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BIOL 4380 Motivation + Sex

Systems of Neuroscience (York University)

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Homeostasis
● Narrow physiological range
● WE have a physiological set point
● Optimal temperature
● Via Hypothalamus
● Sample information in cortical and subcortical
● Help get back to setpoint
● Fluid balance
● Energy balance
● Body temperature
● If deviance
○ Hypothalamus drives it back to set point

Homeostatic Drive
● Regulated parameter (ex. temperature) detected by specialized sensory neurons
● Deviations from optimal range detected by: periventricular zone of hypothalamus
● These neurons trigger an orchestrated (multi-brain region) response to restore optimal
levels
● Regulate osmolarity
● saline content
● Know general location
○ Behind fornix
○ Above Optic Chiasm
● Humoral
○ HYPO neurons stimulate/inhibit pituitary hormone release
○ Hormonal release that’s driven with interaction with the pituitary gland
● Visceromotor
○ Neurons in HYPO adjust sympathetic and parasympathetic outputs
○ Sympathetic and parasympathetic
○ Heart Rate
○ Shivers
● Somatic motor response
○ Lateral hypothalamus induces appropriate motor behavior
○ Sensory responses that re-establish homeostasis

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Hypothalamus

● “Setpoint hub”
● Group of nuclei
○ Anterior
○ Tuberal
○ Lateral-posterior region
● (like basal ganglia)
● Nuclei are different bundles of cells with different functions

Setpoint hub
● Integrates info from the cortex (cognitive) and sensory inputs
● • Integrates information from the forebrain, brainstem and spinal cord
● Compares sensory inputs
○ Like goal directed behaviour
● Being a hub
○ Drives Humoral, visceromotor, and somatic motor response
● Compares to biological setpoint
● The coordinate response across brain region
○ Activates relevant motor, neurohormone and somatic systems
● Contextual info (cerebral cortex + amygdala) and Sensory inputs ⇒ Hypothalamus
● Allows for coordinated response across brain regions for restoring homeostasis

Feeding behaviour
● Hypothalamus is key
● Neurons need glucose
○ Can become unconscious without it
■ Diabetic coma
● Prandial state ​= after meal, blood rich with nutrients

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● During prandial state glycogen and triglycerides stored

● Anabolism = formation of macromolecules from precursors
● Liver
○ Glycogen storage
○ Or triglycerides (anabolism)
● Glycogen is also used for muscles

Body composition
● Intake > Expenditure = Obesity
● Intake < Expenditure = Starvation

Hypothalamus Body composition

● Feeding = Hypothalamus Surveys hormone levels
● Detects nutrients in the system
● If too little food
○ Will initiate a compensatory mechanism
● Attempts to hit a “setpoint” for body weight

Feeding Behaviour
● Feeding = stimulated when neurons to detect reduced levels of hormone signal
○ Detected by periventricular zone neurons
● Stimulate ​lateral hypothalamus
○ Initiated feeding behaviour
○ Will continue to eat

Connection b/w Body Fat and Feeding

● Coleman
● Ob gene = fat reserver
○ Codes for Hormone signalling fat reserve status
● Without Ob (Ob/Ob knockout)
○ Thinks fat reserves are low
○ Satiation is not achieved
○ High motivation to eat
○ Gets fat

Parabiosis
● The long-term physiological and anatomical fusion of 2 animals
● Share common blood supply
● Chubby mouse (Ob/Ob KO) fused with normal mouse (Ob/Ob WT)
○ The KO mouse got skinnier
● Leptin​ is the protein product made for transmitting status of fat reserves
○ Satiation for hypothalamus
○ Injecting it still has an effect

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Leptin as energy reserve signal: inhibits feeding

● Freidman
● Reversed obesity by injecting leptin
● Leptin is released by adipocytes (fat cells)
○ Regulates body mass by acting on neurons in hypothalamus that decrease
appetite and increase energy expenditure

Human obesity and Leptin Supplementation

● It only works if the leptin gene directly mutated
● Other factors can affect obesity
○ Like if leptin cannot pass the BBB
■ Leptin medicine won’t work
○ Reduced leptin receptor expression
○ Altered CNS response to hypothalamic activity
■ Lose signal once it hits hypothalamus
■ Won’t lose food craving

