NROC61 - Final exam notes (Ch.6-11)

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Ito Lee R

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Lecture 6: Central Reward System Intracranial Self- Stimulation •Reward: Feeling of pleasure accompanies certain acts or experience (Hedonic impact) -Feeling of anticipation of impending goal •Olds & Milner: Discovered phenomenon of intracranial self-stimulation (ICSS) -Implanted electrode into rats’ lateral hypothalamus -Rats level press at 7000press/hr to receive electrical stimulation in certain area -Prefer self-stimulating over eating or drinking -Allow and suggest mapping of neuroanatomy of reward pathway •ICSS in animal: Elicit consummation behaviour (eating), hence ICSS may related to consummation behaviour •ICSS response: Behaviour will be maintain even long period of extinction is introduced -No tolerance is shown in ICSS, have accumulation in level-pressing behaviour •ICSS positive sites: Main positive sites for ICSS are found in Medial forebrain bundle across different species - Medial forebrain bundle: Complex bundle of axons originate from VTA through LH and Nacc -Refer as “pleasure centre”, accompanied by consummatory behaviour when stimulated -ICSS of Limbic sites: Septum, hippocampus, prefrontal cortex and amygdala -Produced lower rates of responding, and less behavioural activation -ICSS Punishment sites: ICSS avoided in Penriventricular region ➣ Neural mechanism of ICSS •Sites support ICSS may linked through trajectory / catecholamine system (Dopamine and noradrenaline) •Central noradrenaline system was the first thought as it mediates ICSS -Now they focused on “dopaminergic system= acts on ICSS” instead •Dopaminergic neurotransmission: Able to enhance intracranial self-stimulation -Able to lower brain reward threshold = Higher rate of ICSS generated -High rates of ICSS located in Ventral tegmental area (VTA) and nucleus accumbens -Have dopamine cell bodies project to ventral striatum (Nucleus accumbens) and limbic system Amphetamine: Increased dopaminergic neurotransmission -Cause leftward shift of curve, More sensitive -More response in lower stimulation frequency Microinfusion of DA receptor antagonist/ blockade: -Haloperidol etc., interfere DA synthesis and storage (Reserpine) -Block and depletes ICSS, and shift the curve to the right -High response rate = less sensitive (Need more injection to be rewarded) •Amphetamine: Self-administered directly in nucleus accumbens, not into lateral ventricles •Systematic injection: Inject pharmacological drug into whole brain system and affect the whole -Different from intracerebral injection = Directly into specific region of brain ➣ Nucleus accumbens dopamine and ICSS •Infusion of DA receptor antagonist into nucleus accumben = Block ICSS of medial forebrain bundle •Suggested the importance of DA and nucleus accumbens for ICSS -However nucleus accumbens (Striatal) is associated with motor movement -Dopamine injections might also affect motor activities, with rewarding effect of ICSS  Drug as reward •Dopamine may also critical for reinforcing properties of psychostimulants ➣ Rate of ICSS •Changes in rate of ICSS reflect: 1) Changes in rewarding effect 2) Motor activity 3) motivation •Able to study drug self-administering behaviour (animal able to voluntarily self-administered) ➣ Features of Drug self-administration •Animals tend to self-regulate (Titrate) their intake of drug -when on low schedule of reinforcement, and maintain constant plasma level of drug (Titration effect is shown from dose 0.25mg to 0.5mg of microinfusion) -0.125mg = Point of optimal drug infusion -Below 0.125mg is not yet perceive as rewarding •Titration effect: Animal will have↓response rate when↑ dose of drug -Compensatory responding is observed when lower dose of drug is given -Prevent overdoes = animal will not be over-dose by the drug •”Binges” of drug taking occur when given unlimited access to drug •Reward efficacy: Indicates the rate of responding -Dopamine manipulation cause horizontal shifts in dose response