Module 2: Lecture 3 Notes

Exam Preparation

• Focus on the major conclusions from experiments rather than the minute details of each experiment. Understand the experimental designs and controls used to reach these conclusions.

• Understand the circuits discussed and how they interact, including the roles of different neurotransmitters and receptors within these circuits.

• Lecture readings, especially Stuber and Weiss, are helpful for understanding key results. Also, consult relevant research papers to deepen your understanding.

Start and Stop Signals in Feeding

• Start Signals: Neurons or regions, when activated, initiate feeding, or when inhibited, inhibit stopping feeding. These signals can be influenced by hormones and external cues.

• Stop Signals: Neurons or regions, when activated, stop feeding, or when inhibited, inhibit starting feeding. These signals are integral for maintaining energy balance and can be affected by satiety signals.

Key Circuits and Neurons

• Lateral Hypothalamus (LH) GABAergic Neurons:

  • Start signals; activation initiates feeding. These neurons play a critical role in promoting appetite and food consumption.

  • Inhibit inhibitory neurons in the VTA, disinhibiting dopamine neurons, leading to increased motivation.

  • Dopamine release in the nucleus accumbens leads to food-motivated behavior by enhancing the reward value of food.

  • Activity leads to negative feedback, turning off the initial LH activity to prevent overeating.

• D1 Receptor-Expressing Nucleus Accumbens Shell Neurons:

  • Activation reduces feeding, providing negative feedback. These neurons contribute to satiety and help regulate food intake.

• Lateral Hypothalamus Glutamatergic Neurons:

  • Stop signals; activation stops feeding. These neurons are essential for ceasing food consumption.

  • Activate glutamate neurons in the habenula, which is involved in negative reward signals.

  • Increase activity of GABAergic interneurons in the VTA, decreasing dopamine release and reducing food-seeking behavior.

  • Decrease food-motivated behavior by diminishing the reinforcing properties of food.

• Bed Nucleus of the Stria Terminalis (BNST) GABAergic Projection:

  • Input to the glutamate neurons in the LH. The BNST influences feeding behavior by modulating the activity of stop signals.

  • Turning on these neurons turns off a stop signal, initiating eating.

• Orexin Neurons:

  • Start signals that stimulate hunger and increase arousal and wakefulness related to food seeking.

• Paraventricular Hypothalamus (PVH):

  • Stop signal sensitive to satiety. The PVH integrates hormonal and neural signals to control feeding.

  • Inhibits feeding through the parabrachial nucleus. The PVH activates pathways that decrease appetite.

  • Inhibited by LH GABAergic neurons or AGRP neurons, allowing for feeding.

  • Hunger or activity of GABAergic neurons reduces PVH activity, promoting food-motivated behaviors.

Arcuate Nucleus

• AGRP Neurons:

  • Start signals that broadly control feeding. AGRP neurons are potent stimulators of appetite.

  • Sensitive to satiety but work even without learning, making them crucial for basic feeding drives.

• POMC Neurons:

  • Stop signals that project to the paraventricular hypothalamus. These neurons promote satiety.

  • More active when not hungry and inhibit feeding, helping to suppress appetite.

Hormonal Signals

• Ghrelin: Hunger hormone (start signal) secreted by the stomach to stimulate appetite.

• CCK: Gut-derived satiety signal that increases throughout meals, tracking current satiety state.

• GLP-1 (Glucagon-Like Peptide-1):

  • Satiety signal secreted in response to nutrients, affecting the digestive system and glucose metabolism.

  • Stimulates insulin, inhibits glucagon, and promotes glucose use, improving glycemic control.

  • Agonism reduces food intake; target of drugs like Ozempic for weight loss by enhancing satiety.

• Leptin:

  • Adiposity signal secreted by white fat cells, proportional to body fat, signaling energy stores.

  • Regulates energy, eating, and metabolism. Leptin influences long-term energy balance.

  • Changes how well other satiety signals work. Leptin modulates the effectiveness of other signals.

  • Leptin knockouts gain a lot of weight; leptin deficient individuals also tend to increase feeding.

  • Activates POMC neurons and inhibits AGRP neurons in the arcuate nucleus to decrease appetite.

  • Leptin receptors in VMH also play a role in restricting feeding.

GLP-1 Effects:

• Agonism reduces food and water intake in a dose-dependent manner in rats.

• In humans, reduces hunger and increases satiety; decreases calorie intake and meal duration in a dose-dependent manner.

Leptin’s Role

• Impact on Satiety Signals: Leptin modulates the effectiveness of satiety signals. High leptin amplifies satiety signals, while low leptin diminishes them.

• Systemic Administration: Systemic delivery of leptin reduces feeding in leptin-deficient animals and hungry normal animals.

• Motivation: Leptin and insulin reduce motivation for food-seeking behavior, as measured by lever pressing.

• Hypothalamic Receptors: Leptin receptors are present throughout the hypothalamus, including in the arcuate nucleus and lateral hypothalamus.

• Electrophysiological Effects: Leptin reduces the firing rate of orexin neurons in the lateral hypothalamus by reducing the resting membrane potential.

• Direct Hypothalamic Delivery: Direct delivery of leptin to the hypothalamus reduces food intake and body weight.

Leptin and Arcuate Nucleus (ARC)

• Activation of POMC: Leptin activates POMC neurons in the ARC, which are satiety signals.

• Inhibition of AGRP: Ghrelin increases AGRP activity, while leptin does not have the same effect.

• POMC Knockouts: Knocking out leptin receptors specifically in ARC POMC neurons leads to overeating and increased body weight.

Integration of Signals

• PVN, PDNY neurons project to the PB, acting as a stop signal. These pathways are crucial for satiety.

• ARC AGRP neurons interact with these PVN neurons, modulating the stop signals based on hunger.