Hypothalamus and feeding

● Hetherington and Ranson
● Lesion lateral hypothalamus (lose the initiation of feeding)
○ Anorexia
■ Diminished appetite
● Lesion to the ventromedial hypothalamus
○ Obesity
○ This part regulates satiation signal

Leptin Acting
● Leptin binds to Leptin Receptors in Arcuate Nucleus (AN)
● AN Releases 2 hormones
○ Alpha Melanocyte Stimulating Hormone (alpha MSH)
○ CART (Cocaine and Amphetamine Regulated Transcript)
● So if a big meal
○ Leptin release and activate AN
○ Alpha MSH and CART elevate
● Activate neurons in paraventricular nucleus (PN) to initiate ​humoral response
○ Hormonal levels
● PN controls
○ secretion of TSH and ACTH from anterior pituitary
○ Act on thyroid and adrenal glands and ​raise metabolism
● Arcuate nucleus inhibits feeding behavior by projecting to lateral hypothalamus
● Time to start breaking food down

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Elevated aMSH and CART will also trigger changes in

● Activate ​Visceromotor Response
○ Increase body temperature
○ Increase sympathetic side
○ Increases metabolism
● Activate ​Somatic motor response
○ Decrease feeding behaviour
● Prevent caloric overload
● If inject hormones into brain
○ Will activate like leptin
○ Anorectic peptides
■ Diminish appetite
■ Act as brain’s appetite suppressants
● Can block these peptides
○ Drive feeding behaviours

Alpha MSH and CART

● Activate in Paraventricular Nucleus
○ Initiate humoral response
● Controls TSH and ACTH
● AN inhibits feeding behaviour by projecting to the lateral hypothalamus
○ Spinal cord, lower brain stem and paraventricular nucleus

Increased leptin (too much nutrients)

● Rise is detected by Neurons in the arcuate nucleus that contain αMSH/CART
● AN neurons project to spinal cord, lower brain stem and paraventricular nucleus of
lateral hypothalamus
○ AN receptors
○ Inhibit lateral hypothalamic
■ Decrease feeding behaviour
○ Activate PN stimulates
■ TSH and ACTH
■ Upregulation of metabolic response
● Inhibiting feeding behaviour
○ Also activate metabolic processes
● Decrease feeding and increase metabolism

Reduced leptins (little nutrients)

● Cannot suppress feeding behaviour
● Through activation of alternative arcuate nucleus neurons
○ These neurons are ​Neuropeptide Y and AgRP increase
● Stimulate feeding behaviour (increase)
○ Cause opposite effects (than MSH and CART)

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● Activate melanin-concentrating peptide (MSH) containing neurons of the lateral

hypothalamus that stimulate feeding
● Drive feeding behaviour
● These neurons also project to PN and lateral hypothalamus where
○ Inhibit ACTH and TSH
● Slowdown metabolic behaviour
● Orexigenic peptides
○ stimulate feeding behavior

Lateral hypothalamus regulates feeding behaviour

● Lesions of lateral hypothalamus stop feeding behaviours
● Electrical stimulation of lateral hypothalamus induces eating, even in satiated animals
● AN cells project into lateral hypothalamus
○ Contain melanin concentrating hormone (MCH)
● Lateral hypothalamus cells innervate cortical centres in goal-directed behaviour

Orexin cells
● Drive feeding behaviour
● Work w/ MCH+ cells
○ Promote feeding behaviour
● Orexin promote meal initiation
● MCH keeps you eating

Lateral hypothalamus regulates feeding behavior Cycle

● aMSH and AgRP are antagonistic NTS

● Stimulate or inhibit through the MC4 receptor

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● Affect feeding onset through stimulation (alpha MSH) or inhibition (AgRP) of the MC4
receptor
● MC4​ is a postsynaptic receptor found in the lateral hypothalamus
● When alpha MSH binds to the receptor will inhibit feeding behaviour
● When AgRP binds to MC4 receptor, it will initiate feeding behaviour