curves: -Expose to same dose of drug, but have different response rate (Higher response rate = not sensitive) -Have inverted U- shape of graph 6-OHDA depletion of nucleus accumbens (Dependent of caudate-putamen) •Cocaine and amphetamine self-administration will be abolished •Intra-accumbens administration of D1, D2 DA receptor antagonists increase rates of cocaine self-adminstration -Antagonist blocks the receptor = Less activated by DA = not sensitive = More response rate •Show preferential increase in DA efflux in nucleus accumbens after varies of drugs injected -Many types of drugs cause increase in dopamine release -Rewarding properties of drug is due to their ability to amplify mesolimbic DA release  Hedonia hypothesis: Food and Dopamine •Roy Wise: Proposed “Hedonia hypothesis of reward”, a hypothesis of dopamine function -Stated mesolimbic dopamine system constitutes reward pathway that mediates hedonic impact of reward -Both natural stimuli and drugs of abuse are mediated by mesolimbic DA system -Reduced Nac DA transmission is associated with drug withdrawal → Contribute anhedonic state -Anhedonia: When DA pathway is disrupted, which pleases loses all meaning -Suggested to be correlated with low striatal DA D2 marker level •Mesolimbic dopamine system: Have hypothesized to encode “hedonic tone” •Support for dopamine as hedonia: -Using conditioned place preference task with amphetamine injected, into Nacc lesioned rat Context A: With amphetamine injection Context B: No amphetamine injection -Context A is preferred by amphetamine infusions into Nacc •Showed result of drugs are more preferred in dysphonic, low arousal individuals -Less preferred in people with high baseline of mood -Suggested drugs is rewarding since enable us to self-titrate the optimal level of arousal •fMRI imaging studies: Volkow group -Study pleasure ratings associated with methyphenidate administration - Pleasure ratings is correlated with dopamine receptor occupancy in ventral striatum -D2 receptor binding correlated with subjective reports of “highs” •Drugs acting might also have aversive effects, not always appetitive  Wanting vs. Liking: Hedonic reactions to rewards •Pharmacrological blockade (6-OHDA) of mesolimbic dopamine system -Do not affect on hedonic response to reward or aversive substance (liking/disliking) •Dopamine: Acts as incentive salience attributor -Transforming neutral stimuli into incentive stimuli which elicits “wanting” -“Wanting” system is separable from DA-independent of “liking” system (mediates hedonic impact of reward) ➣ Incentive Salience Hypothesis •Dissociated neural system mediates hedonic impact of reward and incentive motivation of rewards (wanting) •Dopamine function is not needed for mediating hedonic impact (liking), only for “wanting” -Dopamine acts as incentive salience attributor, which neutral stimuli becomes incentive stimuli -Help eliciting “wanting”, but different from “liking” system •Kent Berridge studies: Explore systems involved in generating hedonic “liking” to different rewards -Found sweet taste elicited homologous, positive orofacial reaction: -Same expression of rhythmic, lateral tongue protrusion across species -Found bitter taste elicited “disliking” reaction involved gaping •Berridge et al. studies: -Found neither large 6-OHDA lesion of ascending projections through medial forebrain bundle Nor larger 6-OHDA lesions of Nac and dorsal striatum have effect on taste hedonic effect -Dopamine have no affect on taste hedonic impact •Pharmacological blockade of DA neurotransmission by primozide: -Will not alter the hedonic impact of reward -Concluded dopamine is not necessary for hedonic impact of natural reward Genetically modified mice in proving incentive salience hypothesis: -Using hyperdopaminergic mice = Dopamine transporter (DAT) knockdown mutants (DAT-KO) -Dopamine in the mice will reuptake less = More prolonged responses elicited by dopamine Result: -Exhibit higher reward (food/water) intake + Higher breakpoint measure (e.g. work harder) -Higher wanting: Have reduced positive