Motivation

Motivation

Driving force

Physical need

Wanting, liking

Hypothalamus maintains homeostasis including emotions and behaviour e.g drinking and eating

The body’s energy reserve

• After eating, insulin is high, nutrients enter the blood, and energy is stored: glucose becomes glycogen in liver and muscle, and excess energy is stored as triglycerides in adipose tissue.

• During fasting, insulin is low and glucagon is high, stored energy is released: liver glycogen is broken down, new glucose and ketones are made, and fatty acids from fat tissue supply energy.

• Overall, the body switches between energy storage (fed state) and energy mobilisation (fasting state) to maintain blood glucose and ATP.

What controls feeding behaviour

Leptin

Example:

Parabiosis is the surgical joining of two animals so they share a blood supply.

• Blood-borne signals can act on the hypothalamus to regulate food intake and body weight.

• ob/ob mice are genetically obese because they do not produce leptin, a hormone that suppresses appetite.

• When an ob/ob mouse is connected to a normal mouse, leptin from the normal mouse circulates into the ob/ob mouse.

• This reduces food intake and body weight in the ob/ob mouse.

• Conclusion: body fat and appetite are regulated by a circulating hormone (leptin)

VMH and LH: effects on food intake

• Food intake is controlled by opposing hypothalamic centres.

• Damage to each centre shifts eating behaviour in opposite directions.

• These centres are regulated by leptin signalling from adipose tissue.

Lateral hypothalamus (LH) – hunger centre

• Normally promotes feeding behaviour and food-seeking.

• Activated when energy stores are low.

• Lesion of LH
  

  • Loss of hunger drive.

  • Reduced food intake.

  • Leads to anorexia and weight loss.

• This state is called lateral hypothalamic syndrome.

Ventromedial hypothalamus (VMH) – satiety centre

• Normally inhibits feeding once enough energy is consumed.

• Signals fullness and suppresses appetite.

• Lesion of VMH
  

  • Loss of satiety signals.

  • Excessive eating (hyperphagia).

  • Leads to obesity.

• This state is called ventromedial hypothalamic syndrome.

Role of leptin

• Leptin is released from adipose tissue in proportion to fat stores.

• Leptin acts on the hypothalamus to:
  

  • Inhibit LH-driven hunger.

  • Activate VMH-mediated satiety.

• Disruption of leptin signalling mimics VMH damage → overeating and obesity

Arcuate nucleus

• The arcuate nucleus is the main hypothalamic centre that senses body fat levels.

• Leptin from adipose tissue acts on the arcuate nucleus.

• Leptin inhibits hunger-promoting NPY/AgRP neurons and activates satiety-promoting POMC/CART neurons.

• These neurons project to other hypothalamic areas (PVN and LH) to control feeding.

• High leptin reduces food intake; low leptin increases hunger.

Anorexic response

High leptin signals high energy stores.

• Leptin activates POMC/CART neurons and inhibits NPY/AgRP neurons in the arcuate nucleus.

• α-MSH acts on the paraventricular nucleus to suppress feeding.

• Lateral hypothalamic hunger drive is reduced.

• Net effect: decreased appetite and food intake (anorexic response).J

Orexigenic Response

• An orexigenic response occurs when leptin levels are low.

• Low leptin shifts arcuate nucleus output toward hunger-promoting pathways.

Detection of low leptin

• Reduced fat stores → decreased leptin release from adipose tissue.

• Low leptin is sensed by neurons in the arcuate nucleus.

Arcuate nucleus neuron activity

• NPY / AgRP neurons
  

  • Activated when leptin is low.

  • Release neuropeptide Y (NPY) and AgRP.

• POMC / CART neurons

  • Suppressed when leptin is low.

  • Reduced α-MSH release.

Downstream hypothalamic effects

• Paraventricular nucleus (PVN)
  

  • Inhibited by NPY/AgRP neurons.

  • Reduced release of hypophysiotropic hormones (e.g. CRH, TRH → ↓ ACTH and TSH).

  • Lowers energy expenditure.

• Lateral hypothalamic area (LH)
  

  • Activated by NPY/AgRP neurons.

  • Stimulates feeding behaviour.

  • Some LH neurons release MCH, which promotes eating.

Physiological outcome

• Increased appetite.

• Increased food intake.