Marijuana
● THC
● Stimulate cannabinoid receptor-1 (CB1)
● Activation of CB1 receptors in hypothalamus is orexigenic = stimulates feeding
○ Promote the feeding by
■ Enhances smell
○ Olfactory cortex sends to olfactory bulbs
○ Bulb to cotex to bulb
■ CB1 reduces excitatory inputs onto inhibitory granule cells
■ Increase olfactory response
■ Drives feeding response
● Disinhibits olfactory bulb neurons ⇒ increases olfaction and feeding

Why do we eat?
● Reward centre
● Milner and Olds
● Rats prefer the part of the box associated w/ stimulation
● Would persist to pulling the lever
○ Eventually exhaustion
● The reward system
○ Will still suffer the consequences
● Reward was activating VTA

VTA (Ventral Tegmental Area)

● Provides Dopaminergic projections
● VTA ⇒ Lateral Hypothalamus ⇒ forebrain controlling goal-directed behaviour
● Will increase likelihood of behaviour
● The goal directed behaviour via lateral hypothalamus
● Dopamine will increase plasticity and increase behaviour repetition
● Mesocorticolimbic dopamine system

Self Stimulation
● Heath
● Implant electrodes in patients
● Narcolepsy
○ Put electrode
○ Tell what he feels when the electrode

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○ Enjoyed when ​septal area​ is stimulated

● Stimulate medial thalamus
○ On another patient they liked that
○ “About to recall a memory”
● VTA projects to the septum and medial thalamus
● stimulation in the reward pathway repetitive behaviour in humans

Dopamine as motivation Signal

● Dopamine​ was believed​ to provide “hedonic” (pleasure) reward
● No DA receptors (no dopamine)
○ Stop feeding behaviour
○ Pleasure system was still there
○ “Smack lips” for food
○ Behaves as if the animal likes food, but won’t seek it out
○ Loss of ​motivational ​component of food seeking

Drugs
● Heroin
○ Opioid system in VTA
● Nicotine
○ Cholinergic system in VTA
● Cocaine
○ Blocks dopamine reuptake
○ Cocaine targets nucleus accumbens (VTA projection area)
○ DA and noradrenergic system
● Different psychoactive effects but converge on brain circuitry for motivation
● DA neurons in VTA have both opiate and nicotinic receptors
● All go to VTA
● Nucleus Accumbens
○ Releases dopamine
○ Activates the “rewarding feeling”
● All drugs wither stimulate DA release (heroin, nicotine) or suppress DA reuptake
(cocaine) in the nucleus accumbens

Addiction vs Homeostasis

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● Repeated drug intake

● Takes higher doses to elicit similar physiological responses
● Downregulation of reward response
● Drug discontinuation in addicted animals causes reduced DA release and function in
nucleus accumbens
● Surge of dopamine
○ Tonic dopamine is suppressed
○ A decrease in the baseline
○ Little low-level dopamine
● OD
○ The body cannot compensate

Dopamine Signal and Behaviour

● Schultz
● Sip of juice turns light on
● VTA starts to fire to light and not award
○ So if light turns on
○ Reward is predicting
○ Light is predicting onset of award
● Neurons slightly increase firing in response to reward without associative conditioning
● With repeated pairings (juice + light), associative conditioning takes place
● Now, VTA neurons fire in response to light
● VTA neuron activity serves as an anticipatory signal
● If there is light
○ But no juice
● VTA is suppressed
● Therefore ​VTA predicts award and fires

Neurobiology of Sex
● Prairie voles
○ Monogamous

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○ Socially bond for life

● Meadow (Montaine) Vole
○ Polygamous
○ Players

Love
● See how much time they spend time with partner after sex
● Montane
○ Alone post-sex
● Prarie
○ Cuddles w partner

Purpose of Love
● Enhancing mate selection
● Increases survival
● Reward and Reinforcement is associated w/ bonding and love
● Romantic love
○ Oxytocin and vasopressin
■ Also in maternal love
■ Associated with social recognition and maternal offspring bonding