hedonic “liking” reaction to sucrose taste -Show enhanced acquisition and incentive performance for sweet reward (Direct pathway to goal) ➣ Drug addiction and Incentive salience hypothesis (Dopamine sensitization) •Drug addiction is result of excessive “incentive salience” attribution to drug stimuli -As using more drug, ↑incentive value (wanting) & ↓Subjective pleasure (“liking”) •Drugs have induced sensitization of dopamine system -Drives compulsive drug seeking and lost euphorigenic properties of drug (Loss tolerance) Boileau et al studies: DA sensitization in human •Pre-treatment with 3 doses of oral amphetamine in men -Dose 4 after 14days induced greater DA release (As dose of DA increases) -Used PET scan: ↑Intrasynaptic DA = ↓ Binding potential of raclopride Result: •Increased dopamine release = Greater reduction in raclopride binding •Have greater psychomotor response of blinking rate / alertness •”Liking”= Might referred as “Preparatory / Anticipatory” in other studies •”Wanting”= referred as “Consummatory” Ikemoto & Pankesepp studies: •Investigated neurochemical basis of preparatory vs. consummatory behaviour •Used J shaped shuttle box apparatus and trained rats to perform runway task •Have 3 dependent measures: 1) Conditioned anticipatory activity in start box (Measure preparatory / anticipatory response) 2) Running speed of the rat (Measure of motivation) 3 )Sucrose consummatory behaviour in goal box (Measure of consummatory response) Result: •Dopamine receptor blockade in nucleus accumben: -Decreased running speed and conditioned activity levels (↓Anticipatory activity) •GABA microinfusion have no effects •Lateral of ventral striatum (Nacc core): More involved in anticipatory behaviour (autoshaping) •Medial of ventral striatum (Nacc shell): More involved in incentive salience attribution Wyvell and Berridge studies: •Direct amphetamine injection into shell cause more “wanting” for sucrose ➣ Neural basis of “liking” •Mesolimbic dopamine is implicated in “wanting” •DAMGO microinfusion: Opioid receptor agonists microinfusion •Pecina and Berridge studies: Identified opioid circuits which amplify hedonic impact -Found endogenous cannobinoid and opioid hot spots -Discovered “liking” hotspots in nucleus accumbens shell and ventral pallidum -Suggested endogenous cannabinoids may mediate hedonic “liking” for sweetness in Nacc region ➣ Human ICSS and subjective response •Hot spots for human ICSS: Septal area for narcoleptic patient / Centromedian thalamus for epileptic patient •Narcoleptic patient was fitted with 14 electrodes in different parts of brain •People will have different reasons for response when different hot spots are stimulated (e.g. cool taste / drunk feeling / strongly aversive etc.) •Hippocampus stimulated = Have feelings of mild pleasure •Septal area of forebrain = Hot spot for self-stimulation, more alerted with great feeling •Driving forces of self-stimulation and drug seeking is not always feelings of “pleasure” (hedonic) •Effects of ICSS depends upon function of brain region that is activated by electrical stimulation Lecture 7: Hypothalamus and Motivation  Motivation centre in brain • Responsible in maintenance of homeostasis (Internal milieu) •Features in motivation centre: Setpoints, receptors which responsible for sensing the setpoint -Integration centre, ability to correct the off-value by feedback control ➣Hypothalamus: Centre for Motivational control •Hypothalamus: Small cluster of nuclei, making up less than 1% of entire brain mass -Co-ordinates Homeostasis: Maintains body’s internal environment within narrow physiological range -Functions via integration of: 1)Endocrine system 2) Autonomic system 3) Motivated Behaviour -Functions in hypothalamus: e.g. Control daily cycles in physiological state and behaviour -Temperature regulation, control food and water intake, emotional responses ➣Anatomical features in Hypothalamus •Different motivational states are associated with different hypothalamic nuclei •Ideally located to subserve regulation of motivation: -Able to detect changes