Biological Basis of Behavior

🧭 Overview

🧠 One-sentence thesis

Neuroscience is the study of the nervous system—a flexible, complex network of neurons and glia that uses electrical and chemical signals to coordinate all bodily activity—and scientists learn about it through experimental, observational, and case study methods.

📌 Key points (3–5)

• What neuroscience studies: the nervous system, including how neurons communicate using electrical action potentials and chemical neurotransmitters.
• The brain's remarkable flexibility: blind people can use visual areas for echolocation, stroke survivors regain function, and babies learn multiple languages effortlessly.
• Three main research approaches: experimental design (establishes causality), observational/quasi-experimental studies (show correlation), and case studies (detailed examination of rare individuals).
• Common confusion: "We only use 10% of our brain" is false—we use all parts, just not simultaneously; proper brain function requires precise timing, like a traffic light.
• Neurons vs. glia: the brain contains roughly 86 billion neurons and 86 billion glial cells, each with distinct roles in communication, support, and maintenance.

🧬 What is neuroscience?

🧬 Definition and scope

Neuroscience: the study of the nervous system, the collection of nerve cells that interpret information and allow the body to coordinate activity in response to the environment.

• The nervous system functions like highways connecting cities (organs).
• Communication routes include: signals descending to muscles/organs, signals ascending from sensory systems, and signals between brain areas.
• Example: detecting a visual threat triggers a cascade through the visual system that prepares the body for conflict.

⚡ How neurons work

• Neurons use a combination of electrical and chemical signals.
• The electrical output is an all-or-nothing response called an action potential.
• Neurotransmitters (chemicals) pass information between neurons.
• The brain processes approximately 10^28 operations per second—orders of magnitude faster than any current supercomputer.

🎨 The brain's unique strengths

• Not just raw computational power, but flexibility and adaptability.
• Blind people use visual cortex areas during echolocation.
• Stroke survivors regain motor functions using unaffected circuits.
• Babies effortlessly learn two languages simultaneously in bilingual households.
• The brain generates abstract human functions: consciousness, creativity, thoughts, fears, desires.

🔬 How we learn about neuroscience

🔬 Experimental design (gold standard)

Experimental design: a stepwise process where scientists develop a research question and hypothesis, then test it by manipulating an independent variable and measuring effects on a dependent variable while controlling confounding variables.

Key components:

• Independent variable: the factor being changed by the experimenter.
• Dependent variable: the factor being measured/influenced.
• Confounding variables: extraneous factors that must be controlled.
• Control group: similar to experimental group except for the manipulation.
• Random assignment to groups minimizes bias.

Strength: establishes causality (X causes Y), allowing extrapolation to larger populations if the sample is representative.

Weakness: artificial environments may affect participant performance.

Example: "Does studying more increase exam performance?" Independent variable = hours studied; dependent variable = exam grade; confounding variable = hours slept (poor sleep impairs memory).

📊 Observational/quasi-experimental studies

Quasi-experimental design: studies without random assignment to groups, often used when experiments would be impractical or unethical.

When used: situations where you cannot ethically manipulate the independent variable.

Example: "Do people with traumatic brain injury have worse hand-eye coordination?" You cannot ethically give people head injuries, so you compare an existing group with injuries to a demographically similar control group without injuries.

Weakness: no true randomness means confounding variables may influence results; can demonstrate correlation but not causation (chicken-or-egg problem).

The Adverse Childhood Experiences (ACEs) study examined 17,000 people, linking childhood trauma with premature death—a large-scale quasi-experimental design.

📝 Case studies

Case study: a highly detailed description of a single patient and their condition, often examining individuals with very rare conditions.

Value: provides insight into specific deficits or enhancements that millions of healthy people cannot provide.

Famous example: Phineas Gage (1848)—railroad worker who survived an iron rod through his frontal lobe; personality changes taught us that the frontal lobe regulates inhibitions.

Limitations:

• Shows correlation, not causation.
• Difficult to generalize findings to the larger population.
• Usually describes nearly-one-of-a-kind individuals.

Use in research: case studies help develop hypotheses that can later be tested experimentally in animal models.

🚫 Common neuroscience myths

🚫 "We only use 10% of our brain"

False. We use every part of the brain, just not all at the same time.

• Most of the brain is active most of the time, but at precisely controlled times.
• Analogy: Does a traffic light only use 33% of its lights? No—it uses all three at precise times.
• If too many cells were active at wrong times (like showing green and red simultaneously), chaos ensues—one cause of seizures is excessive neural activity.

🚫 "Each new memory creates a new neuron"

False. Memories are most likely stored at synapses (contact points between neurons), not by creating new neurons.

• Changes in how neurons connect and communicate likely underlie memory formation.
• Most adult neurons do not reproduce.
• Exception: neurogenesis (new neuron growth) does occur in a few areas like the hippocampus and olfactory epithelium.

🚫 "The brain cannot repair itself"

Partially false. The brain exhibits plasticity—the ability to change over time.

• Even when critical areas are damaged, the brain can "rewire itself" to carry out functions without damaged connections.
• Exception: neurodegenerative diseases (Parkinson's, Alzheimer's) progressively worsen; no strong evidence the brain can recover from this destruction.

Contralateral organization: left brain controls right body and vice versa—an unintended consequence of evolution (the vertebrate nervous system likely twists during development).

🚫 "Left brain = analytical, right brain = creative"

False. Nearly every function one hemisphere can do, the other can do equally well.

• Sensory information, voluntary muscle control, memories, and many behaviors are performed equally by both hemispheres.
• Major exception: language processing and production are heavily lateralized in the left hemisphere for most people.

🧪 Neuroscience as an integrative field

🧪 Multiple disciplinary perspectives

Discipline	Contribution	Example
Biology	Studies living processes at molecular, cellular, and cognitive levels	Huntington's disease (genetics); Toxoplasma parasite (ecology/evolution)
Psychology	Top-down view examining whole organisms; addresses mind-body problem and emergence	Does consciousness result from cell activity? Is the whole greater than the sum of parts?
Chemistry	Examines endogenous and exogenous chemical signaling	Neurotransmitters (acidic, basic, polar, fat-soluble, gases); caffeine and cocaine effects
Physics	Describes electrical properties and ion movement	Neurons maintain negative charge (millivolts); action potentials follow magnetism rules (opposites attract)
Computational neuroscience	Mathematical modeling to describe/predict system behavior	Modeling 86 billion neurons requires computer power
Healthcare	Applies research to treat patients	Levodopa for Parkinson's; CT scans for head injury; EEG for epilepsy
Engineering	Develops tools and translates science to therapy	Patch clamp rigs, electron microscopes, deep brain stimulators

🔄 Bottom-up vs. top-down approaches

• Biology: often bottom-up (starts at cells/molecules, builds up).
• Psychology: often top-down (starts with whole organism, examines components).

🌟 Emergence

Emergence: the idea that the whole is greater than the sum of its parts.

The mind-body problem asks whether consciousness—a complex function—can result from activity of a clump of cells.

📚 The evolution of neuroscience knowledge

📚 Historical perspectives

Ancient Egypt (~2500 BCE): Preserved stomach, lungs, liver in canopic jars for the afterlife; the brain was scrambled with sticks and discarded—apparently not needed.

Ancient Greece: Aristotle theorized the heart was the seat of the soul; blood was the life force; the brain's function was to cool blood and calm temper.

Mid-1800s: Paul Broca proposed localization theory—specific brain areas carry out specific functions (e.g., language comprehension in left hemisphere, face perception at brain base, balance/coordination in cerebellum).

Opposing view: Distributive processing theory—behavioral functions require activation across several brain areas. Complex behaviors (emotion, consciousness, cognition) need coordinated action across distinct areas.

Current understanding: Some behaviors are more localized than others, but still rely on signals from many brain areas; absolutes are rare in neuroscience.

🔬 Technological milestones

Year	Technology	Impact
Early 1900s	Microscopy widely adopted	Golgi and Cajal observed neuron shapes, concluded different shapes = different functions
1954	Electron microscope	Visualized synapses (~20 nanometers)—1,000× smaller than human hair width
1991	fMRI (functional magnetic resonance imaging)	Visualized brain activity during active behaviors (decision-making, observing stimuli)
Today	CLARITY method	Renders entire brain transparent to map nervous system connections

🚀 Rapid advancement

More neuroscience studies were published between 2015–2020 than in the previous seventy years.

Challenge: Our current understanding is only a snapshot; future discoveries will reinforce some knowledge but may find compelling evidence against long-standing theories, prompting paradigm shifts.

🧠 Cellular components (preview)

🧠 Neurons

• Main units of the nervous system.
• Estimated 86 billion neurons in the adult human brain (calculated using the "brain soup" isotropic fractionator method by Suzana Herculano-Houzel).
• Neurons are about 0.2% of all body cells (37 trillion total).

Unique characteristics:

1. Electroactive: maintain negative electrical charge (membrane potential); can rapidly change voltage.
2. Specialized for rapid communication: millisecond-scale electrical and chemical signaling.
3. "Forever" cells: mature nervous system generally does not create new neurons (exception: olfactory system and hippocampus).
4. Capable of change: exhibit plasticity—can alter structure and function throughout life.

🧠 Glia

• Roughly 86 billion glial cells in the brain (equal to neuron count).
• Name derives from Latin for "glue" (historical misnomer—they do much more than structural support).

Five main types mentioned:

1. Astrocytes: star-shaped; maintain blood-brain barrier; modulate synapses (tripartite synapse); produce trophic factors.
2. Oligodendrocytes (CNS): myelinate multiple axon segments; increase conduction speed.
3. Schwann cells (PNS): myelinate single axon segments; aid nerve regeneration after injury.
4. Microglia: immune cells; act as cellular scavengers; destroy protein clumps, dead cells, pathogens.
5. Ependymal cells: line ventricles; produce cerebrospinal fluid (CSF); part of choroid plexus.

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Note: The excerpt contains substantial additional technical detail about neuronal anatomy (dendrites, soma, axon, synapses), neuron classifications, and glial functions that were not fully extracted here due to length. The material transitions into cellular anatomy chapters that appear to be separate instructional units.

🧭 Overview

🧠 One-sentence thesis

Neurons communicate through electrical signals (action potentials) that travel down axons and trigger chemical signals (neurotransmitters) at synapses, allowing the nervous system to process information and coordinate behavior.