• Energy conservation during low fat / starvation states.

MC4 Receptor

Feeding behaviour is controlled by competition at the MC4 receptor.

• Anorexigenic and orexigenic signals converge on this single receptor.

MC4 receptor (MC4R)

• Located on hypothalamic neurons (especially in PVN/LH pathways).

• When activated → feeding is inhibited.

α-MSH (anorexigenic signal)

• Produced from POMC neurons in the arcuate nucleus.

• Release is promoted by high leptin.

• Binds and activates MC4R.

• Result:

• Suppresses appetite.

• Increases energy expenditure.

AgRP (orexigenic signal)

• Released from NPY/AgRP neurons in the arcuate nucleus.

• Promoted by low leptin.

• Antagonises / inhibits MC4R.

• Prevents α-MSH from activating the receptor.

• Result:

• Promotes feeding.

• Reduces energy expenditure.

Role of leptin

• High leptin

• ↑ α-MSH

• ↓ AgRP

• MC4R activated → feeding inhibited

• Low leptin

• ↓ α-MSH

• ↑ AgRP

• MC4R blocked → feeding stimulated

LH: MCH and Orexin

• The lateral hypothalamus (LH) promotes feeding.

• Two key peptides from LH neurons fine-tune when eating starts and how long it continues.

Melanin-concentrating hormone (MCH)

• Produced by a subset of LH neurons.

• Has widespread projections throughout the brain.

• Main effect
  

  • Prolongs food consumption once eating has started.

• Functional role

  • Maintains feeding.

  • Supports sustained intake and positive energy balance.

• Overactivity is associated with weight gain.

Orexin (hypocretin)

• Produced by a different subset of LH neurons.

• Also has widespread cortical and brainstem connections.

• Main effect

  • Initiates feeding behaviour.

• Functional role

  • Triggers meal onset.

  • Links feeding to arousal, wakefulness, and motivation.

How they differ

• Orexin → starts the meal.

• MCH → keeps the meal going.

Integration with leptin pathways

• When leptin is low:

  • Arcuate NPY/AgRP neurons activate LH neurons.

  • Orexin and MCH activity increases.

• Result: increased hunger, meal initiation, and prolonged eating.

Satiety

Satiety is short-term meal control.

• It suppresses eating after a meal using gut-derived signals that act on the brain.

What satiety is

• A feeling of fullness that suppresses hunger for a period after eating.

• Determines meal size and time to the next meal, not long-term body weight.

Where satiety signals come from

• Signals begin as soon as food is consumed and continue during digestion and absorption.

• Main sources:

• Stomach: stretch/distension.

• Intestine: nutrients entering the gut.

• Gut hormones (e.g. CCK, GLP-1, PYY).

• Signals travel via:

• Vagal afferents.

• Blood-borne hormones to the brainstem and hypothalamus.

How satiety stops a meal (short-term model)

• Eating starts → orexigenic drive is high.

• As food enters the gut:

• Satiety signals rise.

• These inhibit feeding circuits.

• When satiety signals peak:

• Food intake stops.

• Over time:

• Satiety signals fall.

• Orexigenic drive rises again → next meal begins.

Brain integration

• Brainstem (e.g. NTS) receives gut signals first.

• Hypothalamus integrates these with motivational circuits.

• Satiety pathways temporarily override hunger pathways.

The Satiety Cascade

Short-term regulation of feeding controls when a meal starts and when it ends.

• It is driven by a cascade of signals that begin before eating, rise during eating, and peak after food enters the gut.

• These signals produce satiation (meal termination) and satiety (suppression of hunger after the meal).

Phase 1: Cephalic phase (before eating)

• Triggered by sight, smell, taste, and anticipation of food.

• Ghrelin is released when the stomach is empty.

• Ghrelin:

• Activates NPY/AgRP neurons in the arcuate nucleus.

• Increases hunger and meal initiation.

• Cephalic insulin release prepares the body for incoming nutrients.

• This phase explains why hunger can occur before food is consumed.

Phase 2: Gastric phase (during eating)

• Begins once food enters the stomach.

• Gastric distension activates stretch receptors.

• Signals are sent to the brain via the vagus nerve.

• Produces satiation:

• Gradual reduction in eating rate.

• Contributes to ending the meal.