in CSF, blood composition -Hypothalamic capillaries are fenestrated, allow large molecules to enter the brain -Afferents conveying gustatory/ sensory information 1) Retina: Pass directly to suprachiasmatic nucleus -Indirectly influences the pineal gland, which involves in sleep-wakefulness cycles 2) Olfactory: Pass directly to lateral hypothalamic “feeding centre” -Indirectly via amygdala, nucleus accumbens (reward system) 3) Cutaneous: Pass indirectly to hypothalamus (Skin sensations) -e.g. Nipple sucking and lactation, Pain and stress responses 4) Visceral: Mostly via nucleus of solitary tract -e.g. Internal states: Important for parasymthetic activation or inactivation •Nuclei form walls of third ventricle, bathed in CSF: Easily senses hormonal level in CSF •Anterior hypothalamic area: Involved in osmotic control, drinking, temperature control •Suprachiasmatic nucleus: Biological “clock” -Receive direct retinal innervations, to synchronize circadian rhythms with light-dark cycles •Paraventricular nucleus: -Consist of “Magnocellular” and “Parvocellular” neurosecretory cells i) Magnocellular cells: Oxytocin and vasopressin (Not all project to posterior pituitary) ii) Parvocellular neurosecretion cells: CRH and TRH •Arcuate nucleus: -Origin of portal dopamine (control prolactin), growth hormone-releasing hormone -Consists receptors for appetite-controlling hormones (e.g. Leptin and insulin) •Ventromedial nucleus: the “Satiety centre” -Senses metabolities (glucoses and fatty acid), regulates feeding and metabolism •Lateral hypothalamic area: the “feeding centre” •Posterior hypothalamic area: Central control of sympathetic activation ➣ Neural connections: Inputs to Hypothalamus •Each side of hypothalamus has 3 functional zones: 1) Lateral 2) Medial 3) Periventricular •Lateral and medial zones have extensive connection with brain stem •Periventricular zone: Cells in this region lie next to wall of third ventricle •Brain stem: -Noradrenaline fibres from Locus coeruleus -5-HT fibres from Raphé nucleus -Fibres conveying visceraception from nucleus of tractus solitaries -Fibres from peraqueductal grey associated with nociception •”Higher” centres: Most of which are Limbic system -From hippocampal formation via fornix and via Medical septum-complex sensory stimuli -From amygdala and piriform cortex via Ventral amydalofugal path and BNST -From septum -From oribitofrontal cortex in particular, via Mediodorsal nucleus of thalamus ➣ Neural connections: Output from hypothalamus •Neuroendocrine control: Exerted directly on peripheral organs via posterior pituitary -Indirect via release of neurohormones into pituitary portal vessels to control anterior pituitary •Neural control: Fibres descend via medial forebrain bundle to control brainstem autonomic centre 1) Parasymthetic N.S: The “Rest and digest” system -Responses help body to recover as well as prepare for stressful situations by storing nutrient 2) Sympathetic N.S: “Flight and fight” system -Responses promote survival in dangerous situation ➣ Intrinsic sensitivity of hypothalamic neurons •Hypothalamic neurons respond synaptic inputs and physiological variables 1) Osmotic pressure: Osmosensitive neurons, especially in antero-ventral hypothalamus 2) Temperature: Thermosensitive neurons in anterior hypothalamus; involved in fever 3) Plasma glucose, free fatty acid: Involved in feeding/ stress -Neurons sensitive to metabolic substrate in ventromedial nucleus 4) Hormones: Affect hypothalamus as part of feedback loops (e.g. Cortisol T3) -Influence certain functions (e.g. Sex steroids) in hypothalamus •Hypothalamic stimulation must be able to override negative feedback (e.g. stress) ➣ Three important functions in hypothalamus •Feedback system: Hypothalamus correct deviations from given set-point -Compares current value with supposed value, then make adjustments to achieve supposed value •Feedforward system: Hypothalamus can override feedback under special conditions -e.g. Stress responses, fever (set point is changed to higher temperature) •Anticipation: Hypothalamus