📌 Key points (3–5)

• Electrical properties: Neurons use ion channels and electrochemical gradients to generate action potentials—rapid, all-or-none electrical signals that propagate down axons.
• Action potential mechanism: Voltage-gated sodium channels open during depolarization, then voltage-gated potassium channels open during repolarization, creating a characteristic waveform.
• Chemical synapses: Neurotransmitters stored in vesicles are released when calcium enters the axon terminal, then bind to receptors on the postsynaptic neuron.
• Receptor types: Ionotropic receptors allow direct ion flow (fast), while metabotropic receptors use G-proteins and second messengers (slower but more diverse effects).
• Common confusion: Electrical vs. chemical synapses—electrical synapses share cytoplasm through gap junctions (fast, bidirectional), while chemical synapses use neurotransmitter diffusion (slower, unidirectional, more versatile).

⚡ Electrical properties of neurons

🚪 Ion channels

Ion channels: Transmembrane proteins with a pore that allows specific ions to cross the cell membrane.

• The cell membrane is selectively permeable—some molecules pass easily, others cannot.
• Ion channels act as "cellular doors" that permit ions to move through the membrane.
• They distinguish ions by:
  • Pore size: Larger ions cannot fit through narrow channels.
  • Electrical charge: Charged amino acids lining the pore attract or repel specific ions.
  • Hydration shell: Water molecules surround ions; channels favor ions whose water shells are easier to remove.

🔓 Types of ion channels

Channel type	Opening condition	Example
Leak channels	Always open	Potassium leak channels
Voltage-gated	Membrane voltage changes	Sodium, potassium, calcium channels
Ligand-gated	Neurotransmitter binding	Ionotropic receptors
Sensory	Physical stimuli	Stretch, light, temperature sensors

⚖️ Electrochemical gradient

Two forces act on ions when channels open:

Electrical gradient:

• Opposite charges attract, like charges repel.
• At rest, the cell interior is negative (~-70 mV), attracting positive ions inward and pushing negative ions outward.
• When the cell depolarizes to positive potentials, the forces reverse.

Chemical gradient:

• Ions move from high concentration to low concentration (diffusion).
• Example: Sodium is concentrated outside the cell, potassium inside.
• This gradient remains relatively constant because only tiny numbers of ions move during signaling.

🧮 Equilibrium potential

Equilibrium potential (Ex): The membrane voltage at which the electrical and chemical gradients for an ion are perfectly balanced, resulting in no net ion movement.

• Calculated using the Nernst equation (includes temperature, ion charge, and concentration ratio).
• A simplified "back-of-the-envelope" version exists for quick estimates at body temperature.
• Different for each ion:
  • Sodium (Na⁺): ~+55 mV
  • Potassium (K⁺): ~-80 mV
  • Chloride (Cl⁻): ~-60 mV

Example: When a potassium channel opens, K⁺ is attracted inward (electrical gradient) but pushed outward (chemical gradient). At -80 mV, these forces balance.

📐 Goldman-Hodgkin-Katz equation

• Combines the Nernst potentials of multiple ions (Na⁺, K⁺, Cl⁻) weighted by their permeability.
• Predicts the actual membrane potential (Vm) when multiple ion channels are open.
• Higher permeability for an ion "pulls" Vm closer to that ion's equilibrium potential.
• At rest, potassium permeability dominates, so Vm (-70 mV) is close to EK (-80 mV).

🔥 The action potential

📈 Depolarization and threshold

Action potential: A brief (~1-2 ms), all-or-none change in membrane potential that propagates down the axon.

• Depolarization: Vm becomes more positive (e.g., from -70 mV toward 0 mV).
• Hyperpolarization: Vm becomes more negative (e.g., from -70 mV to -80 mV).
• Action potential threshold: Typically around -55 mV; depolarization above this triggers an action potential.
• Sub-threshold changes are called graded potentials and do not propagate.

🧪 Five steps of the action potential

1. Depolarization from incoming neurons:

• Neurotransmitters cause small postsynaptic potentials (PSPs).
• EPSPs (excitatory) depolarize; IPSPs (inhibitory) hyperpolarize.
• Multiple EPSPs sum via spatial summation (from different inputs) or temporal summation (same input, close in time).
• If total depolarization exceeds threshold at the axon hillock, an action potential begins.

2. Opening of voltage-gated Na⁺ channels:

• Depolarization opens these channels.
• Na⁺ rushes in (both electrical and chemical gradients favor entry).
• Further depolarization occurs, driving Vm toward +40 mV.

3. Opening of voltage-gated K⁺ channels:

• These open more slowly than Na⁺ channels.
• K⁺ exits the cell (electrical gradient repels positive ions; chemical gradient pushes K⁺ out).
• Outward K⁺ current begins to repolarize the cell.

4. Inactivation of voltage-gated Na⁺ channels:

• At positive potentials, an inactivation gate blocks the Na⁺ channel pore.
• Happens very rapidly (< 1 ms).
• Prevents further Na⁺ entry.

5. Deactivation of voltage-gated K⁺ channels:

• K⁺ channels close slowly (a few milliseconds).
• During this time, continued K⁺ efflux causes afterhyperpolarization (Vm more negative than rest).
• Vm gradually returns to resting potential.

📊 Three phases of the action potential

Phase	Voltage change	Main ion current	Duration
Depolarization	-70 mV → +40 mV	Na⁺ inward	~0.5 ms
Repolarization	+40 mV → -70 mV	K⁺ outward	~0.5 ms
Afterhyperpolarization	-70 mV → -80 mV → -70 mV	K⁺ outward (declining)	Few ms

🚫 Refractory periods

Absolute refractory period: Time window (~0.5-1 ms) when a second action potential cannot be triggered, because voltage-gated Na⁺ channels are inactivated.

Relative refractory period: Time window (a few ms) when triggering an action potential is harder than normal, because some Na⁺ channels are still inactive and many K⁺ channels remain open.

• These periods ensure action potentials move in one direction (forward) and limit firing frequency.

🏃 Movement of the action potential

• Na⁺ entering at one location diffuses to adjacent membrane regions, depolarizing them.
• This triggers voltage-gated Na⁺ channels in the next segment, creating a chain reaction.
• The action potential moves in one direction because:
  1. Na⁺ diffuses toward lower concentration (forward).
  2. The previous segment is in the absolute refractory period (cannot fire backward).

🧬 Role of myelin

Myelin: Lipid layers wrapped around axons that increase conduction velocity by blocking leak channels.

• Nodes of Ranvier: Unmyelinated gaps dense with voltage-gated Na⁺ channels.
• Saltatory conduction: The action potential "jumps" between nodes, speeding transmission.
• Example: Myelinated axons conduct signals much faster than unmyelinated ones.

Don't confuse: Myelin doesn't generate action potentials; it insulates the axon so depolarization spreads farther before needing regeneration at the next node.

🔗 Synaptic communication

⚡ Electrical synapses

Electrical synapse: Direct cytoplasmic connection between two neurons via gap junctions.

• Connexons (hemichannels) made of six connexin proteins form the gap junction.
• Synaptic gap: ~3.5 nanometers (very close).
• Bidirectional: Signals can pass either way.
• Fast: Nearly instantaneous transmission.
• Advantages: Speed (escape reflexes), synchronized network activity (hormone release, coordinated inhibition).
• Common in simpler organisms and specific circuits requiring rapid coordination.

🧪 Chemical synapses

Chemical synapse: Communication via neurotransmitter release from the presynaptic neuron to the postsynaptic neuron.

• Synaptic gap: ~20-40 nanometers (larger than electrical synapses).
• Unidirectional: Signal flows from presynaptic to postsynaptic cell.
• Versatile: Can be excitatory, inhibitory, or modulatory depending on the neurotransmitter and receptor.
• Neuromuscular junction (NMJ): Specialized chemical synapse between motor neuron and muscle; uses acetylcholine.

📦 Synaptic vesicles

Two types:

Vesicle type	Diameter	Contents	Location
Small vesicles	~40 nm	Glutamate, GABA, dopamine, etc.	Axon terminals
Large dense-core vesicles	100-250 nm	Neuropeptides	Cell body, axon, terminals

🔋 Loading vesicles

• v-ATPase pumps H⁺ into vesicles using ATP energy, creating an acidic interior.
• Vesicular transporters (e.g., vGluT, VGAT, VAChT, VMAT) use the H⁺ gradient to pump neurotransmitter into vesicles.
• These are antiporters: H⁺ moves out as neurotransmitter moves in.

📍 Vesicle pools

1. Readily releasable pool (RRP): Docked at the membrane, ready for immediate release.
2. Recycling pool: Being refilled after release; require moderate stimulation.
3. Reserve pool: Farthest from membrane; require intense stimulation.

🔓 Vesicle release mechanism

Key proteins:

• v-SNAREs (on vesicles): Synaptobrevin, synaptotagmin.
• t-SNAREs (on terminal membrane): Syntaxin, SNAP-25.

Steps:

1. Action potential reaches terminal.
2. Voltage-gated calcium channels (VGCCs) open.
3. Ca²⁺ enters the terminal (both gradients favor entry).
4. Ca²⁺ binds to synaptotagmin.
5. v-SNAREs and t-SNAREs form a SNARE complex, pulling vesicle to membrane.
6. Vesicle fuses: full fusion (complete release) or kiss-and-run (partial release).

Don't confuse: Botulinum toxin cleaves SNARE proteins, preventing vesicle fusion and causing paralysis; medically, low doses ("Botox") treat muscle spasms or wrinkles.

🎯 Receptors and signaling

🔌 Ionotropic receptors

Ionotropic receptors (ligand-gated ion channels): Receptors that open an ion channel when a neurotransmitter binds, allowing rapid ion flow.

• Fast: Effects occur within milliseconds.
• Direct: Ion movement immediately changes membrane potential.
• Example: Nicotinic acetylcholine receptors (nAChRs) are Na⁺ channels; activation causes depolarization (excitation).

🔄 Metabotropic receptors

Metabotropic receptors (G protein-coupled receptors, GPCRs): Receptors that activate intracellular signaling cascades via G proteins when a neurotransmitter binds.