Phase 3: Intestinal / substrate phase (after eating)

• Triggered as nutrients enter the intestine and are absorbed.

• Gut hormones released:

• CCK (especially in response to fat).

• GLP-1, somatostatin.

• Effects:

• Act via vagal afferents and circulation.

• Inhibit feeding circuits.

• Slow gastric emptying.

• Insulin released from pancreatic β-cells:

• Acts on the arcuate nucleus.

• Reinforces satiety signals.

• Oxidative metabolism of glucose, amino acids, and fat sustains satiety.

Satiation vs satiety

Satiation

• Develops during a meal.

• Causes meal termination.

Satiety

• Develops after a meal.

• Suppresses hunger until the next meal.

• Leptin modulates this system long-term but is not the main short-term signal.

Dopamine

• Dopamine is a neurotransmitter that changes how strongly neurons signal in circuits controlling motivation, reward, learning, and movement.

• Its key effect is modulating neural activity, not simply “causing pleasure”.

• It signals the importance or value of an outcome and helps reinforce behaviours that lead to it.

Dopamine in reward and motivation

• Dopamine release increases when an outcome is better than expected.

• This strengthens synaptic connections in reward circuits, making the brain more likely to repeat the behaviour.

• It is central to reinforcement learning (learning from rewards and prediction errors).

Major dopamine pathway (reward circuit)

• Dopamine neurons originate in the ventral tegmental area (VTA).

• They project to the nucleus accumbens, part of the limbic system.

• Activation of this pathway increases motivation, wanting, and goal-directed behaviour.

Addiction Cycle

• Addiction is driven by a shift in brain motivation systems: behaviour moves from being reinforced by dopamine-mediated reward to being driven by avoidance of negative emotional states.

• The key change is a progressive dysregulation of reward (dopamine) and stress systems, which locks behaviour into a repeating cycle.

Stage 1: Acute reinforcement / social drug-taking

• Drug use initially increases dopamine release in reward pathways.

• This produces positive reinforcement: the behaviour is repeated because it feels rewarding.

• Use is typically voluntary, intermittent, and context-dependent.

• Learning links the drug with environmental cues.

Stage 2: Escalation and compulsive use

• Repeated exposure causes neuroadaptations in dopamine signalling.

• Larger or more frequent doses are needed to achieve the same effect (tolerance).

• Control over intake weakens and use becomes habitual and compulsive.

• Stress and conditioned cues increasingly trigger use.

Stage 3: Dependence

• The brain’s baseline state changes.

• Normal dopamine signalling is reduced when the drug is absent.

• Stress systems become overactive.

• Drug use is no longer mainly about reward, but about maintaining a new “normal”.

Stage 4: Withdrawal

• When the drug is removed, dopamine activity drops further.

• Stress and anxiety systems dominate.

• Symptoms include dysphoria, irritability, anxiety, and physical effects.

• Drug-taking now produces negative reinforcement: it relieves unpleasant withdrawal states.

Stage 5: Protracted withdrawal

• Even after acute withdrawal ends, reward and stress systems remain dysregulated.

• Sensitivity to stress is high and mood remains low.

• This state strongly increases vulnerability to relapse.

Relapse

• Stress, environmental cues, or small re-exposures reactivate learned drug associations.

• Craving emerges due to long-lasting changes in brain circuits.

• The cycle restarts, often rapidly returning to compulsive use.

What shifts from non-dependent to dependent states

• Non-dependent: behaviour driven mainly by dopamine-based positive reinforcement.

• Dependent: behaviour driven mainly by relief from negative emotional and physical states.

• Stress circuits increasingly dominate over reward circuits as dependence develops

D2 receptors

• Both obesity and drug addiction show reduced dopamine D2 receptor availability in reward circuits (especially the striatum/nucleus accumbens).

• Lower D2 signalling means rewards feel less effective, so behaviour escalates to compensate (more food or more drug).

• Chronic overstimulation of dopamine causes down-regulation of D2 receptors, reinforcing compulsive use.

• Reinforcement circuits (VTA → nucleus accumbens, with amygdala, hippocampus, and prefrontal cortex input) become biased toward habitual, cue-driven behaviour.

• Over time, behaviour shifts from reward-seeking to relief of a low-reward, high-stress baseline state, increasing relapse risk.