Considerations

• Redundancy: There are multiple redundant circuits in the brain for feeding, suggesting evolutionary importance. This ensures that feeding behavior is robust.

• Interactions: The circuits interact with satiety signals and learning processes, integrating internal and external cues.

Incentive Motivation

• Goes beyond homeostasis to address factors like liking and wanting, which are key drivers of food choice.

• Addresses additional factors such as time of day, convenience, social cues, boredom, stress, and environmental cues.

Social & Environmental Factors

• Social Eating Habits: Eating with friends vs. eating alone can significantly impact food intake.

• External Cues: Billboards, songs, smells, and other associative cues can trigger eating behavior.

• Economic Factors: Availability and cost of food impact dietary choices and eating patterns.

Liking vs. Wanting

• Liking:

  • Pleasurable response to stimulation, reflecting the hedonic value of food.

  • Measured through self-report and facial expressions.

• Wanting:

  • Motivational signal, representing the drive to obtain food.

  • Value of reinforcers or cues that predict reinforcers.

  • Can occur without liking, indicating that motivation and pleasure are dissociable.

Cues and Eating

• Studies show that cues paired with food can increase eating behavior in both rats and humans.

• CS+ (Conditioned Stimulus paired with food) increases eating, while CS- (unpaired cue) does not.

• Advertising leverages this by associating cues with desired products, motivating responses.

Limitations of Homeostatic Theory

• Overeating: Homeostasis cannot explain why people often eat beyond their metabolic needs, driven by pleasure and external cues.

• Preference: Homeostasis does not account for food preferences, such as preferring non-caloric sweeteners, which are unrelated to energy needs.

Neural Mechanisms of Liking

• Challenges in Measuring Liking: Difficult to differentiate from wanting behaviorally, requiring specific tools.

• Taste Reactivity: Objective way to measure liking through facial reactions in rodents and humans, providing insight into hedonic responses.

• Emotional Expressions: Well-conserved in mammals, facilitating cross-species studies.

Neural Circuits of Liking

• Initial Hypotheses: Dopamine was initially thought to mediate pleasure in the brain.

• Evidence Against Dopamine's Role in Liking:

  • Excessive dopamine does not increase pleasure responses, indicating it primarily drives motivation.

  • Amphetamine-induced dopamine release does not change affective measures of taste reactivity.

  • Blocking dopamine receptors does not affect pleasure reactivity, further dissociating dopamine from liking.

  • Lesioning dopamine neurons does not alter hedonic reactions.

  • Parkinson's patients still experience pleasure from sweet foods despite dopamine deficits.

  • Human PET scans show no correlation between dopamine release and liking.

• Role of Opioids: Endorphins, specifically through mu opioid receptors, mediate pleasure.

  • Opioids and pain perception: the endogenous opioid system primarily functions to help us deal with pain, particularly in cases where we don't wanna feel pain.

Measuring Dopamine

• Fast Scan Cyclic Voltammetry:

  • Technique to detect dopamine levels in the brain using electrophysiological properties.

  • Involves applying voltage pulses to an electrode and measuring oxidation and reduction reactions.

  • The shape of the voltage curve is used to identify the neurotransmitter being measured.

  • During self-stimulation tasks, dopamine release is observed in response to both the lever press and predictive cues.

• Fluorescent Biosensors:

  • Use fluorescent molecules that bind to specific receptors, allowing measurement of dopamine changes.

Dopamine and Various Behaviors

• Self-Stimulation: Animals will self-stimulate dopamine neurons, indicating the rewarding nature of dopamine release.

• Punishment Resistance: Some animals will continue to self-stimulate dopamine neurons despite punishment, demonstrating the power of dopamine-driven motivation.

• Food and Water: Dopamine release occurs in response to both food and water retrieval.

• Sexual Stimuli: Sexual interactions also lead to increased dopamine levels.

• Social Interactions: VTA dopamine release is modulated by social interactions and is influenced by social novelty. Novelty evokes a larger release event than more familiar contexts.

mu Opioid Receptors

• Seven transmembrane G protein-coupled receptors that are primarily presynaptic and inhibitory.

• Endogenous chemicals that impact opioid receptors: endorphins, enkephalins, and dynorphins.

Ventral Striatum and Liking

• Ventral Pallidum is medial and ventral to the nucleus accumbens shell.

• Ventral tegmental area and nucleus accumbens shell: DAMGO to nucleus accumbens increases ventral pallidum activation.

• DAMGO - mu opioid receptor.

  *DAMGO administration increases liking reactions; effects depend on location within VP.

Interaction between Nucleus Accumbens (NAcc) and Ventral Pallidum (VP)

• Reciprocal Connections: N.Acc and VP are connected; activation of one increases the activation of the other

Hot Spot Mapping

• Delivery of minute quantities of DAMGO, a mu opioid agonist to various points in the nucleus accumbens can affect taste reactivity via hedonic reactions

The Summary

• Medial Nucleus Accumbens Shell and Liking Reactions:

  • The medial nucleus accumbens shell is sufficient for causing liking reactions. Activation in this region promotes positive hedonic responses to stimuli, enhancing the perception of pleasure.

• Effects of Nucleus Accumbens Shell Agonism:

  • When there is agonism in the nucleus accumbens shell, aversive reactions decrease. This suggests that stimulating the nucleus accumbens can reduce negative or unpleasant responses, shifting the balance towards more positive experiences.

• Impact of Naloxone Administration:

  • Administration of naloxone, a mu opioid receptor antagonist, leads to a decrease in taste reactivity and licks. Naloxone blocks opioid receptors, which are crucial for mediating pleasure and reward, thus reducing the positive response to taste stimuli.

  • Naloxone's effect highlights the importance of opioid signaling in the nucleus accumbens for taste-related reward and motivation.