• Slower: Effects take milliseconds to seconds (or longer).
• Indirect: Use second messengers to alter cell function.
• Structure: Seven transmembrane domains (7-TM receptors).
• G proteins: Bind GTP (active) or GDP (inactive); have α, β, γ subunits.

🧬 G protein types

G protein	Effect	Mechanism
Gαs	Excitatory	Activates adenylate cyclase → ↑ cAMP → ↑ PKA → phosphorylates targets (e.g., glutamate receptors stay open longer)
Gαi	Inhibitory	Inhibits adenylate cyclase → ↓ cAMP → ↓ PKA
Gαq	Excitatory	Activates phospholipase C (PLC) → produces IP₃ (releases Ca²⁺) and DAG (activates PKC)

• PKA and PKC are kinases that phosphorylate proteins, changing their activity.
• Long-term effects: Gene transcription, receptor trafficking, structural changes.

🔙 Presynaptic receptors

• Located on axon terminals, not dendrites.
• Often inhibitory; provide self-regulation.
• Autoreceptors: Respond to the same neurotransmitter the neuron releases (negative feedback).

🧪 Major neurotransmitters

⚡ Glutamate (Glu)

• Main excitatory neurotransmitter in the brain.
• Marker: vGluT (vesicular glutamate transporter).
• Ionotropic receptors: AMPA (Na⁺), NMDA (Na⁺ and Ca²⁺; blocked by Mg²⁺ at rest), kainate.
• Metabotropic receptors: mGluRs (Group I excitatory via Gq; Groups II & III inhibitory via Gi).
• Excitotoxicity: Excessive glutamate signaling (especially via NMDA receptors) can kill neurons; implicated in stroke, concussion, neurodegenerative diseases.

🛑 GABA and glycine

• GABA: Main inhibitory neurotransmitter in the brain.
• Synthesized from glutamate by glutamic acid decarboxylase (GAD).
• Marker: GAD.
• Receptors: GABA_A (ligand-gated Cl⁻ channel), GABA_B and GABA_C (metabotropic, Gi).
• Glycine: Inhibitory in spinal cord and brainstem; activates ligand-gated Cl⁻ channels.

🎉 Dopamine (DA)

• Synthesized from tyrosine; marker: tyrosine hydroxylase (TH).
• Produced in midbrain: ventral tegmental area (VTA) and substantia nigra (SN).
• Receptors: D1-D5 (all metabotropic; D1 & D5 excitatory via Gs; D2, D3, D4 inhibitory via Gi).
• Functions: Reward, motivation, learning, motor control.
• Parkinson's disease: Loss of DA neurons in SN causes tremor, rigidity, bradykinesia; treated with L-DOPA (DA precursor), but chronic use can cause dyskinesia.

😊 Serotonin (5-HT)

• Synthesized from tryptophan; marker: tryptophan hydroxylase.
• Produced mainly in Raphe nucleus (brainstem).
• Receptors: Seven families (5-HT1 through 5-HT7); mostly metabotropic (5-HT3 is ionotropic).
• Functions: Mood regulation, anxiety, sleep.
• SSRIs (e.g., fluoxetine) block serotonin reuptake, increasing synaptic serotonin; used to treat depression.

💪 Acetylcholine (ACh)

• Synthesized by choline acetyltransferase (ChAT).
• First neurotransmitter discovered (Otto Loewi, 1936 Nobel Prize).
• Ionotropic: Nicotinic receptors (nAChRs; ligand-gated Na⁺ channels; excitatory).
• Metabotropic: Muscarinic receptors (mAChRs; can be Gs or Gi).
• Functions: Muscle contraction at NMJ, attention, learning.
• In heart: Muscarinic activation slows heart rate.
• Alzheimer's disease: Early theory linked symptoms to loss of ACh neurons in basal forebrain.

🚨 Norepinephrine (NE)

• Synthesized from dopamine by dopamine beta-hydroxylase.
• Produced in locus coeruleus (pons).
• Receptors: α1, α2, β1, β2, β3 (all metabotropic).
• Functions: "Fight-or-flight" response (sympathetic nervous system), alertness, attention.
• Clinical: Beta blockers lower blood pressure; beta agonists treat asthma.

🌟 Atypical neurotransmitters

🧬 Neuropeptides

• Large molecules (molecular weight 570-2000+).
• Examples: Enkephalin, dynorphin.
• Stored in large dense-core vesicles near the nucleus.
• Activate opioid receptors (δ, μ, κ, nociceptin; all inhibitory via Gi).
• Function: Pain modulation (periaqueductal gray).
• Clinical: Morphine, oxycontin, fentanyl are opioid agonists; effective for pain but risk of overdose and addiction.

🌿 Endocannabinoids (eCBs)

• Lipid-based; examples: 2-AG, AEA.
• Retrograde signaling: Synthesized by postsynaptic neuron, signal to presynaptic terminal (opposite of typical direction).
• Synthesized on demand (not stored in vesicles).
• Receptors: CB1 (nervous system), CB2 (immune system); both inhibitory via Gi.
• Most abundant GPCRs in the body.
• Named because they resemble compounds in Cannabis plants.

💨 Nitric oxide (NO)

• A gas; synthesized from arginine by NO synthase (NOS).
• Not stored; made as needed.
• Diffuses across membranes easily.
• Receptor: Soluble guanylate cyclase (sGC) (intracellular).
• Signaling: cGMP → protein kinase G (PKG); can be excitatory or inhibitory.

🔬 Clinical connections

🦠 Charcot-Marie-Tooth (CMT) disease

• Genetic disorder damaging peripheral nerves.
• Symptoms: Muscle weakness, walking difficulty, abnormal sensations.
• One form: Mutation in Cx32 (connexin in Schwann cells) disrupts myelin in PNS.

🤕 Chronic pain and allodynia

• Allodynia: Pain from non-painful stimuli.
• Linked to changes in voltage-gated Na⁺ channels, increasing pain neuron excitability.

💉 Botulism

• Caused by Clostridium botulinum toxin.
• Cleaves SNARE proteins, preventing ACh release at NMJ.
• Symptoms: Muscle weakness, paralysis, respiratory failure.
• Medical use: "Botox" injections for cosmetic wrinkles or treating muscle spasms, migraines.

🧠 Parkinson's disease (PD)

• Loss of DA neurons in substantia nigra (~60-80% by symptom onset).
• Symptoms: Tremor, rigidity, bradykinesia.
• Treatment: L-DOPA (DA precursor); chronic use can cause L-DOPA-induced dyskinesia (LID) (excess movements).
• Alternative: Deep brain stimulation of subthalamic nucleus.

🧭 Overview

🧠 One-sentence thesis

Understanding the nervous system requires both knowledge of its anatomical organization—from the brain and spinal cord down to individual neurons—and familiarity with the diverse research methods used to image structure, measure function, and manipulate neural activity.

📌 Key points (3–5)

• Anatomical organization: The nervous system divides into the central nervous system (CNS: brain and spinal cord) and peripheral nervous system (PNS: all other nerves), with information flowing between them as afferent (incoming to CNS) and efferent (outgoing from CNS) signals.
• Brain structure and development: The brain develops from five embryonic vesicles and organizes into lobes (occipital, temporal, parietal, frontal) with specialized functions like vision, hearing, touch, and motor control.
• Research methods span scales: Techniques range from gross anatomy imaging (CT, MRI) to functional measures (EEG, fMRI, PET) to cellular visualization (microscopy, staining) to manipulation (optogenetics, electrophysiology).
• Common confusion—spatial vs. temporal resolution: High spatial resolution means distinguishing close points in space (measured in distance/volume), while high temporal resolution means distinguishing close events in time (measured in time units); no single method excels at both.
• Human vs. non-human studies: Humans are ideal for studying complex cognition and testing therapies directly, but non-human models allow controlled experiments, genetic manipulation, and procedures that would be unethical in humans.

🧠 Central Nervous System Organization

🧠 CNS components

Central nervous system (CNS): The brain and spinal cord.

• The brain weighs ~1.5 kg (3 lbs), occupies ~1400 cubic centimeters, yet uses one-fifth of the body's total energy despite being only 2% of body weight.
• The spinal cord runs from the neck to the lower back (~44 cm long), carrying information up to the brain and down to the body.
• Both structures are continuous but anatomically distinct organs.

🧭 Anatomical language

The nervous system uses three paired directional terms:

Axis	Direction 1	Direction 2	Meaning
Front-back	Rostral/Anterior	Caudal/Posterior	Toward beak/before vs. toward tail/after
Top-bottom	Dorsal/Superior	Ventral/Inferior	Above/on top vs. below/underneath
Center-side	Medial	Lateral	Toward midline vs. toward sides

• Contralateral: Opposite side (e.g., left brain controls right body).
• Ipsilateral: Same side (e.g., right hand is ipsilateral to right brain hemisphere).
• Example: The frontal lobe is anterior to the parietal lobe; the parietal lobe is dorsal to the temporal lobe.

📐 Brain visualization planes

Three main ways to slice/image the brain:

• Coronal: Vertical slices from front to back (like a crown).
• Horizontal: Slices from top to bottom (parallel to ground).
• Parasagittal: Slices from left to right (parallel to midline; never symmetrical since they sample one hemisphere).

Don't confuse: A true sagittal slice divides left and right hemispheres exactly; parasagittal slices are parallel to that plane.

🎨 Gray matter vs. white matter

• White matter: Pale tissue representing communication pathways; appears white due to myelin (fatty insulation on axons).
• Gray matter: Darker pink/gray tissue dense with cell bodies.
• Corpus callosum: Major white matter tract connecting left and right hemispheres (a decussation—crossing pathway).

🌱 Brain Development and Structure

🌱 Embryonic origins

The nervous system develops from the neural tube (formed from ectoderm in weeks 3-4 of gestation).

• Starts as three vesicles, then divides into five vesicles that become adult brain regions.
• From posterior to anterior:

Vesicle	Adult Structure	Key Functions
Myelencephalon	Medulla oblongata	Breathing, heart rate, blood pressure, vomiting reflex
Metencephalon	Pons, Cerebellum	Breathing, hearing, taste; motor coordination, balance, posture
Mesencephalon	Midbrain	Pain response, movement coordination, visual reflexes, reward/motivation
Diencephalon	Thalamus, Hypothalamus	Sensory relay; endocrine communication
Telencephalon	Basal ganglia, Cerebral cortex	Motor/habit learning, emotion; attention, memory, language

• Phylogenetic organization: Posterior (hindbrain) = basic survival functions; anterior (forebrain) = complex functions like planning and personality.