Expression of Receptors
● Monogamous Voles
○ Higher in caudate-putamen, ventral pallidum and Nucleus accumbens
■ Associated w/ DA signaling
○ Increased oxytocin receptor
○ Vasopressin high in the ventral pallidum
○ Causes “romantic love”
● Polygamous Voles
○ Overexpress oxytocin
■ Will cause monogamous mating style
○ Promiscuous voles show decreased expression of vasopressin receptors in the
ventral pallidum
● Vasopressin antagonist
○ CSF prefer Partner
○ VP prefer stranger
● Inhibiting D2 receptors in nucleus accumbens in females similarly decreases partner
interaction preference

In romantic love
● Increase ventral tegmental Area and caudate nucleus

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Breakup in a relationship
● Individuals recently rejected by a love interest retain maximal activation in the VTA and
caudate nucleus in response to viewing former loved one
● But add cortical regions associated with motivation, calculation of gain and loss,
emotional regulation and even drug craving that are not activated in the "in love"' state
● More cortical region
○ Loss, emotional regulation is active
● Increase in NA
○ Substantia nigra
○ Amygdyla
○ Prefrontal cortex

Enduring love
● Married for long time
● Activated regions w/ attachment
○ those regions activated by parent-child bondingare preferentially activated.
● Decreased activity
○ MT = medial temporal pole
○ LPF = lateral prefrontal cortex
○ PC = posterior cingulate
○ OP = occipital/parietal junction
○ Amygdala
■ Big gestures
○ Social vigilance
■ Surveying to find a better mate
● Increased
○ Reward circuits when interacting w/ partner
● Regions of the brain essential for social vigilance and caution including several cortical
regions and the amygdala = ​diminished activation

Sex hormones
● Don’t know paths
● Testosterone increase masculine gestation period
○ Testosterone in converted to estradiol by aromatase

Sex steriods
● Direct
○ NT synthesis
○ Release and reuptake
○ Membrane permeability
● Indirect
○ Regulate transcription

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Estradiol
● Within preoptic area, hypothalamus and amygdala
● Suggests some regions play specific roles in regulation of sex and sex-related (maternal
behavior) functions.

Sexual dimorphism
● Spinal cord
○ Spinal motor neurons
○ Innervate bulbocavernosus muscle
■ For genital muscle
○ Testosterone trophic actions
■ Allows sexual dimorphism
● Females
○ Don’t have the trophic factors (testosterone)
■ those moton neurons start to die

Spinal nucleus of the bulbocavernosus (SNB)

● Helps with control erections and urination
● In fifth lumbar spinal cord segments
● Larger in males

Onuf’s Nucleus
● VL region
○ Larger in males vs females
● Corresponds to certain sexual behaviours
● Human analog of the SNB; structure controlling perineal muscles which is larger in
males relative to females

AVPV (anteroventral periventricular nucleus)

● Dopaminergic neurons
● Larger in females
● For cyclic ovulation
● Over express estrogen
○ Have a phenotype similar to females

Sexually dimorphic nucleus of the preoptic area (SDN-POA)

● Larger in males than females
● Lesion in males
○ Lose copulatory features
■ Sexual behavior in which a male introduces sperm into the female's body
■ And mountiing
● Lesion in females
○ Increase conscious

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■ Reduce lordosis (permissive sexual positioning)

○ Decrease sexual behaviour
● Testosterone drives differentiation of SDN-POA
● Size and number increases in testosterone
● Mediate mate selection and preparatory copulatory
● Regulates motor and visceral aspects
○ Intromission and ejaculation motor functions
■ AP of these neurons fire more during these behaviours

Monkey Move
● Monkey presses button
○ Moves female monkey closer
● Medial preoptic area
● Female in view will fire MPA
○ Still high in mating sequence
○ Loses it in ejaculation

Pregnancy
● Feeding behaviour
● High concentration of leptin receptors in the ventromedial nuclei of the hypothalamus
(VMH)
○ And in the arcuate nucleus (AN) in the anterior hypothalamus
● Activate leptin turns on STAT kinase phosphorylation
● pSTAT+ neurons is less in pregnant people
○ Less satiation (suppress appetite)
○ More hunger

