NSCI Exam 3

Secretory hypothalamus

Uses hormones with widespread, longer-lasting influences over the brain and body

ANS

Coordinates multiple, widespread, and relatively slow visceral responses using balance of excitation and inhibition

Diffuse modulatory systems

Widespread neural networks that modulate brain acitivity

Homeostasis: Negative feedback

Primary homeostatic mechanism where deviation from a set point triggers compensatory action

Homeostasis: Set zone

The tolerable range around a set point

Homeostasis: Redundancy

Physiological systems are monitored by more than one mechanism

Hypothalamic dysfunction

Even a tiny lesion can cause fatal, widely dispersed disruptions of bodily functions

Magnocellular neurosecretory cells

Large neurons in the hypothalamus extending axons into the posterior pituitary lobe to release neurohormones directly into capillaries

Oxytocin

Triggers: Sensory stimuli (somatic, visual, auditory) processed via cortex/thalamus

Functions: Milk letdown reflex, social bonding, uterine contractions during childbirth, and sexual arousal

Anxiety and stress can inhibit its release

Vasopressin (antidiuretic hormone/ADH)

Triggers: Decreased blood volume and increased salt concentration detected by cardiovascular pressure receptors and hypothalamic sensors

Interacts with kidney-released renin and angiotensin (via the subfornical organ, which lacks a blood-brain barrier) to stimulate thirst and regulate blood pressure/salt balance

Oxytocin/vasporesin projections

Paraventricular nucleus (PVN) and supraoptic nucleus (SON)

Oxytocin/vasporesin pathways

Projections extend to the mesocorticolimbic pathway (reward system, including nucleus accumbens and ventral tegmental area) and regions tied to non-reproductive social recognition, empathy, and parental care

Prarrie voles vs. meadow voles

Prarie voles form monogamous pair bonds due to specific oxytocin/vasopressin receptor expression and epigenetic mechanisms; meadow voles do not, but can exhibit monogamous behavior when dosed

Anterior pituitary

A true endocrine gland controlled by parvocellular neurosecretory cells via the hypothalamo-pituitary portal circulation (a direct blood supply highway)

The HPA axis steps

1. Hypothalamus: Senses stress and releases CRH (corticotropin-releasing hormone)

2. Portal system: CRH travels directly to the anterior pituitary

3. Anterior pituitary: Releases ACTH (adrenocorticotropic hormone) into the general bloodstream

4. Adrenal glands: ACTH targets the adrenal cortex to release cortisol

Rapid brain stress signaling

CRH and vasopressin act on receptors in the amygdala, locus coeruleus (norepinephrine/alertness), hippocampus, thalamus, and prefrontal cortex

Stress vs. anxiety

Stress: The body/brain’s response to demands requiring adaptation

Anxiety: An emotional state involving worry and anticipation of a future threat (normal anxiety has an adaptive function, but chronic/excessive anxiety impairs function)

Structural difference between ANS and somatic motor systems

Somatic motor systems use a monosynaptic pathway to skeletal muscle; the ANS uses a disynaptic pathway (preganglionic neurons to autonomic ganglia to postganglionic neurons)

Sympathetic divisions

Functions: Fight, flight, fright, freeze, sex; increases heart rate/blood pressure, mobilizes glucose, depresses digestion

Outflow: Preganglionic fibers originate only from the thoracolumbar spinal cord

Neurotransmitters: Postganglionic fibers mostly release NE

Parasympathetic divisions

Functions: Rest, digest, growth, immune response, energy storage; slows down heart rate, drops blood pressure, increases digestion

Outflow: Preganglionic fibers originate only from the brainstem and sacral spinal cord

Neurotransmitters: Postganglionic fibers release ACh locally

Sympathomimetic

Mimic/promote NE actions or inhibit ACh

Parasympathomimetic

Mimic/promote muscarinic ACh actions or inhibit NE

Humoral response

Stimulating/inhibiting pituitary hormones (e.g., TSH, ACTH) to maintain homeostasis

Visceromotor response

Adjusting symapthetic/parasympathetic balance to maintain homeostasis

Somatic motor response

Inciting motivated behaviors via the lateral hypothalamus to maintain homeostasis

Anabolism (prandial state)

Building energy stores (glycogen, triglycerides)

Long-term regulation

Catabolism (post-absorptive state)

Breaking down stores for energy during fasting

Long-term regulation

Cephalic phase

Sight/smell of food triggers parasympathetic preparation (saliva, insulin via beta cells)

Short-term regulation

Gastric phase

Food enters the stomach; gastric distension signals via the vagus nerve to the nucleus of the solitary tract; CCK is released to suppress meal size/frequency

Short-term regulation

Substrate phase

Nutrients absorbed; insulin peaks to clear blood glucose

GLP-1 suppresses appetite and slows gastric emptying

Short-term regulation

Ventromedial hypothalamus (VHM)

The satiety center

Lesions cause obesity and overeating

Lateral hypothalamus (LH)

The feeding center

Lesions cause anorexia and severe weight loss/lateral hypothalamic syndrome

LH peptides include MCH (prolongs consumption) and Orexin (promotes meal initiation)

Leptin

Released by fat cels (adipocytes) to signal high energy stores, decrease appetite, and increase energy expenditure

High leptin (excess adiposity)

Activates arcuate nucleus neurons releasing alphaMSH and CART (anorectic peptides)

Results in decreased food intake and increased metabolism (humoral. viscometer, and somatic pathways)

Low leptin (fat loss/fasting)

Activates arcuate neurons releasing NYP and AgRP (orexigenic peptides)

Stimulates LH, increases appetite, and decreases metabolic rate

Leptin resistance

High circulating leptin levels in obesity fail to reduce appetite due to decreased receptor sensitivity or blood-brain barrier transport issues