🧩 Four cortical lobes

The cerebral cortex has raised ridges (gyri, singular gyrus) and grooves (sulci, singular sulcus or fissure).

Key landmarks:

• Longitudinal fissure: Divides left and right hemispheres (anterior-posterior).
• Central sulcus: Runs dorsally to ventrally at the midpoint.
• Lateral fissure: Runs anterior-posterior, curves dorsally.

Lobe	Location	Primary Functions
Occipital	Posterior-most	Visual processing (primary visual cortex, V1)
Temporal	Ventral, anterior to occipital	Auditory processing (A1), memory (hippocampus), language comprehension
Parietal	Dorsal, between occipital and frontal	Touch, temperature, pain, proprioception (primary somatosensory cortex, S1)
Frontal	Anterior-most, largest	Motor control (M1), personality, planning, inhibition, "higher order" functions

Clinical example: Phineas Gage survived a tamping rod through his frontal lobe but experienced dramatic personality changes—became irreverent and unreliable, showing the frontal lobe's role in personality and social behavior.

🦴 Spinal Cord and Peripheral Nervous System

🦴 Spinal cord structure

• Runs from neck to lower back (~44 cm), diameter 6.5-13 mm.
• Protected by the vertebral column (bones).
• Divided into regions named by overlying vertebrae (letter + number):

Region	Pairs	Innervates	Notes
Cervical (C1-C8)	8	Neck, shoulders, arms, hands, diaphragm	C3-C5 injury can stop breathing; widest diameter
Thoracic (T1-T12)	12	Trunk, intercostal muscles, abdominal muscles, internal organs	Autonomic (fight-or-flight) responses
Lumbar (L1-L5)	5	Hips, thighs, knees, ventral legs	Swelling for leg innervation
Sacral (S1-S5)	5	Toes, dorsal legs, genital organs, colon, bladder	Parasympathetic nerves

• Spinal nerves (31 pairs total): Formed by merging dorsal (sensory, afferent) and ventral (motor, efferent) nerve roots.
• Dorsal root ganglion: Clump of sensory neuron cell bodies outside the spinal cord.

Don't confuse: More anterior injuries affect more body parts; posterior injuries are more localized (e.g., FDR's posterior injury affected legs but not arms; Christopher Reeve's C1 injury caused complete paralysis from neck down).

🌐 Peripheral nervous system branches

Peripheral nervous system (PNS): All nerve cells outside the CNS; intermediary between CNS and body.

Three main branches:

1. Somatic nervous system: Voluntary control; senses external environment and controls skeletal muscles.

   • Example: Nerves detecting foot pressure (afferent) or controlling leg muscles while running (efferent).

2. Autonomic nervous system: Involuntary control of internal organs, smooth muscles, glands.

   • Sympathetic (thoracolumbar origin): Fight-or-flight response—increases heart rate, dilates pupils and bronchioles, activates liver enzymes.
   • Parasympathetic (cranial + sacral origin): Rest-and-digest response—decreases heart rate, promotes digestion; driven largely by vagus nerve (CN X).
   • Both systems act simultaneously on organs; balance shifts depending on situation.

3. Enteric nervous system: ~500 million neurons surrounding digestive organs; regulates digestion independently of vagus nerve.

🧠 Twelve cranial nerves

Nerves exiting directly from the brain (not spinal cord), mostly serving the head:

• Sensory only: CN I (olfactory—smell), CN II (optic—vision), CN VIII (vestibulocochlear—hearing, balance).
• Motor only: CN III, IV, VI (eye movement), CN XI (neck/shoulder muscles), CN XII (tongue muscles).
• Both sensory and motor: CN V (trigeminal—face sensation, chewing), CN VII (facial—facial expressions, taste), CN IX (glossopharyngeal—swallowing, taste), CN X (vagus—parasympathetic control of organs).

🛡️ Support Structures

💧 Cerebrospinal fluid and ventricles

Ventricles: Four interconnected fluid-filled chambers in the brain.

• Lateral ventricles (paired, one per hemisphere) → third ventricle → aqueduct → fourth ventricle → central canal (runs through spinal cord).
• Filled with cerebrospinal fluid (CSF): High-salt solution (~140 mM Na⁺, 110 mM Cl⁻).

Functions:

• Buoyancy: Brain weighs ~1.5 kg in air but <50 g in CSF, preventing ventral cells from being crushed.
• Cushioning: Protects brain from rapid head movements (though too abrupt can still cause traumatic brain injury).
• Waste removal: CSF volume (~150 mL) turns over multiple times daily (~500 mL produced/day), washing out cellular waste.

Clinical correlation—Hydrocephalus: Excess CSF volume increases intracranial pressure; in newborns, causes skull bulging and forehead expansion; treated with a shunt draining to the abdomen.

🧱 Meninges

Three protective membranes surrounding CNS (from outside to inside):

1. Dura mater: Thick (~0.8 mm), fibrous, attached to skull; "tough mother."
2. Arachnoid mater: Delicate, web-like; most CSF exists in the subarachnoid space below this layer.
3. Pia mater: Fragile, directly contacts brain surface, follows gyri and sulci; "pious mother."

Clinical correlation—Meningitis: Inflammation of meninges (often bacterial/viral infection) compresses brain, increases intracranial pressure; symptoms include fever, stiff neck, headache, seizures, altered mental status; treatable with antibiotics if bacterial.

🩸 Blood supply and blood-brain barrier

• Blood reaches brain via vertebral arteries (merge into basilar artery) and internal carotid arteries.
• Circle of Willis: Loop-like structure providing redundancy; branches into anterior, middle, and posterior cerebral arteries.
• Brain receives ~15% of cardiac output despite being only 2% of body weight.

Blood-brain barrier (BBB): Selective barrier (endothelial cells + astrocytes) that transports necessary substances while excluding toxins and pathogens.

• Challenge: Many drugs cannot cross BBB (e.g., dopamine); workaround is giving L-DOPA, which crosses and converts to dopamine.
• BBB disruption occurs in stroke, epilepsy, Alzheimer's disease.

Clinical correlation—Stroke:

• Ischemic stroke (>80%): Blood clot blocks vessel, depriving tissue of oxygen; treatable with clot-busting drugs.
• Hemorrhagic stroke (~20%): Burst vessel causes bleeding, increases intracranial pressure; more deadly; clot-busters would worsen it.
• Symptoms depend on affected artery (e.g., middle cerebral artery blockage → left motor cortex loses blood → right-side paralysis due to contralateral organization).

🔬 Imaging Anatomy Methods

🔬 CT scan (Computerized Tomography)

How it works: 3D X-ray; X-ray gun revolves around person moving through circular scanner; computer compiles 2D images into 3D reconstruction.

• Dense materials (bone) appear white; less dense (air, CSF) appear dark.
• Spatial resolution: ~0.5 mm.

Advantages:

• Noninvasive.
• Quick (minutes for full head scan).
• Identifies tumors (increased density), hydrocephalus (enlarged ventricles), meningitis (increased contrast).

Limitations:

• X-rays are mutagenic; single head CT = few months of background radiation exposure.
• Diagnostic benefit usually outweighs cancer risk.

🧲 Diffusion Tensor Imaging (DTI)

How it works: Uses MRI to detect water molecule movement; water diffuses differently in white matter (anisotropic—preferentially along tracts) vs. gray matter (isotropic—random).

• Spatial resolution: Millimeters.
• Visualizes white matter tracts by detecting anisotropic diffusion.

Advantages:

• Identifies white matter pathways and volume differences.

Limitations:

• Cannot determine directionality of axonal projections (which end is soma vs. terminal).

🔍 CLARITY

How it works: Brain flushed with gel matrix surrounding all cellular structures; lipids washed away with detergent; brain becomes transparent; "mold" of cell membranes remains visible.

• Spatial resolution: Microns (microscopic level).

Advantages:

• Visualizes connectivity at microscopic scale.
• Can see individual dendritic spines and axon terminals.

Limitations:

• Extremely destructive; cannot be used in living organisms.
• Like a mold of a hand—shows structure but no function remains.

📊 Imaging Function Methods

📊 EEG (Electroencephalography)

How it works: Electrodes on scalp detect electrical currents from synchronized cortical neuron activity; gel conducts signals; 20-128 electrodes feed into computer.

• Detects voltage changes as small as 10 microvolts.
• Software extracts frequency components (beta waves 13-30 Hz, delta waves 0-4 Hz, etc.).

Advantages:

• Noninvasive, harmless.
• Excellent temporal resolution: Samples at ~10,000 Hz (millisecond precision).
• Relatively cheap and mobile (fits in backpack).
• Diagnoses epilepsy (detects seizure activity), sleep disorders, migraines, possibly Alzheimer's, depression, ADHD.
• Used during anesthesia to monitor unconsciousness level.

Limitations:

• Poor spatial resolution: ~7 cubic centimeters even with 128 electrodes.
• Only detects signals from outer cortex, not deep structures.

Don't confuse: EEG has great temporal resolution but poor spatial resolution; fMRI (below) has the opposite trade-off.

🔴 PET scan (Positron Emission Tomography)

How it works: Radioactive tracer (e.g., fluorodeoxyglucose-F18, FDG) injected into bloodstream; tracer emits positrons that interact with electrons, producing gamma rays detected by scanner.

• FDG is radioactive glucose analog; metabolically active areas take up more FDG.
• Can also use radiolabeled compounds to visualize receptor density (e.g., dopamine receptors).

Advantages:

• Diagnoses tumors (high metabolic activity).
• Assesses cognitive deficits (Alzheimer's, Pick's disease).
• Visualizes receptor levels in vivo.

Limitations:

• Radioactive exposure (mutagenic).
• Very poor spatial resolution: 5-10 cm³ minimum.
• Very poor temporal resolution: Tens of seconds to minutes.
• Difficult to identify tissue boundaries; often combined with CT scan.

🧲 fMRI (Functional Magnetic Resonance Imaging)

How it works: Powerful magnet (10,000-100,000 gauss) + radio waves interact with protons; oxygenated hemoglobin (diamagnetic) vs. deoxygenated (paramagnetic) respond differently; detects blood oxygenation level-dependent (BOLD) signal.