adjusts its output to meet future needs -e.g. insulin secretion prior to food intake (Similar to Pavlovian conditioning)  Regulatory mechanism for feeding •Walter Canon: Proposed food intake is controlled by reflex action -“Hunger signal” from stomach, leading to eating -Begins to produce gastric hormones after 2 hours the stomach empties itself -Gastric hormones stimulate local nerve to send signal to brain -then brain signals digestive muscles to restart Peristalsis (muscle contraction) -e.g. stomach starts to rumble when we’re hungry, which lead us to eat •Long Term/ Tonic regulation: Signals arise from tissue stores (e.g. adipose tissue) -Influences expression of appetite •Short term/ Episodic regulation: Mainly inhibitory signals elicited by episodes of eating -Associated with signaling of satiety ➣Regulatory mechanism in Long term feeding •Prandial state: Condition which blood is filled with nutrients (During or after meal) •Postabosrptive state: Condition which stored macromolecules broken down to provide supply as fuel -When fasting condition between meals •Anabolism: Assembly of macromolecules (glucose and triglyceride) from simple precursoers •Catabolism: Complex macromolecules are broken down to provide fuel for cellular metabolism ➣Dual centre hypothesis (Stellar et al. ) • Hypothesis is dependent on level of glucose •Hypothalamus has 2 distinct centres responsible for hunger and satiety 1) Lateral hypothalamus (LH): Function as Hunger centre -Electrolytic lesion: Aphagia (lack of eating), not interested in food, needed to force fed -Stimulation: Sated rat will return to food and resume eating 2) Ventromedial hypothalamus (VMH): Function as satiety centre -Electrolytic lesion: Hyperphagia (over-eating), rapid weight-gain -Stimulation: Hungry rat in midst of meal will drop the food pellet -Ignore food for few minutes following a brief burst of stimulation of VMH ➣ Issues with LH= Hunger centres •Eventually recovered voluntary eating when the LH-lesioned rat was forced feedings •Rat began nibbling on food pellet when LH is stimulated -but other behaviours are also induced (e.g. run on the wheel when is provided) -Stimulation may involved in raising arousal in general activity, but not specifically to hunger -General motivation are increased when stimulated, not increases motivation in feeding only •Lesions induced impairments in almost all motivated behaviour and basic sensorimotor process ➣ Role in Lateral hypothalamus •Winn & Dunnett studies: Using ibotenic acid LH lesion, which spare fibres of passage -Causes aphagia, hence LH still involved in some aspects of appetite control •Edmund Rolls study: Perform single cell recording in squirrel monkeys -LH neurons response to taste and sight of food -Responsiveness of LH neurons to sight and taste of food ↓= Satiety increases -LH neurons are more responsive when they’re hungry, especially for preferred food •LH neuron firing decreased when “preferred food” is presented •LH acts as interface between sensory inputs: -Conveying rewarding information and hunger/satiety signals that modulate reward •Photoactivation of inhibitory BNST-LH circuit: -Produces voracious feeding of energy dense food in well-fed mice -BNST = Consist GABA receptor LH= Consist of glutamatergic receptor -Photoactivation: Able to activate specific neurons population -Laser on: Activates neuron-circuit Laser-off: No stimulations -Direct LH- stimulated = Inhibit eating even I food-derived groups -Direct photostimulation of glutamatergic LH neurons led to suppressed feeding in food-deprived mice ➣ Issues with VMH as Satiety centre •Rat will cutback some of the eating and weights will level off after period of over-eating -Will still have set-point even though VMH is lesioned (BUT higher set-point) •Would overeat and regain lost weight if rat were put on diet and lost weight, and allowed to feed freely again •Still have evidence of weight regulation, but at higher set-point than pre-lesion period •VMH-lesioned rats are fussy eaters: -Over-eating occurred when food tasted good, will