow. Cortisol levels drop throughout the day and regenerate at night. Stages of sleep: Beta waves (short waves), theta waves (longer waves), sleep spindles (final burst of activity), stage II and II go down, and then delta waves at stage-iv. Then finally you peak and you hit REM sleep and you're almost as active as when you're awake. Roughly every ~90minutes to hit REM sleep which lasts about 10min. Sleep apnea is what my dad has, you stop breathing and your cycle resets to stage II/III sleep. We're pretty sure that you dream during REM. You are definitely not sleepwalking sleeptalking. No night terrors; you are effectively dead to the world but brain running at high speed. Consolidation of memories occurs during REM sleep.

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Melatonin comes down to the pontine reticular formation and activates GABAergic neurons and these do a series of things that comes down to the DNC and inhibits it. Through another pathway it activates a glutamitergic pathway that activates glycine also activating glutamatergic pathways that activate parts of the cortex. Sensation goes away as you fall asleep and movement is inhibited to the point where you are effectively paralyzed. Sleep Phenomena: Hypnic jerks (hypnogogia): Started to paralyze you. No matter how much you try to move, you can't. It's in full effect during REM sleep. Lucid dreaming/false awakenings: There's a definite switch that switches off consciousness when you're asleep. Lucid dreaming is the case where you come up enough to consciousness and watch your dreams occur. False awakenings: Dream that they woke up and walked to the bathroom and come to the bed, but they never went out of the bed. When someone's asleep, they remember everything they saw. Other parts (parietal cortex) are actively being stored. Narcolepsy: Bobbing along and doing everything normally, without having benefit of going into anything, you fall asleep. In some narcoleptic cases they get a full night's rest (stage I to REM in 30s).

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29 November 2007
The increase in awakeness that occurs during the end of sleep also occurs during the course of the day. Hypocretin Eating disorders go through the exact same wiring as drugs. They light up the same centers of the brain to equal intensity as some of these powerful drugs. Caffeine is just as big a drug is the same caffeine in the chocolate bean. Chocolate has phenylthalines (emulate love pleasures, tiny amount) and caffeine that makes you addicted to it. Addiction: Nucleus acccumbens and Vental Tegmental Area. This is a structure that is largely midbrain but its an area. There is no hardcore medical definition for addiction, but there is a physiological set of symptoms. Addiction implies dependent cravings, massive cravings for something. You cannot maintain your normal physiological state without your cravings being satisfied. The other component is fuzzier, and that's the notion of tolerance. With increased exposure, we gain tolerance. Cerebellum: Learning and motor controlled pairing motor intent with proprioceptive info and sensory input basal ganglia: reptitive motor control reticular formation: fine motor control Hippocampus: learning declarative memories pairing sensory information with emotional state nucleus acumbens: cravings/pleasure centres amygdala: perception of fear hypothalamus: stress state Neucleus accumbens: sexual arousal, waking arousal (usually the same thing for most people) , VTA is a center that branches out in every direction you can think of. Executive function makes you you. Prefrontal cortex says “yes its chocolate, there are higher things to consider.” Abrogating that pathway in any way leads to addictive behaviors. Pre-limbic structures directly transmit the concept of structure. VTA transmits notion of reward in response. If both the VTA (dopamine) and Pre-Limbic (glutametergic onto nucleus accumbens) fire in coincidence detection circuit, dopamine accentuates effects of glutamate and this is called cravings. Nucleus accumbens says “do that again.” Through the amygdala you detect a cue, a relational memory. Takes these cues and the basolateral amygdala. The extended amygdala has just been described. Those wires come from the hypothalamus and the stria terminalis also responds to hypothalamus an dthis is the component where stress and cues come through the amygdala. The medium spiny neurons of the NA get bigger and fatter and their complexes get more bulky in presence of amphetamine. Amphetamines mimic the development of cravings, there is aphysiological change in the nucleus accumbens called addiction. Lateral hypothalamus is responsible for arousal and awakening.

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Novelty: Hippocampus perceives novelty, a major way of activating NA. Has to do with tolerance and all sorts of stuff. Novelty seems to be able to drive addictive behavior. Hippocampus stores a daytimes worth of experiences in the dentate structures which gets replayed backwards in dream states. Because of those results, predictions are made and the CA1 circuit gauges what we've learned about experiences and senses reality (was that really a good thng). The CA1 circuits compare what you've already experienced to what you're experiencing and are asking “have I ever seen this before?” If you really have a novel experience, if its a new kind of pleasure (first time of heroine), much greater experience than your second or third time. The novelty loop is the pleasure-driven acquisition. You have a medial prefrontal cortex has a major input onto other centers (NA). Has an inhibitory glutamatergic input on the NA and is the major mediating factor. VTA talks to mPFC and NA, hippocampus and amygdala and the take home point from this is that the mPFC can regulate the feedback loop to avoid cravings and addiction. Alcohol, one of the first things it inhibits is the executive function of the prefrontal cortex.

