NROC61 - Lecture 7 Hypothalamus and Motivation

Motivation centre in brain

Hypothalamus

What is the hypothalamus?

Small cluster of nuclei

Co-ordinates homeostasis

What does the hypothalamus integrate?

Endocrine system, Autonomic system, Motivated behaviour

Hypothalamus functions

Temperature

Food + Water intake

Sexual behaviour

Daily physiological cycles

Emotional (stress) responses

Anatomical features of Hypothalamus

Many nuclei form walls of third ventricle

bathed in CSF

Anterior hypothalamic area (AHA)

Osmotic control, drinking, temperature (heat loss)

Suprachiasmatic nucleus (SCN)

biological clock

Paraventricular nucleus (PVN)

Magnocellular - oxytocin and vasopressin

Parvocellular - corticotrophin-releasing hormone (CRH) + thyrotrophin-releasing hormone (TRH)

Arcuate Nucleus (ARC)

Dopamine to control prolactin (growth hormone releasing hormone)

Receptors for leptin and insulin (hunger)

Ventromedial Nucleus (VMH)

Senses metabolites (glucose)

Regulates feeding & metabolism

Lateral hypothalamus (LH)

feeding centre

Posterior hypothalamic area (PHA)

Sympathetic (fight or flight) activation

Why is Hypothalamus ideal physically?

Capillaries are fenestrated (porous) to entry of molecules from blood and detect changes in blood

Neural connections to hypothalamus

Afferents conveying gustatory/sensory information (retina, olfactory, cutaneous, visceral)

noradrenaline from locus coeruleus

5-HT fibres from raphe nucleus

Neuroendocrine system Direct control

Paraventricular nucleus (PVN) magnocellular cells release ADH and oxtocin via posterior pituitary

Neuroendocrine system Indirect control

PVN parvocellular cells release CRH and TRH into pituitary portal vessels to release from anterior pituitary

Posterior Pituitary pathways

ADH to Kidneys

Oxytocin to Breasts

Anterior Pituitary pathways

ACTH to Adrenal Cortex

GH to bone and muscle

MSH to skin

TSH to Thyroid

Gonadotropins (FSH, LH) to genitals

Prolactin to breasts

Neural control

Fibres descend via MFB to control brainstem autonomic centres

parasympathetic nervous system

Rest and digest

Help body recover and store nutrients

sympathetic nervous system

Fight or flight

Promote survival in danger

Two main function systems of Hypothalamus

Feedback and Feedforward system

Feedback system

Corrects deviations from set point; compare current value with supposed and make adjustments

Feedforward system

Override feedback under extreme conditions to adjust output to meet future needs

Regulation of feeding

Two sets of signals, long term (tonic) or short term (episodic) control apetite

Long term (tonic) regulation

Signals arise from tissue stores to express appetite

Short term (episodic) regulation

Mainly inhibitory

Associated with satiety

Dual Centre Hypothesis

Hypothalamus has two centres responsible for hunger and satiety: Lateral hypothalamus (LH) and Ventromedial Hypothalamus (VMH)

LH as hunger centre

Electrolytic lesions showed aphagia, lack of interest in food leading to wasting

Stimulation showed a sated rat continue eating

VMH as satiety centre

Electrolytic lesions showed hyperphagia (over-eating), rapid weight gain

Stimulation showed hungry rat stop eating

Issues with LH=Hunger Centre

Rats with lesions recovered voluntary eating after stimulation

LH lesions impaired basic sensorimotor processes, showing it is not specific to hunger but also general activity

Why excitotoxins are better than electrolytic in studying the LH?

Excitotoxins spare the DA fibre systems passing through the LH and only targets cell bodies

Produced activity in some parts of appetite control, but not specific enough

Homeostatic insults to LH

2-deoxyglucose injections to the LH that induce feeding failed to elicit feeding

Results of Optogenetic technique

Photoactivation of BNST (GABA) neurons showed inhibition of LH glutamatergic neurons that led to intense feeding or suppression in sated and hungry mice

LH glutamatergic neuron regulation

Activation = inhibit feeding

Suppression by GABA = promotes feeding

Issues with VMH = Satiety centre

Motivational drive

VMH-lesioned rats work less for food rather than showing the heightened motivation expected of an animal that has “lost” satiety control.

Food selectivity (finickiness)

They overeat only palatable diets; when food is made bitter with quinine they refuse it

Lipostatic theory

Everyone has a set-point for body fat, deviations leads to compensatory food intake or metabolism

Experiment to find lipostatic factor?

Parabiosis

Parabiosis results

Obese + Control = Ob lost weight

Diabetic (no satiety signal) + control = Control starved

Obese + Diabetic = Ob lost weight, both coexist

Parabiosis conclusion

Diabetic mice have a circulating factor causing obese and control mice to stop eating but their satiety centre is not working

Obese mice do not have satiety signal

Leptin

Signaling molecule secreted from fat cells

Levels mirror adipose mass

Adipocytes control energy levels

Neural mechanisms of Leptin

Leptin receptors in arcuate nucleus

Response to increased leptin

Activation of anorectic neuropeptides CART and alpha-MSH

Inhibition of orexigenic neurons containing NPY and AgRP

Arcuate nucleus projections (Increased Leptin)

To LH inhibits feeding

To paraventricular nucleus (PVN) activates humoral response from anterior pituitary

Increased metabolism

Raises body temp

Response to Decreased leptin

Activation of orexgenic peptides NPY and AGRP

Inhibition of anorectic peptides

Arcuate nucleus projections (decreased Leptin)

To LH neurons induces feeding

Inhibits PVN neurons at anterior pituitary

Decreased metabolism

Insulin

Pancreatic hormone

Levels proportional to fat

Release from Beta-cells

Functions of Insulin

Enables glucose to enter cells (NOT NEURONS)

Promotes conversion of energy in blood into fat

Reduction in food appetite and increase metabolism

Insulin on Arcuate Nucleus

Increased insulin stimulates CART/alpha-MSH neurons

Inhibits NPY/AgRP neurons

Diabetes Mellitus Type I

Pancreatic Beta-cells destroyed, no insulin made

Cells cannot use glucose, fatty acids used instead = ketoacidosis

Hyperglycemia - in urine

Polyuria - kidneys excrete additional water to dilute glucose in urine

Polydipsia - abnormal thirst

Increased hunger, but weight loss

Type II Diabetes

More prevalent

Body resistant to insulin due to reduced receptors

Normal insulin levels

Hyperglycemia

No ketoacidosis

Ghrelin

Orexigenic peptide (hunger drive)

Increased concentration during fasting, decreased after eating

Neural Mechanism of Ghrelin

Activates NPY and AgRP, inhibits CAR/alpha-MSH neurons

Orexigenic peptides

NPY and AgRP

Promote food intake

Anorectic peptides

POMC/Alpha-MSH and CART

Inhibit food intake