• Active brain areas need more oxygen → blood vessels dilate → change in oxygenation detected.
• Spatial resolution: Millimeters (better with stronger magnets).
• Temporal resolution: Seconds to tens of seconds (limited by blood vessel dilation speed).

Advantages:

• Visualizes brain activity during complex behavioral tasks in real time.
• Example: Seeing faces activates fusiform face area; gambling tasks activate prefrontal areas.

Limitations:

• Tunnel is small and claustrophobic (difficult for anxiety/panic disorder patients).
• Very loud (challenging for young patients).
• Powerful magnet dangerous with metallic implants (aneurysm clips, IUDs, shrapnel, some tattoos).
• Data analysis difficult; high false-positive rate (famous study showed "activity" in dead salmon).
• Assumes blood flow directly correlates with neural activity (not always true).
• BOLD signal change is tiny (~0.4% perfusion increase).

🔬 Imaging Cells Methods

🔬 Microscopy

How it works: Uses lenses and light (or electrons in electron microscopes) to magnify structures.

• Standard lab microscope: 40-1,000× magnification.
• Electron microscope: Up to 1,000,000× magnification; nanometer-scale resolution.
• Fluorescence microscope: Uses specific wavelengths to excite fluorescent proteins (e.g., green fluorescent protein, GFP), which emit different wavelengths detected by the scope.

Advantages:

• Standard tool for neuroscience research.
• Visualizes structures invisible to naked eye.

🎨 Staining

How it works: Thin brain slices exposed to chemicals with affinity for specific cell components.

• Luxol Fast Blue: Stains myelin (white matter).
• Cresyl violet: Stains neurons.
• DAPI: Stains cell nuclei (genetic material).
• Golgi stain: Silver-based; fills entire neuron (dendrites to axons), turning <1% of neurons black; allows tracing individual neurons.

Procedure:

1. Fixation: Tissue exposed to paraformaldehyde (PFA) via perfusion; crosslinks proteins, kills microorganisms, inactivates degrading enzymes.
2. Sectioning: Microtome or cryostat slices brain into 10-100 micron sections.
3. Staining: Chemicals permeate thin sections.

Tract tracing:

• Anterograde trace: Stains soma → axon terminal (shows where axons project).
• Retrograde trace: Taken up by terminals, stains soma (shows where cell bodies are located).

Limitations:

• Only works on fixed (dead) tissue.

🧬 Immunohistochemistry (IHC)

How it works: Uses antibodies to detect specific proteins with high specificity.

1. Primary antibody: Binds to target protein (antigen) of interest (e.g., anti-NeuN for NeuN protein).
2. Secondary antibody: Binds to primary antibody; conjugated with fluorophore (light-producing molecule).
3. Fluorescence microscopy activates fluorophore, revealing protein location.

• Can identify protein location at subcellular level (e.g., tubulin in microtubules).
• Immunocytochemistry: Same technique applied to cultured cells (in vitro) instead of tissue slices.

Advantages:

• High specificity for individual proteins.
• Can visualize multiple proteins simultaneously (different fluorophores).

Limitations:

• Nonspecific binding: Antibodies sometimes bind wrong targets (false positives, increased background noise); minimized by thorough rinsing and blocking agents.
• Antibody must exist for target protein; not all proteins have antibodies.
• Some structurally similar proteins cannot be differentiated (e.g., dopamine receptor type 2 vs. type 3).

⚡ Manipulating Neural Activity Methods

⚡ Electrophysiology (Ephys)

How it works: Specialized rig uses glass micropipettes filled with electrolyte solution inserted into neurons; detects and controls electrical currents (e.g., Na⁺ during action potentials).

• Originally used squid giant axon (~1 mm diameter, easy to access).
• Requires microscope for cellular-level work (neurons ~tens of microns).
• Can detect currents or manipulate electrical properties (excite/inhibit neurons).

Advantages:

• Versatile: Studies behavior, circuitry, individual neurons, or ion channels.
• Can record activity during behavior or stimulate to modify behavior.
• High temporal precision (milliseconds).

Limitations:

• Many experimental preparations (intact anesthetized, brain slice, culture, frog oocytes); moving away from awake behaving animal reduces generalizability.
• Trade-off: gain control, lose ability to generalize.

🧲 Transcranial Magnetic Stimulation (TMS)

How it works: Electrical current through handheld wire coil generates magnetic field via induction; magnetic field induces electrical current in brain tissue beneath scalp.

• Activates small brain areas noninvasively.
• Example: TMS over motor cortex → muscle contractions; over occipital lobe → perception of light flashes.

Advantages:

• Completely noninvasive.
• Potential therapeutic benefits: Alleviates chronic pain, Parkinsonian symptoms, improves post-stroke motor function, decreases anxiety/depression, reduces cigarette craving, minimizes auditory hallucinations/tinnitus.

Limitations:

• Side effects: Temporary headaches, localized pain, hearing/sensation changes, seizures (most severe).
• Still highly experimental.
• Dangerous with magnetosensitive implants (deep brain stimulators, cochlear implants, aneurysm clips).

🧬 Genetic Modification

How it works: Manipulates animal genomes to create disease models or study gene function.

• Knock-out: Remove gene (e.g., gene for leptin hormone).
• Knock-in: Insert exogenous gene (e.g., humanized mice with human gene versions).
• Knock-down: Moderate decrease in function.
• Upregulation: Increase in function.
• Conditional knock-out: Normal until exposed to certain chemicals.
• CRISPR-Cas9 (2012): Targeted genome editing with simplicity, efficiency, and precision.

Advantages:

• Wide variety of genetically modified mice commercially available.
• Can create multiple genetic crosses for complex questions.
• Potential therapeutic applications (CRISPR).

Limitations:

• Difficult to generalize findings beyond specific genetic strain (e.g., mouse therapy may not work in humans).
• Unexpected side effects from genetic changes.
• Hard to predict how gene manipulation interacts with other physiological aspects.

💡 Optogenetics

How it works: Light-sensitive ion channel protein (channelrhodopsin, ChR2) inserted into specific neurons via genetic modification or viral delivery; blue light opens channel → Na⁺ influx → action potential.

• ChR2 derived from rhodopsin (visual system protein).
• 0.5 ms light flash triggers single action potential; channel closes in <1 ms.
• Temporal resolution: Milliseconds.
• Other proteins: Halorhodopsin (yellow-green light, pumps Cl⁻ in, inhibits); Archaerhodopsin (light-driven H⁺ pump, inhibits).

Advantages:

• High specificity: Targets unique cell populations within mixed brain areas (solves "fibers of passage problem").
• Excellent temporal resolution.
• Can combine with other techniques (e.g., electrophysiology, behavioral testing).

Limitations:

• Currently only used in non-human research animals.

💊 Chemogenetics (DREADD)

How it works: Designer receptor exclusively activated by designer drugs (DREADD); G-protein coupled receptor inserted into neurons; activated only by exogenous drug (not endogenous neurotransmitters); triggers intracellular signaling to excite or inhibit neuron.

• No activity change at rest; only when exposed to designer drug.

Advantages:

• High specificity (like optogenetics).
• Can combine with other techniques.

Limitations:

• Poor temporal resolution: Ex vivo = seconds to tens of seconds; behaving animal = minutes (drug must enter system, activate GPCR, produce behavioral change).
• Currently only used in non-human research animals.

🔍 Research Design Considerations

🔍 Resolution concepts

Spatial resolution: Ability to differentiate two points in space; measured in distance/volume units.

• Higher spatial resolution = can distinguish closer points.
• Example: Electron microscopy (highest spatial resolution) vs. PET scan (lowest, 5-10 cm³).

Temporal resolution: Ability to distinguish two events in time; measured in time units.

• Higher temporal resolution = can distinguish closer events.
• Example: Electrophysiology (hundreds of microseconds) vs. PET scan (tens of seconds to minutes).

Don't confuse: Methods with high spatial resolution often have low temporal resolution and vice versa (e.g., EEG has great temporal but poor spatial resolution; fMRI has better spatial but poor temporal resolution).

👥 Human vs. non-human subjects

Human advantages:

• Direct understanding of human nervous system → therapies for humans.
• Follow directions easily without training ("lie still").
• Perform complex cognitive tasks (e.g., imaginary currency scenarios).
• Self-report symptoms and feelings.
• Often cheaper (undergraduates may participate for course credit; ~$10/hour for others).

Non-human advantages:

• Ethical constraints allow experiments that would harm humans.
• Study behaviors unique to non-humans (flying, slithering).
• Controlled variables: Food, living conditions, day-night cycles eliminate variability.
• Genetic manipulation possible.
• Avoid WEIRD bias (Western, Educated, Industrialized, Rich, Democratic—96% of psychology studies but only 12% of global population; WEIRD people perform differently on tasks, even visual illusions).

Common model organisms (by genetic similarity to humans):

• C. elegans (worm), Drosophila (fruit fly), zebrafish, songbirds, mice, rats, macaque monkeys (~93% genetic similarity to humans).

🧪 Experimental preparations

Preparation	Description	Strengths	Weaknesses	Ethical regulations
In vivo	Intact living organism	Most predictive of human condition	Thousands of uncontrolled variables	Very strict
Ex vivo	Tissue section (brain slice, biopsy, detached frog leg)	Moderate control, moderate predictability	Intermediate	Moderate
In vitro	Cultured cells or isolated molecules (DNA, RNA, protein)	Excellent control over variables	Less reliable for translating to therapy	Lax (protects experimenter, not subject)

Don't confuse: Moving from in vivo → ex vivo → in vitro increases experimental control but decreases ability to predict therapeutic potential in living organisms.

🧭 Overview

🧠 One-sentence thesis

Neuropharmacology reveals that drugs of misuse hijack the brain's natural reward circuitry—particularly dopamine pathways from the ventral tegmental area to the nucleus accumbens—and chronic exposure drives homeostatic adaptations (tolerance, withdrawal, dependence) that can escalate casual use into compulsive addiction.