refuse to eat when small amount of quinine added -Non-lesioned rats: Balked at eating bitter food, but soon consume it when nothing else available -Result of finicky eater is due to being overweight, not direct result of VMH-lesions -Normal rats force-fed to become over-weight are equally finicky eaters ➣ Regulatory mechanism for long-term feeding •Signal arise from tissue stores (adipose tissue), influences expression of appetite •Lipostatic theory: Fat deposition feedback system, proposed by G. Kennedy -Body fat is normally maintained at relatively constant level -Proposed that everyone has set-point for body fat: -Deviation will lead to compensatory adjustment in food intake / metabolic rate Liposuction in female squirrels – Forger et al. •White adipose tissue removed from squirrels •Have recovery of body mass and total lipid mass without changes in food intake within 2 weeks •Hypothesize the presence of lipostatic factor  Lipostatic factor •Connection between body fat and feeding behaviour = Have communication from adipose tissue to brain •Douglas Coleman Parabiosis studies: Found bloodborne signal as circulating lipostatic factor - Ob genes: Produce hormones which involved in telling the brain about fat reserves is normal -Obese mice: Lack of both copies of gene ob, lack in circulatory satiety signal -Parabiosis: Long term anatomical and physiological union of 2 animals, with common blood supply -Ob/ob mice: Lack of hormonal satiety signal -Db/db mice: Diabetic mice, lack of satiety signal receptors -Db/WT mice: Do not have receptor, but still produce satiety signal but signals are failed to response  Discovery of Leptin •Jeffrey Friedman: Identified Leptin using ob/ob mouse strain -Leptin: Protein encoded by ob gene, signaling molecule secreted from adipocyte -Circulating levels of leptin mirrored body adipose mass -Regulate body mass by↑energy expenditure and ↓ appetite -Adipose: Not only a lowly fat storage molecule, also involved in controlling energy levels -Leptin receptor: Located in arcuate nucleus of hypothalamus, close to CSF -Hence obesity is a “disease”, but not a character flaw ➣ Leptin and Treatment of Obesity •Able to reverse obesity in ob/ob mice by leptin administration •Some patients fail to response to leptin therapy -Obesity may also due to decreased sensitivity of brain neurons to leptin ➣ Response to increased Leptin = Suppress appetite Increased leptin level → Activation neurons contains CART and a-MSH + Inhibition of neurons NPY and AgRP -Arcuate neurons: Contains anorexigenic neuropeptides CART and a-MSH -or POMC neurons= Precursor of CART -NPY and AgRP: Orexigenic peptides, located in arcuate neurons •Projection to LH: Leads to inhibition of feeding behaviour •Projection to paraventricular nucleus (PVN): -Activates humoral response from anterior pituitary (TSH, ACTH) → Increased metabolism -Activates sympathetic autonomic response to raise body temperature ➣ Response to decreased leptin = Stimulate appetite Decreased leptin level → Activates NPY and AgRP + Inhibition of CART and a-MSH •Leads to Inhibition of neurons in PVN: -Control release of thyroid stimulating hormone TSH and ACTH = Reduce metabolism •Leads to stimulation of LH neuron: Contains MSH/ orexin, induce feeding behaviour  Pancreatic hormone- Insulin •Insulin: Released from pancreatic B cells, similar to leptin in actions -Circulating levels are proportional to body adipose mass -Hence level of insulin = level of leptin = proportional to body adipose mass •Insulin receptors: Expressed in POMC/ CART + NPY/AgRP neurons in arcuate nucleus Insulin binding → Stimulates POMC/CART + Inhibit NPY/ AgRP neurons -Result in reduction in food appetite and increased metabolism  GI tract hormone Ghrelin: The hunger drive •Ghrelin: Orexigenic peptide, high concentration in stomach -Sensitive to nutritional state = ↑ [Ghrelin] during fasting / ↓ [Ghrelin] after food intake •Intravenous ghrelin administration: Appetite and food consumption is stimulated -via Activation of NPY and AgRP in arcuate nucleus + Inhibition of POMC/CART