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04 December 2007
Major function of higher-order function is Memory! The main driving form of memory as we consider it (declarative memory) is via the hippocampus, which is affected by the nucleus accumbens. It makes a contribution to the hippocampal decision as to whether or not a circumstance is worth remembering based on imput from prelimbic cortex (pleasure), medial PFC (executive function), vta (reward), basolateral amygdala (cues, stimuli that are being percieved and if they are only innocuous cues the amygdala says “that is not bad” and it relieves an inhibitory effect on NA), hypothalamus (low-level stress activates NA). Cravings are the activity of the VTA on the NA (the dopaminergic afference onto the NA that starts its hightened level of response). They are long-lasting, meaning that after the stimulus you want that stimulus again. They make a psycological/neurological distinction between a craving and a desire or addiction. Desire invokes an emotional state and that evocation of state can be tied to a physiological form. There is actually a hormonal release. Then there's lust. Lust is something that people try to decide is a form of love as they try to define it that's based purely on the physical stimuli rather than prefrontal stimuli. There is a profound physiological need to maintain homeostasis with regard to a stimuli as a result of modifcations in the brain. If you don't satisfy a craving and are physiologicaly depressed because of it, you are addicted. There are paths of addiction and the thing that breaks addiction most often is executive control; you have a prefrontal cortex... If you have some notion (novelty or input) causes NA to inhibit the Ventral Pallidum (which normally inhibits VTA), To finish up with addiction: Orbital frontal cortex and medial OFC are the parts of the brain that generate pre-executive function ( i really shouldnt do this) they can mediate the vta and actually mediate the substantia nigra but they discovered that there are lots of different types of addictions; sexual addiction and appetite are almost indistinguishable from oneanother. What happens with lack of executive function; (Phinnaes Gage); the spike functionally wiped out prefrontal cortex. Went from being a very nice guy to being a dick. No loss of motor control and little memory loss, but pretty much lost ability to determine consequences. Notion of love seems to elude executive function. You seem to abandon executive function quite rapidly when you're in love. Theobromine is an analogue to caffeine and has a stimulating effect in your body; is present in good chocolate in 450x the level in caffeine in coffee. Chocolate increases the levels of norephinephrine in the system. Lust is part of the desire pathway. We have dopamine saying i like this state, we have noreph and testosterone eing hightened awareness and aggressiveness. Oxytocin is a bonding hormone. Also fear, love has a fear component

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Things that go bump in the night: amygdala All the primary visual and secondary cortices have afference to the amygdala. Visual, auditory, gustatory, olifactory, and somatosensory all talk to amygdala bypassing a lo tof the secondary cortices. However there is some neocortical imput here; amygdala talks to hypothalamus saying 'we are scared, something is wrong.” It is the last of the limbic systems other than when all of this talks to hypothalamus. Sensory cortex talks to amygdala which talks to hippcoicampus, VTA, and hypothalamus. The amygdala drives that fear, that sensation going through your guts. The amygdala themselves have 3 general regions: central, lateral, and basal. Info comes in through the basolateral structures and gets processed in somewhat scentral area and leaves through central amygdala. Cortical inputs come through and fuse into central. Hippocampal omes in theough basal. There is some hypothalamic feedback to the medial amygdala. In general, you have inputs of meny differenct tyes (GABA, NE, and Opioid) which bring amygdala up to heightened sensityivty and then back down. It has a feedback mechanism which gets you more and more and more frightened. There are two paths: Innate (sensory thalamus to amygdala) and learned (sensory thalamus -> sensory cortex -> amygdala), one of the reasons we have binocular vision is so we can accommodate fear (darkening skies, hissing noise of a snake, a flashing light) makes amygdala fire. Amygdala talks to temporal lobes which are hotbeds for epilepsy; flashing lights can cause enough stimulus coming from anygdala to cause a temporal lobe seizure. Only left-temporal epilepsy leads to “spiritual accensions,” vs right-temporal which is lack of ability to perceive fear. The amygdala consolidates information and creates a stimulus which leads to a behavioural response. If you have a body language that invokes a fearsome stance you can put fear into people even by smiling at them. Amygdala: Fear, Freezing, Fleeing. Triggers parasympathetic system and leads to hypothalamic response: Fleeing, Fighting, Feeding, and Fucking. Auditory stimulation to amygdala is non-learned. Visual stimuli are ipsalateral; eyes send stimulus to thalamus to visual cortex. Aprosodia: Affective language disorder in which speech is devoid of emotion; alexithymia: Patients have diffculty recognising emotional content of speech. Aprosodia and Alexithymia are unilateral; comes from right amygdala to a part opposite wenicke's area and its only the right amygdala that does this. Toxoplasmosis: 83-85% of france, up to 25% of US. It's a protist that is transmitted in a hand to mouth fashion and its spreading apart the world. Cats have this protist in the system and they develop in the cats (they have a sexual life course in cats) , if it infects people it will get into children (as far as we can tell to no effect). The real pathway: cats eat things, and those things are infected with toxoplasmosis. In the cat it can go to sexual cycle and it can go into humans; the infected rodent undergoes behavioral modifcation; in rodents it shuts down the amygdala and we don't know if this has an effect on people.