📌 Key points (3–5)

• Routes of administration matter for abuse potential: faster routes (IV injection, inhalation, insufflation) deliver drug to the brain within seconds to minutes, producing rapid highs and higher misuse risk; slower routes (oral, transdermal) spread drug effect over hours and carry lower abuse potential.
• Reward pathway anatomy: the mesolimbic pathway (VTA dopamine neurons → nucleus accumbens) mediates reward; drugs of abuse increase dopamine release in the NAc, mimicking natural rewards like food or sex.
• Molecular drug actions: agonists activate receptors, competitive antagonists block the active site, and allosteric modulators change receptor sensitivity without occupying the active site—understanding these distinctions is essential for overdose treatment (e.g., naloxone as a competitive antagonist for opioid overdose).
• Common confusion—tolerance vs. dependence vs. addiction: tolerance is reduced drug effect after repeated exposure (requiring higher doses); dependence is the presence of withdrawal symptoms when the drug is absent; addiction (substance use disorder) is compulsive drug-seeking despite harm—tolerance and dependence can occur without addiction.
• Why some users become addicts: the transition from casual use to compulsive addiction involves genetic, environmental, and neurobiological factors; animal self-administration models help identify protective and risk factors.

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💊 How drugs enter the body and reach the brain

💊 Routes of administration overview

Route of administration: the pathway by which a drug enters the body; can be classified as enteral (absorbed through the gastrointestinal tract) or parenteral (bypasses the digestive tract).

• The route determines speed of onset and abuse potential.
• Faster routes → more rapid brain delivery → stronger "high" → higher misuse risk.

🍽️ Oral administration (enteral)

• How it works: swallow a pill, food, or drink; drug is absorbed through the gut wall into the hepatic portal system, then passes through the liver before entering systemic circulation.
• Speed: slow onset (tens of minutes to hours).
• Advantages: convenient, no special equipment, can design sustained-release formulations (up to 24 hours), can expel drug by vomiting or stomach pumping in overdose.
• Disadvantages: slow onset makes it less useful in emergencies; requires conscious swallowing (not useful if unconscious); nausea can prevent retention; subject to first-pass metabolism in the liver.

First-pass metabolism: enzymatic degradation of a drug in the liver before it reaches systemic circulation, reducing the effective dose that reaches the brain.

• Prodrugs: inactive substances that become active after enzymatic processing (e.g., psilocybin → psilocin in acidic stomach conditions).
• Example: A person takes a pain pill; it takes 30–60 minutes to feel relief because the drug must be digested, absorbed, and survive liver enzymes.

💉 Intravenous (IV) injection (parenteral)

• How it works: needle delivers drug directly into the bloodstream.
• Speed: fastest route—drug effects within seconds.
• Why it matters for abuse: heroin users prefer IV injection because it produces the most rapid, intense high; faster onset = higher abuse potential.
• Advantages: no first-pass metabolism (dose delivered = dose experienced); useful in emergencies (e.g., naloxone for opioid overdose reversal); can deliver slow IV drip to minimize overdose risk.
• Disadvantages: one-way street (cannot decrease blood concentration once injected); requires syringes (cost, risk of bloodborne illness transmission, injection-site infections); repeated use damages veins.

🌬️ Inhalation (parenteral)

• How it works: drug is volatilized (burned or vaporized) and inhaled into the lungs; gas exchange occurs at the alveoli (pulmonary capillaries).
• Speed: very rapid—drug effects within tens of seconds.
• Why it's efficient: lungs are extremely effective at gas exchange (same process that captures oxygen and expels CO₂); each breath cycles drug into bloodstream.
• Advantages: rapid onset; rapid clearance (useful for anesthesia—switch from anesthetic gas to normal air and patient wakes quickly); breathing is unconscious and natural.
• Disadvantages: inhalation of hot burnt solids (tobacco, marijuana smoke) damages airways; inhalation of compressed-gas propellants can cause hypoxia (low blood oxygen → brain damage); many "rewarding" sensations from inhalants are actually hypoxia symptoms.
• Example: Surgical anesthesia via inhalation allows precise control—patient breathes anesthetic gas, falls asleep within seconds; when switched to normal air, anesthetic clears rapidly and patient wakes.

👃 Insufflation (snorting, parenteral)

• How it works: drug is pulverized into fine powder and inhaled through nostrils; powder sticks to nasal cavity lining and is absorbed by blood vessels in the nose.
• Speed: rapid—drug effects within minutes.
• Why it's used: cocaine is commonly insufflated; avoids first-pass metabolism, so higher dose reaches the brain.
• Don't confuse with inhalation: insufflation = absorption through nasal blood vessels; inhalation = gas exchange in the lungs.

🩹 Transdermal (parenteral)

• How it works: drug is placed on skin surface and diffuses slowly through skin into blood vessels.
• Speed: very slow—drug effect over up to 24 hours.
• Example: nicotine patch for smoking cessation.
• Advantages: steady, prolonged delivery minimizes abuse potential; convenient.
• Disadvantages: skin is an effective barrier, so only small, lipid-soluble molecules effective at milligram doses can be used.
• Don't confuse with topical: transdermal = drug enters bloodstream and affects brain; topical = drug acts only locally (e.g., Tiger Balm) and does not significantly alter blood concentration or brain activity.

🔄 Other routes

• Rectal: avoids most first-pass metabolism; useful if patient has severe nausea.
• Sublingual (under the tongue) and transbuccal (absorbed by gums): avoid first-pass metabolism; e.g., LSD sublingually, nicotine dip transbuccally.
• Intramuscular (IM): injection into muscle (e.g., flu shot); slower than IV (tens of minutes) but easier to perform.
• Subcutaneous (SC): injection into fat layer under skin; ideal for lipid-soluble drugs.

⚠️ Drug interactions: Cytochrome P450 enzymes

Cytochrome P450s (CYP): a class of liver and small-intestine enzymes that metabolize many substances entering the body.

• Grapefruit juice contains bergamottin, which inhibits CYP enzymes.
• Two opposite effects:
  1. Prodrugs (e.g., codeine → morphine via CYP): grapefruit juice inhibits conversion, so less morphine is produced → reduced drug effect.
  2. Drugs degraded by CYP (e.g., buspirone, fentanyl): grapefruit juice inhibits degradation, so more drug reaches the brain → elevated concentration, risk of overdose.
• Example: A patient on buspirone (anti-anxiety) drinks grapefruit juice; normally only 4% of the dose is effective, but with CYP inhibition, much more reaches the brain → overdose symptoms.
• More than 85 pharmaceuticals interact with grapefruit juice; some interactions can cause life-threatening cardiovascular/respiratory effects or permanent kidney damage.

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🧠 The brain's reward and aversion pathways

🎁 Why reward circuits evolved

• Evolutionary advantage: organisms that experience pleasure from adaptive behaviors (drinking water when thirsty, eating high-calorie food, reproducing) are more motivated to seek those stimuli → higher survival and reproduction rates.
• Reward circuitry is highly conserved across species.

🧠 Anatomy of the reward pathway

Ventral tegmental area (VTA): midbrain region containing dopamine (DA) neurons (also called A10 neurons); the largest group of DA cells in the brain.

Mesolimbic pathway: VTA dopamine neurons → nucleus accumbens (NAc, also called ventral striatum); the major pathway mediating reward.

• How it works: engaging in rewarding activities (eating, sex, video games) increases dopamine release in the NAc.
• Drugs of abuse hijack this pathway: cocaine, amphetamine, heroin, etc., cause dopamine overflow in the NAc, mimicking natural rewards.
• Mesocortical pathway: VTA → prefrontal cortex (PFC); involved in decision-making and inhibition of actions.
  • Maladaptive changes in this pathway may explain poor decision-making and loss of control in addiction (prioritizing immediate reward despite long-term harm: job loss, family alienation, health risks).

🚫 Anatomy of the aversion pathway

Lateral habenula (LHb): brain region that sends inhibitory GABA projections onto VTA dopamine neurons; the "antireward" pathway.

• How it works: aversive stimulus (e.g., bitter taste, air puff to face) → LHb neurons increase activity → inhibit VTA DA neurons → less dopamine in NAc.
• Opposite of reward: rewarding stimulus → LHb decreases activity → VTA DA neurons increase activity → more dopamine in NAc.
• Expectation and disappointment: if an animal expects a reward after a cue (Pavlovian conditioning) and the reward is withheld, LHb activity increases.
• Example: A monkey receives a squirt of fruit juice (reward) → LHb activity drops, VTA activity rises; an air puff to the face (aversive) → LHb activity rises, VTA activity drops.

🐀 Intracranial self-stimulation (ICSS) experiments

• Classic experiment (Olds & Milner, 1950s): rats with electrodes implanted in brain regions; lever press → electrical activation of neurons.
• Result: rats with electrodes in septal nucleus pressed lever ~2000 times/hour (one press every 2 seconds); rats chose electrical stimulation over food, even to the point of starvation.
• Human studies: patients with electrodes in reward centers also pressed stimulation button extensively; when food was brought in, hungry patients (7+ hours without eating) looked at the meal but couldn't stop pressing the button long enough to eat.
• Conclusion: artificial activation of reward centers is more motivating than natural rewards like food.

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🔬 How drugs act at the molecular level

🔬 Key vocabulary

Stochastic: random; the movement of neurotransmitter molecules in the synapse is random—they float around, sometimes bump into receptors (activating them), sometimes bump into reuptake proteins (clearing them from the synapse), sometimes float out of the synapse.

Dose-response curve: a graph plotting receptor activation (y-axis) vs. increasing drug dosage (x-axis); typically sigmoidal (S-shaped).

Ligand: a substance that binds to a receptor to form a ligand-receptor complex.

✅ Agonists

Agonist: a chemical substance that activates receptors by binding to the orthosteric site (also called the active site).

• Lock-and-key analogy: receptor = lock (large transmembrane protein with an outward-facing binding site); agonist = key (binds to the active site, causing the receptor to change shape and trigger a downstream reaction).
• Ionotropic receptors: agonist binding → receptor changes shape → allows or blocks ion movement across membrane (e.g., nicotine activates ionotropic acetylcholine receptors).
• Metabotropic receptors: agonist binding → receptor activates G-proteins → downstream signaling (e.g., morphine activates metabotropic opioid receptors).