neurons •Hansen et al. studies: -Weight loss is associated with increased circulating levels of ghrelin -Ghrelin may acts as compensatory hormone, involved in longer tem regulation of energy balance •Arcuate nucleus: Appears to act as centre of control for food intake -Receive information on body fat reserve and satiety signals -Have site of 2 major neural pathway which influences appetite regulation: -POMC/CART neurons: Inhibit food intake NPY/ AgRP neurons: Promote food intake •Other hypothalamic nuclei receive projections from arcuate nucleus: -PVN: Direct influence on metabolic rate -LH: Glucose-sensing, orexin and MCH neurons that promotes eating Receives dopamine projection from VTA •VMN: Leptin receptors have been identified in this region -Stimulation of leptin-sensitive neurons lead to decrease in food intake ➣Exercise and Food regulation •Ebal et al. Studies: Rats were assigned to exercise for 5 days/ week for 5 weeks -Rats were forced to grip and maintain climbing position on vertical wire netting for 3 X 30 sec -Training program progressively increased by adding load to tail -Body weight and food intake were monitored, blood-hormone level were measured each week Result: Significant decrease in body weight and fat mass in training rats -Decreased insulin and ghrelin level in bloodstream Lecture 8: Hypothalamus and Motivation  Regulatory mechanism for feeding •Short term ( Episodic) regulation: Mainly inhibitory signals elicited by episodes of eating -Associated with satiety signal, which long term regulation influences appetite expression -Satiety can be overridden over biological controlled process ➣Model of Short Term Regulation •Consists of three phases: 1) Cephalic phase: Food cues elicit anticipatory activation of autonomic systems Mobilization of salivation, gastric juices 2) Gastric phase: Increasing intensity of response when food consumption starts 3) Substrate phase: Absorption of food begins to occur •Meal initiation: Affects of many factors: -External factors: Emotional factor, time of day, threat from environment (store fat and ready for threat) Availability and palatability of foods (High palatability food are more preferred) -Internal factors: Orexigenic signal (Ghrelin), involved in both short and long-term regulation •Meal termination: Determine by onset of satiety -Still occurs even all neuronal connections between forebrain and hindbrain are severed -Might be mediated in hindbrain, not forebrain -Satiety: Biological state induced by neurohumoral stimuli Generated during food ingestion which leads to meal termination  Short Term Satiety Signals ➣ Gastric distension: by specialized mechanoreceptor (e.g. Stretch of muscle in intestine) •Monitor physiological activity and pass information to brain via vagus nerve ➣Cholecystikinin (CCK): Role in fat regulation •Food consumption stimulates CCK release from duodenal mucosal cells •Release in response to stimulation of fat and protein ingestion •Signal transmitted via Afferent fibres of Vagus nerve→ Nucleus tractus solitaries (NTS) in brainstem -then relayed to hypothalamic region → Integration with other signals •Functions: Mediate pre-absorptive satiating effect of intestinal fat infusions -Satiety effect of fat can be blocked by CCK-A receptor antagonist Loxiglumid -OLETF rat: Increase food takes and meal when CCK-A-receptor knockout Result in hyperphagia induced obesity •High fat consumption produce greater satiety feeling = Increased endogenous plasma CCK levels  Overriding satiety: Overeating •Affected by: 1) Sensory specific satiety: New tastes can lead to more consumption 2) Emotional/ Social factors: Comfort eating, group eating etc. 3) Hedonics: More rewarding in palatable food ➣Homeostasis and Hedonics •Hedonic process is viewed as function of nutritional need-state -But reward as consequence of fulfilling nutritional need cannot explain non-homeostatic food intake -e.g. Overconsumption of palatable foods than nutritious chow • In Depletion: Enhanced hedonic response to energy providing food In Replete: Hedonic effect of