GLP-1 receptor agonists (e.g., Wegovy, Ozempic)

Act on AgRP neurons to shut down neuronal activity, decrease appetite, lower blood sugar, and reduce body weight by 15-20%

Effective in treating Type 2 diabetes and obesity

THC

CB1 receptors are widespread in brain areas controlling feeding and smell

THC stimulates appetite by enhancing olfactory sensitivity and altering hypothalamic reward circuits

Clinical use: Dronabinol (synthetic THC) treats AIDS-related weight loss and chemotherapy-induced naesea

Anorexia & basal-forebrain-VTA circuit

Stress-activated basal forebrain neurons excite VTA glutamate neurons, reducing dopamine release in the nucleus accumbens (NAc), making food less rewarding and motivating

Langauge & stigma

Use person-first, clinical language (e.g., “substance use disorder” or “alcohol use disorder”) instead of stigmatizing terms like “addict” or “alcoholic” to improve treatment-seeking behavior

Naloxone mechanism

A competitive opioid receptor antagonist that binds to mu-opioid receptors with higher affinity than opioids like heroin/fentanyl, rapidly reversing respiratory depression and preventing overdose death

Wanting

Motivation/incentive salience

Driven by dopamine

Liking

Pleasure

Driven by endogenous opioids (endorphins/enkephalins)

Exogenous opioids

Morphine, codeine, heroin (produce anaglesia, euphoria, drowsiness, mental clouding, nausea, constipation)

Endogenous opiods

Endorphins and enkephalins (small peptide neurotransmitters)

Opioid mechanism of action

Suppress presynaptic glutamate release and hyperpolarize postsynaptic membranes

An extensive endorphin network in the spinal cord dorsal horn, PAG, and raphe nuclei prevents nociceptive signal transmission to the brain, blocking pain perception

Naloxone as research tool

Blocks endogenous opioid receptors; antagonizes morphine analgesia and can abolish placebo-induced analgesia

k-Opioid receptors (KOR)

Activated during stress, it directly contributes to drug-seeking behavior initiation in animals and replacement in humans

Dopamine depletion studies

Animals with mesolimbic dopamine still show normal facial expressions of “liking” when sweet food is placed in their mouths, but will not perform work or move to obtain (“want”) the food, eventually starving if not force-fed

In heavy drinkers, acute dopamine depletion reduces attentional bias toward alcohol-related environmental cues

Electrical self-stimulation (ICSS)

Animals lever-press to stimulate VTA dopamine projections to the nucleus accumbens, prioritizing self-stimulation over food, water, and survival until exhaustion

Dopamine receptor antagonists decrease self-stimulation behavior

Dopamine firing pattern in learning

Unconditioned reward (before training): Dopamine neurons fire bursts immediately after an unpredicted reward (e.g., juice delivery)

Conditioned cue (after training): Once a neutral stimulus (e.g., light) reliably predicts reward, dopamine neurons shift their burst firing to the cue, not the reward itself

Omitted reward: If the cue is presented but the expected reward is omitted, dopamine neuron firing drops below baseline at the exact time the reward was anticipated (negative RPE)

Vagal communications & food reward

Gut-to-brain signaling via the vagus nerve acts as a tonic regulator of the mesolimbic dopamine system

Constitutive vagal tone provides a permissive signal sustaining VTA dopamine neuron firing and enabling downstream nucleus accumbens (NAc) dopamine surges during nutrient ingestion

Effects of subdiaphragmatic vagotmy

Surgical disruptions of the vagus nerve blunts VTA activity and NAc dopamine release

Significantly reduces consumption of palatable high-fat foods and abolishes learned place preference for food-paired environments (demonstrating gut vagal signals shape incentive learning)

Heroin, nicotine, and cocaine

These three major addictive drugs artificially elevate dopamine concentration within the nucleus accumbens (NAc) via mesolimbic projections originating in the VTA

Heroin

Activates u-opiod receptors on VTA neurons (and disinhibits GABAergic interneurons), increasing VTA dopamine cell firing rate

Nicotine

Activates nicotinic acetycholine receptors (nAChRs) directly on VTA dopamine neurons, increasing action potential frequency and NAc dopamine release

Cocaine

Blocks the dopamine transporter in the NAc, preventing the reuptake of extracellular dopamine and leaving high concentrations in the synaptic cleft

Also blocks NE transpoters

Amphetamine

Reverses dopamine transporters (and NET), pumping intracellular dopamine out into the synaptic cleft while blocking reuptake

D2 receptor down-regulation

Chronic drug use overstimulates dopamine receptors, causing target NAc neurons to down-regulate surface D2 receptors (visible on PET scans)

Blunted endogenous system

Baseline dopamine synthesis and release drop below normal levels; natural rewards (food, social interaction) no longer evoke sufficient dopamine signals

Tolerance and dependence

The brain requires higher doses of the drug to achieve the same reward effect; drug removal leads to hypodopaminergic withdrawal states characterized by intense dysphoria and drug craving

Cue-induced relapse

Environmental stimuli paired with past drug use (e.g., lighters, paraphernalia, specific locations) evoke dopamine spikes that trigger intense craving and drug seeking behavior through learned cortico-straital circuits

Challenges to treatment

Neuroplastic changes in D2 expression, persistent cue-conditioned memory circuits, overlap between addiction pathways and basic biological survival circuits, and individual variability

Detoxification/withdrawal support

Benzodiazepines for acute alcohol withdrawal (enhance GABA A receptor activity to prevent seizures, tremors, and delirium tremens)

Substitution/agonist therapy

Methadone (full u-opioid agonist) or buprenophrine (partial agonist) or opioid dependence; nicotine replacement patches for smoking cessation

Aversive/metabolic alternative

Disulfiram (antabuse) inhi