Three classes of agonists:

Class	Definition	Example
Full agonist	Activates receptor to maximal degree at high concentrations; sets the 100% value on dose-response curve	Glutamate (endogenous neurotransmitter)
Partial agonist	Binds to orthosteric site but cannot fully activate receptor, even at high doses; produces less-than-maximal effect	Some drugs for anxiety, psychosis, chronic pain
Inverse agonist	Causes opposite response to an agonist	(Not detailed in excerpt)

🚫 Competitive antagonists

Competitive antagonist: a substance that binds to the orthosteric site (same site as agonist) and physically blocks the agonist from activating the receptor.

• Concentration-dependent: more antagonist present → higher agonist concentration needed for activation → dose-response curve shifts to the right.
• Key point: antagonist alone (without agonist) has no effect on cell excitation; if an antagonist alone changes cell excitability, it means some agonist is already present at rest.
• Example—naloxone (Narcan) for opioid overdose:
  • Opioid overdose → opioids activate opioid receptors → shut down respiratory drive → fatal.
  • Naloxone is a competitive antagonist at opioid receptors; given via IV or nasal spray, it blocks opioid action within minutes → restores normal breathing.

🔀 Allosteric modulators

Allosteric modulator: a substance that binds to a different site on the receptor (the allosteric site, not the orthosteric active site) and changes the potency of agonists.

• Positive allosteric modulator (PAM): increases agonist action.
• Negative allosteric modulator (NAM): decreases agonist action.
• Key distinction from agonists/antagonists: allosteric modulators do not activate or block the receptor directly; they only modulate the effect of an agonist that is already present.

Example—benzodiazepines and barbiturates:

• Both are PAMs at GABA receptors.
• GABA is an inhibitory neurotransmitter; when benzodiazepine (e.g., Valium) is present, the same amount of GABA has a stronger inhibitory effect.
• Clinical use: enhance inhibition to treat anxiety, epilepsy, insomnia (disorders caused by overexcitation).

Mechanism at ionotropic receptors:

• Receptor normally allows Na⁺ to move across membrane when agonist is present.
• PAM + agonist → more Na⁺ moves across → greater excitability.
• NAM + agonist → less Na⁺ moves across → reduced excitability.

🧪 "Dirty drugs"

• A single drug can have different actions at different receptor classes.
• Example—clozapine (antipsychotic): antagonist at some dopamine and serotonin receptors; partial agonist at other serotonin receptors.
• Drugs with many sites of action are called dirty drugs.

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💊 Six major classes of misused substances

🍺 Alcohol (ethanol)

• Prevalence: most widely used substance—85% of US adults report lifetime use (2015 survey).
• Chemistry: ethanol (C₂H₆O); tiny molecule, water-like properties, diffuses easily through cell membranes.
• Molecular targets: GABA receptors, glutamate receptors, potassium channels, serotonin receptors, and more (not highly specific).
• General effect: depressant on neurons; activates VTA dopamine neurons.
• Acute effects (dose-dependent):
  • Low dose: elevated mood, decreased anxiety, increased risk-taking, slowed reflexes, impaired judgment.
  • High dose: memory deficits, loss of consciousness, analgesia, areflexia, possible death via respiratory depression.
• Chronic effects: low-level chronic use has some cardiovascular benefits, but overall negative (liver disease, cancer, alcohol-related violence/injuries).
• Health impact: leading risk factor for premature death in males aged 15–59 globally; top cause of preventable death.
• Production: metabolic byproduct of yeast breaking down sugars; CO₂ dissolved in solution makes fermented products fizzy.

🚬 Nicotine

• Source: alkaloid compound synthesized by tobacco plant (highest concentration) and other Solanaceae family plants (eggplants, tomatoes) as anti-herbivory adaptation.
• Routes: inhalation (cigarettes, cigars, vape), transbuccal (chew, dip, snuff), transdermal (nicotine patch).
• Addiction potential: highly addictive—rated as addictive as cocaine or heroin.
• Molecular target: agonist at nicotinic acetylcholine receptors (nAChRs)—excitatory ionotropic receptors expressed widely across the body.
• Effect: stimulant; activates sympathetic nervous system → norepinephrine release; smoking a cigarette produces a rapid rush/high within tens of seconds.
• Health impact: leading cause of preventable death in US (~1 in 5 deaths); chronic smoking greatly increases risk of lung/throat/mouth cancers, coronary heart disease, stroke.
• Trends: cigarette smoking among 12th graders declined from ~30% (mid-1970s) to 4% (2018) due to anti-smoking campaigns and stricter marketing laws; however, teen e-cigarette use is rising—teen e-cigarette users are >3× more likely to start smoking cigarettes.

🌿 Cannabis (THC)

• Source: derived from flowering buds or other parts of Cannabis sativa plant.
• Routes: inhalation (smoking joint/blunt) most common; oral preparations increasingly common as cannabis is decriminalized/legalized.
• Main psychoactive ingredient: delta-9-tetrahydrocannabinol (THC).
• Molecular target: activates cannabinoid receptors (CB receptors)—CB1 (psychoactive effects) and CB2 (immune system).
  • The body naturally produces endocannabinoids (eCBs) that activate these receptors.
• Effects: felt within minutes—euphoria, relaxation, distorted perception, lightness (high) or heaviness (stoned).
• Legal status: federally Schedule I; as of 2019, 10 US states legalized recreational use, 20 permit medicinal use; Illinois legalized recreational sales starting January 2020.
• Stigma vs. evidence: "evils of cannabis" largely stem from 1930s propaganda (e.g., film Reefer Madness); current medical understanding: far less harmful than once believed, but significant adolescent exposure increases risk of psychiatric conditions (e.g., schizophrenia) later in life.

💉 Opioids

• Definition: class of drugs (natural or synthetic) that bind to and activate the body's opioid receptors.
• Examples: opium (natural, from poppy plant), heroin (street drug), morphine, fentanyl (medicinal).
• History: human use dates back >5000 years to ancient Sumer.
• Endogenous opioids: the body naturally produces opioids (e.g., endorphin); activation of opioid receptors → potent analgesia (pain relief), sedation, euphoria.
• Clinical use: gold standard for pain relief.
• Routes: heroin and morphine often via IV injection; prescription opioids often oral (for long-term pain).
• Opioid epidemic: dramatic increase in overdose deaths over past 20 years; recent spike due to synthetic opioids (especially fentanyl—10-fold increase in deaths 2013–2017); ~130 Americans die daily from opioid overdose.

⚡ Cocaine

• Source: psychostimulant derived from coca plant.
• Routes: insufflation (powder cocaine), inhalation (crack cocaine), IV injection, transbuccal/oral (chewing leaves).
• Effect: sympathomimetic (activates sympathetic nervous system) → "fight-or-flight" physiology: elevated heart rate/blood pressure, dilated pupils, increased respiration.
• Molecular mechanism: reuptake inhibitor—blocks transporter proteins that clear dopamine, norepinephrine, and serotonin from the synapse → elevated neurotransmitter concentration → greater receptor activation.
• Legal status: Schedule II (high addiction/harm potential, but some medicinal applications—potent local anesthetic and vasoconstrictor, used in facial/nose surgeries).

🌈 Psychedelics

• Definition: class of drugs formerly called hallucinogens; can be natural (psilocybin from mushrooms) or synthetic (LSD).
• Effects: visual distortions, synesthesia, altered sense of self (ego dissolution), sudden connection with nature or higher power.
• Chemistry: many psychedelics structurally similar to serotonin → activate serotonin receptors.
• History: used for centuries in religious ceremonies; troubled US history (1970s counterculture adoption of LSD, secret CIA research, loose research ethics) → negative press, tainted public opinion.
• Recent research (since 2010): growing evidence that psychedelics can treat PTSD, terminal illness-related depression, and drug addiction.

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🔄 Tolerance, withdrawal, and dependence

🔄 Tolerance

Tolerance: a decrease in the action of a drug due to repeated exposure; the person must take progressively higher doses to experience the desired effect.

• Graphical representation: rightward shift in dose-response curve.
• Example: A drug-naive person feels strong effect from low dose; a tolerant person needs higher dose for the same effect.

🧪 Metabolic (dispositional, pharmacokinetic) tolerance

Metabolic tolerance: the body becomes more efficient at eliminating the substance; less drug reaches the site of action.

Example—alcohol (ethanol):

• Liver enzymes break down ethanol in two steps:
  1. Alcohol dehydrogenase: ethanol → acetaldehyde (toxic).
  2. Acetaldehyde dehydrogenase: acetaldehyde → acetic acid (harmless, used in citric acid cycle).
• Chronic alcohol exposure → homeostatic upregulation: liver enzymes increase in function/amount → ethanol degraded more rapidly → less ethanol reaches brain.
• Why tolerance varies: people who never drank have low enzyme levels → stronger drug effect; frequent drinkers have high enzyme levels → weaker effect; genetic variation in enzyme efficiency also contributes.

🧬 Functional (pharmacodynamic) tolerance

Functional tolerance: decreased sensitivity to the substance at the cellular/molecular level.

• Mechanism: chronic exposure to agonist → receptor internalization (surface receptors taken into the cell) → fewer receptors available for activation → diminished drug signal.
• Example—opioid etorphine: frequent exposure → opioid receptors internalized → less response to same dose.

🎯 Conditioned tolerance

• Definition: the body physiologically prepares for drug effect before the drug is present, initiating an opposite somatic effect (likely a protective mechanism).
• Trigger: drug-associated cues (e.g., preparing IV injection, being in the usual drug-use environment).
• Example—heroin and analgesia:
  • Heroin causes analgesia (pain relief).
  • Cues predicting heroin administration → body produces hyperalgesia (increased pain sensitivity) in anticipation.
  • User needs more drug to overcome this anticipatory change.
• Lethal consequence: A bedridden cancer patient regularly received morphine in his dark, humming bedroom; he developed tolerance. One day, he received his normal dose in the brightly lit living room (different environment, no conditioned cues) → overdose death (Siegel, 2001).

🔁 Sensitization (reverse tolerance)

Sensitization: the opposite of tolerance—drug effect increases after chronic exposure.

• Example: nicotine, cocaine, amphetamine can produce psychomotor sensitization after repeated dosing (e.g., a rat exposed to amphetamine over multiple days shows increased locomotor activity in response to the drug).

😣 Withdrawal

Withdrawal: a set of symptoms experienced when abstinent from a substance after tolerance has developed; results from long-lasting homeostatic changes.