food is reduced, in satiation ➣Interaction between hedonia neural systems and Homeostatic mechanisms •Leptin signaling: Defective when high hypothalamic endocannabinoid levels Hypothalamic endocannabinoid levels involved in hedonic systems •Highly palatable food: Drive is maintained by reward circuit -Information transmitted to reward circuit, not satiety signals activation -Leads to release of reward mediators: Endocannabinoid and opiates -Blunted response to satiety signals ➣Outside of Hypothalamus: Feeding control at other levels of neuraxis •Downstream of brainstem: -Hypothalamus is not necessary for reflexive elements of feeding behaviour -Hypothalamus is not necessary for processing short term satiety signals •Upstream of Limbic system: -Have activation of amygdala when show menus with pictures of their preferred food -Hypothalamus activated when subjects are hungry -Activates portions of oribitofrontal cortex when had to choose between menus -Higher cortical mechanism in making decision between alternative goal objects  Drinking and Thirst •Distribution of body water: 67% intracellular + 33% Extracellular •Osmolarity: Plasma osmotic pressure, Osm/L -↑ Plasma osmotic pressure when in water deprivation / consume salt ➣ Terminologies in Osmosis •Isotonic: [Solutes in cell] = [Solutes in interstitial fluid] -No movement of fluid into or out of cells •Hypertonic: [Solutes in cell] < [Solutes in interstitial fluid] -Water moves out of cell, cell may become dehydrated when interstitial fluid loses water •Hypotonic: [Solutes in cell] = [Solutes in interstitial fluid] -Water moves into cell, cell may be burst ➣Fluid regulation •Cellular functions: Depends on ionic composition of intra & extracellular fluid -Normally interstitial fluid is isotonic with intracellular fluid •Total volume of body fluid need to be regulated since it contributes blood pressure •Consists of 2 sets of osmoreceptors: 1) One set to monitor changes in intracellular fluid volume 2) One set to monitor changes in blood volume •Have 2 correctional mechanisms: Manifested as thirst for water / salt appetite ➣Two types of Thirst: Osmotic and Volumetric Thirst •Osmotic thirst: Induced by cellular dehydration -Produced by ↑osmotic pressure of interstitial fluid relative to intracellular fluid -Causes hypertonicity when salt added → Water leaves intracellular → Cell volume shrink → Thirst •Volumetric thirst: Triggered by drop in blood volume Fluid and electrolyte withdrawn from body → No change in ionic concentration → Thirst -Triggered by loss of blood/ fluid that contain water and solutes -Consists of 2 sets of receptors: Kidney and Heart Baroreceptors •Kidney Baroreceptors: Detection of hypovolemina in kidneys •Heart baroreceptor: or known as atrial baroreceptors (pressure receptor in heart/vessels) -Inform brain about dropping in extracellular volume -Initiates thirst to replace water and salt hunger for salt ➣Neutral regulation of Intracellular Volume •Changes in osmolarity is detected by osmoreceptor in OVLT OVLT: Vascular organ of Lamina Terminalis, activated by hypertonic NaCl -Small periventricular region, which lacks of blood brain barrier Lesion of OVLT: Abolish hypertonic NaCl-induced drinking •Osmoreceptors also presents in Adjacent medial preoptic nucleus and Subfornical organ -Have most effect on hypertonicity-induced drinking by lesion these 3 regions •Antidiuretic hormone (ADH)/ Vasopressin: -Hypertonic conditions → Stimulate ADH release | Hypotonic conditions → Inhibit ADH release -Release of ADH is controlled in Supraoptic nuclei and Paraventricular nuclei of hypothalamus -ADH released from pituitary gland → Kidneys switches on water conservation -Little increase in plasma osmolatity = 2/3 fold increase in plasma levels of ADH •Diabetes Insipidus: Failure to secrete ADH, with symptoms of thirst and polyurea - Result in excess urine output and dehydration, no hypergluceamia ➣ Termination of Drinking •Water in oropharynx/ duodenum/ stomach does not stop drinking •Duodenal/ Por
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