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Men basically get dumb when infected by this, and women get lower fear levels and they become more calm and happy.

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06 December 2007
Hypothalamus is the link between what you perceive and what your body wants to do. The amygdala is the major input into hypothalamus, hippocampus does too. The hypothalamius sends singals down through ganglia Parasympathetic system calms you downstream Sympathetic system makes you alert Memory is sensory infromation, gets stored along with everything else in the hippocampus and the amygdala provides cues as to whether or not this information is worth keeping. The autonomic system which is drivign sleep through hypothalamus is feeding back through the hippocampus that consolidates memoery and sends it to frontal/parietal lobes. The hypothalamus talks to hippocampus, the amygdala largely tells hippocampus about things you don't want to remember. At low levels amyg has stimulatory effect on hippocampus. If fear gets too great it inhibits hippocampal activity. Whereas pleasurable stimuli at low levels is largely forgettable (inhibitory), the NA talks to the VTA will have an input that causes it to disregard this information. At high levels it is largely strimulatory. We become addicted to things when our control functions (mainly involvement of prefrontal cortex) is broken. The thalamus receives all primary sensory input (key player), if it gets inhibited then the information doesnt cue prefrontal cortex. Amygdala recieves secondary sensory input. Amygdala all by itself can drive low levels of stimulation (cues) or high levels (fear). You can engage your fear levels just by perceiving danger. Ergo, the amygdala can shut down NA with lots of fear. Slightly stimulatory causes hippocampus to be more alert. We are more likely ot remember stimulatory experiences; things that are novel and a bit more extreme than normal drives generation of craving moreso. Because you're stimulated you have more norephinephrine which drives more activity in the hippocampus. Oxytocin has a phenomenal effect. If oxytocin is released, all voles look the same but a prarie vole is a monogamous creature. Oxytocin works on the amygdala as well. With the placebo the amygdala fires so many times but with oxytocin it induces trust between random invidiuals. Amygdala perceives danger directly through a sensory pathway, through the cueing (recognizing individuals who we don't trust). Sensory input: primary, secondary, physiologic, proprioceptive -> limbic system -> motor output: emotions, memory, autonomic, physiological Body attitude drives the limbic system. (Pyramidal smile) Muscle flexes -> Cerebellar Responses -> Emotions -> Autonomic Responses -> Muscle flexes (Duchenne smile)

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Thalamus -> Hippocampus -> Hypothalamus (circadian rhythms, thirst/hunger, blood pressure, autonomic systems) The difference btween the sympathethic and parasympathetic system is the liver. When you liberate glucose, carbohydrates, and steroids. No parasympathetic control of the adrenal gland. The sympathetic control of adrenaline releases epinephrine (heart to beat faster, muscles to pump up, state) and the norephephrine hightens the activity of amygdala and makes you more stressed. If the amygdala still perceives more danger, it drives this harder and harder. Under stress you drive the looping sympathetic system. Two events occur: Animals living in tanzania etc constantly find themselves in stressful situations (OMG LIONS MEW MEW MEW) and then go back to normal within 90s. This zebra handles these events that you get so stessed out so much that the sympathetic system drives you into a state of shock (opiates flow out of brain at incredible rate), DNC is completely numb and dopamine/endorphin levels are higher than you would ever get in a living creature, higher [ ] than morphine would kill them. Humans perceive dangers at a far greater danger than we ever have in the past, but they do perceive real danger. As a natural preservation, they have a way of releasing themselves from this sympathetic loop. The amygdala eventually says “screw it, everything's ok.” Some of us go through this cycle on a regular basis. We have an extraordinary [pacinian(sp?) corpuscles], they can be in the 10s of millions per square mm in certain parts of body. If they are stimulated a low rate, it will cause the nucleus accumbens to engage, do it again. If you continue to stimulate them, you start to engage centers that release hormones that normally affiliated with bonding (oxytocin and norephinephrine), as you continue norephinephrine triggers sympathetic response, even faster then the norephinephrine triggers adrenal glands which releases epinephrine and stimulates amygdala. You're afraid. A good 5-20 minutes later you don't feel anything, and your sense of bonding is phenomenal. It is your amygdala that is responsible for the totallity of the orgasm driven by fear to the point where your body turns off its sympathetic system and prepares to die.

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