Lactation
● Paraventricular nucleus (PVN) and supraoptic nucleus (SON) trigger lactation
● Astrocytic process inhibit the relevant neurons and dendrites from coming together
● Once birth
○ Process leaves
■ Electrical synapse contact
■ Increases onset of lactation
● Action potential discharge from electrically coupled neurons of the PVN and SON in
female rat
● Drives Oxytocin surge
● Drives milk ejection
● Physical pressure on mammary gland
○ Feeding increases neuron firing (synaptic contact)
● • Increased AP frequency generates high-frequency discharge (more milk ejection)

Ventrum

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● Region associated w/ nipples

○ Expansion of nipples in female rates after giving birth
● Increase sensitivity by increase somatosensory cortex
● Somatic sensory neurons occupation
○ Helps w/ lactation process
● Smaller receptive fields
○ More sensitive
● Ventrum increases in size but receptive fields shrinks

Licking and grooming

● Some rats have lick and groom
○ Care more for the pups
● Low licking
○ Neglect to pups
● Rats will arch
○ Provide easier entry to nipples

High Maternal lick and groom mothers

● Licking and grooming promote additional 5- HT secretion
● 5-HT binds to serotonin receptor and increases PKA activation
● Will demethylate glucocorticoid receptors for negative feedback of stress
○ Increased glucocorticoid receptors in hippocampus
● Downregulates stress factors

Low Maternal lick and groom mothers

● Rat pups that do not get adequate licking and grooming
● DNA remains methylated in the region of the GR gene that would normally bind NGFl-A
● NGFI-A cannot bind to the methylated DNA

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● Limits transcription of the GR gene

● Glucocorticoid receptor protein is not present to negatively regulate the stress response.

Crossing Pups
Pups will become stress-resistant w/ crossing
● Cross families
● Give a stressed pup to a high L/G mother
○ Will de-stress the pup
● Learned behaviours
○ Not a strong genetic behavior

Estrogen and Testosterone

● Progesterone is a precursor for both estrogen and testosterone
● Treatment with estradiol increases neurite genesis
● Female rat hippocampal neurons
○ Increase spine density in response to
○ Shows that estrogen can modify the plasticity of structures associated with
synapses
● Trophic effects to neurons
● Hypothalamic cells
○ Will increase in branching when exposed to progesterone
● Effects of testosterone on embryonic spinal cord neurons in cell culture.
● In response to testosterone, processes become thicker and more highly branched
● Cell body (soma) also grows In size.
● These hormones powerfully regulate cell growth, dendrite development and synaptic
plasticity
● Estrogen receptors are found through the hippocampus
● Estrogen receptor alpha (Er alpha) localizes to postsynaptic processes
● Increase spine density w/ response to estrogen
○ More excitatory synapse
○ Estrogen boost synaptic transmission in the hippocampus of female rat
○ Also enhances response of synapse to incoming stimuluses
○ Synapses become much stronger
○ Increase K+ and Ca2+ activity
○ Better plasticity processes
○ Promotes LTP

Estrogen and androgen

● Within hypothalamic nuclei
● High ER and AR in
● Cortex = role in cognition, learning and memory
● Hippocampus = learning and memory • Amygdala = stress, emotion
● Thalamus/brainstem = pain processing

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● Substantia nigra/cerebellum = motor control

Sexual Orientation
● Interstitial Nuclei of the Hypothalamus were less in homosexual men
○ Suggested that INAH3, a sexually dimorphic subnucleus of the interstitial nuclei
of the hypothalamus was smaller in homosexual men
● But sampling bias
○ Due to HIV
● Expose Androgen to the hypothalamus, elicits activity in the hypothalamus in
● Heterosexual Female
● Homosexual Male
● Expose Estrogen
○ Increas cingulate cortex in homosexual female
● In lesbian women, estrogen elicits some activation in the hypothalamus, similar to that
seen in heterosexual men.

Sexual Dimorphism
● Cingulate gyrus
○ Larger in female
○ Processing emotions and behavior regulation
○ And surrounding cortical regions
● Men have larger body size and brain normally
● Orbital frontal cortex and corpus callosum
○ Larger in males
● Women outperform in verbal tasks and comprehension
● Men outperform
○ Rotate objects better

Sexual dimorphism
● In recalling emotionally charged content
○ Frightening films/images
● Lateralization of amygdala
○ Right more in men
○ Left more in females
● Suggests lateralization may be source of sexual dimorphism

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