• Characteristics: highly aversive state; can be relieved by taking more drug; symptoms are often opposite of the drug's effects.
• Example—heroin:
  • Heroin effects: euphoria, analgesia, relaxation, constipation.
  • Withdrawal symptoms (after opioid receptor downregulation): dysphoria (depression), pain hypersensitivity, restlessness, diarrhea.

☕ Withdrawal from antagonists

• Tolerance and withdrawal occur with antagonists too.
• Example—caffeine:
  • Caffeine is an antagonist at adenosine receptors.
  • Chronic caffeine → homeostatic upregulation of adenosine receptors.
  • When caffeine is absent → endogenous adenosine overactivates receptors → withdrawal symptoms (difficulty staying alert, headache).

🔗 Dependence

Drug dependence: the urge to take the drug when withdrawing.

• Physical dependence: seeking drug to relieve physical withdrawal symptoms or to experience positive sensations.
• Psychological dependence: intense cravings, fixation on drug acquisition, mood/behavioral changes in absence of drug.

⚠️ Don't confuse: Tolerance vs. Dependence vs. Addiction

• Tolerance: reduced drug effect after repeated exposure (need higher doses).
• Dependence: withdrawal symptoms when drug is absent.
• Addiction (substance use disorder): compulsive drug-seeking and drug-taking despite harm (job loss, relationship damage, health risks).
• Key point: tolerance and dependence can occur without addiction; not everyone who develops tolerance/dependence becomes an addict.

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🧬 Understanding addiction: theories and models

❓ The central question

"Why do some people transition from user to addict?"

• Many people use highly addictive substances (cocaine, heroin) casually without becoming addicts; their use remains recreational.
• Others quickly develop pathological addiction with compulsive drug-seeking.
• Research goal: identify protective vs. risk factors (environmental, genetic) and develop effective treatments.

🐀 Animal models of addiction

Self-administration: an experimental paradigm where an animal (monkey, rat, mouse) has an indwelling IV tube connected to a pump; pressing a lever or nose-poking triggers drug infusion into the bloodstream.

• Why it's useful: closely mimics human drug-seeking behavior.
• What researchers study: Do cellular circuits change permanently? Are genes/proteins up/downregulated? Can pharmacological or behavioral interventions change drug-taking/seeking behavior?

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📋 Summary table: Six major drug classes

Drug class	Main substance(s)	Route(s)	Molecular target(s)	Key effects	Health risks
Alcohol	Ethanol	Oral	GABA, glutamate, K⁺ channels, serotonin receptors (non-specific)	Low dose: mood elevation, decreased anxiety, impaired judgment; high dose: memory loss, unconsciousness, respiratory depression	Leading risk factor for premature death (males 15–59); liver disease, cancer, violence/injuries
Nicotine	Nicotine (from tobacco)	Inhalation, transbuccal, transdermal	Nicotinic acetylcholine receptors (nAChRs)	Stimulant; rapid rush/high; sympathetic activation	Leading cause of preventable death in US; lung/throat/mouth cancers, heart disease, stroke
Cannabis	THC	Inhalation, oral	Cannabinoid receptors (CB1, CB2)	Euphoria, relaxation, distorted perception	Adolescent exposure increases risk of schizophrenia; less harmful than once believed
Opioids	Opium, heroin, morphine, fentanyl	IV, oral	Opioid receptors	Analgesia, sedation, euphoria	Opioid epidemic: ~130 US deaths/day; respiratory depression in overdose
Cocaine	Cocaine (from coca plant)	Insufflation, inhalation, IV	Dopamine/norepinephrine/serotonin reuptake inhibitors	Sympathomimetic: elevated heart rate/BP, dilated pupils	High addiction potential; cardiovascular risks
Psychedelics	LSD, psilocybin	Oral, sublingual	Serotonin receptors	Visual distortions, ego dissolution, connection with nature	Emerging therapeutic use for PTSD, depression, addiction

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📚 Key terminology reference

Term	Definition
Neuropharmacology	The study of drugs that affect the nervous system
Pharmacodynamics	The study of the effect of drugs on the body
Pharmacokinetics	The study of the effect of the body on drugs
First-pass metabolism	Enzymatic degradation in the liver before systemic circulation
Prodrug	Inactive substance that becomes active after enzymatic processing
Hypoxia	Low blood oxygen levels
Ventral tegmental area (VTA)	Midbrain region with dopamine neurons; origin of reward pathways
Nucleus accumbens (NAc)	Target of VTA dopamine neurons; mediates reward
Mesolimbic pathway	VTA → NAc; major reward pathway
Mesocortical pathway	VTA → prefrontal cortex; decision-making and inhibition
Lateral habenula (LHb)	Sends inhibitory projections to VTA; "antireward" pathway
Operant conditioning chamber (Skinner box)	Experimental cage where subject manipulates device (lever, nose-poke) to receive response
Intracranial self-stimulation (ICSS)	Experimental paradigm where subject activates brain electrodes via lever press
Stochastic	Random; describes random movement of molecules
Dose-response curve	Graph plotting receptor activation vs. drug dosage
Ligand	Substance that binds to a receptor
Agonist	Substance that activates receptors
Orthosteric site (active site)	Receptor site where agonists bind
Competitive antagonist	Substance that blocks agonist by binding to orthosteric site
Allosteric modulator	Substance that binds to allosteric site and changes agonist potency
Positive allosteric modulator (PAM)	Increases agonist action
Negative allosteric modulator (NAM)	Decreases agonist action
Dirty drug	Drug with many sites of action
Tolerance	Decreased drug effect after repeated exposure
Metabolic tolerance	Body becomes more efficient at eliminating drug
Functional tolerance	Decreased cellular sensitivity to drug
Conditioned tolerance	Body prepares for drug effect via opposite physiological response triggered by cues
Sensitization	Increased drug effect after repeated exposure
Withdrawal	Aversive symptoms when abstinent after tolerance develops
Dependence	Urge to take drug when withdrawing
Self-administration	Animal model where subject self-infuses drug via lever press

🧭 Overview

🧠 One-sentence thesis

The excerpt provides supplementary resources (videos and readings) on stimulants, cannabis, opioids, and psychedelics, and briefly discusses the Brain Disease Model of Addiction (BDMA), which frames addiction as a neurological condition rather than a moral failing, though it has both policy successes and significant criticisms.

📌 Key points (3–5)

• BDMA core claim: compulsive drug use is driven by underlying brain circuitry, not poor morals or weak willpower.
• Policy impact: the BDMA has led to increased mental health resources for addiction recovery and improved outcomes for nonviolent drug offenders.
• Major criticisms of BDMA: most people stop addictive use spontaneously without treatment; it overemphasizes biochemical therapies over public policy; it has not produced successful therapeutic strategies.
• Common confusion: addiction as a "choice" vs. a neurological condition—BDMA argues it is not a choice but a result of brain circuitry changes.
• Supplementary materials: the excerpt lists videos and readings on stimulants, cannabis, opioids, and psychedelics for further study.

🧠 Brain Disease Model of Addiction (BDMA)

🧠 Core framework

The Brain Disease Model of Addiction (BDMA): a framework that explains compulsive drug use and seeking as driven by underlying brain circuitry, not by moral weakness or lack of willpower.

• Addiction is framed as a disease, similar to other medical conditions.
• Genetics modify inherent risk-taking behaviors, the magnitude of drug effects, and the risk of relapse.
• The model shifts the explanation away from personal choice or character flaws.

Example: An addict compulsively seeks drugs not because they lack self-control, but because their brain circuitry makes stopping difficult.

🚫 What addiction is NOT (according to BDMA)

• Not a moral failing: addicts are not "bad people" who made poor ethical decisions.
• Not a willpower issue: the inability to stop is not due to weakness of character.
• Don't confuse: the BDMA explicitly rejects the idea that compulsive drug use is a "choice" the person makes.

📊 Accomplishments and criticisms of BDMA

✅ Policy successes

Policy area	What changed	Impact
Mental health access	Mental Health Parity and Addiction Equity Act of 2008	Increased financial support for recovery programs
Criminal justice	Improved outcomes for nonviolent drug offenders	Better reintegration with society outside prisons

• The BDMA has influenced public policy to treat addiction as a health issue requiring resources, not just punishment.

❌ Major criticisms

The excerpt lists three significant faults of the BDMA:

1. Spontaneous recovery: Most people stop their addictive use patterns by themselves without any treatment.

   • This challenges the idea that addiction is a "disease" requiring medical intervention.

2. Overemphasis on biochemical therapies: The BDMA focuses heavily on medication and brain chemistry rather than public policy approaches to treatment.

   • This may neglect social, economic, and environmental factors in addiction.

3. Lack of therapeutic success: The BDMA has not produced a successful therapeutic strategy to help with addiction.

   • Despite the framework's influence, effective treatments remain elusive.

Don't confuse: The BDMA's policy successes (increased resources, better criminal justice outcomes) with its therapeutic effectiveness—the excerpt states it has not led to successful treatment strategies.

📚 Supplementary resources

📹 Video materials

• Black Lives / Black Lungs (Lincoln Moody): investigates the tobacco industry's infiltration into the Black community.
• Health Meets Psychedelics (TEDx Talks, Burton Tabaac): discusses psychedelics in a health context.

📖 Reading materials

The excerpt lists three academic readings:

1. National Academies of Sciences, Engineering, and Medicine (2017): Chapter 2 on health effects of cannabis.
2. Doherty & Alsufyani (2021): Journal of Clinical Pharmacology article on pharmacology of stimulants.
3. Fagerstrom (2014): article on nicotine's pharmacology, toxicity, and therapeutic use.

These resources cover stimulants, cannabis, opioids, and psychedelics for further study beyond the main text.

🧭 Overview

🧠 One-sentence thesis

The excerpt provides supplementary resources (a video and readings) for exploring opioids and psychedelics but does not contain substantive content explaining these topics.

📌 Key points (3–5)

• What this section is: a resource list titled "Additional Video and Readings" under the heading "Opioids and Psychedelics."
• Video resource: a TEDx talk titled "Health Meets Psychedelics" by Burton Tabaac at TEDxUCLA.
• No explanatory content: the excerpt does not define opioids or psychedelics, describe their mechanisms, or discuss their effects or therapeutic uses.
• Context clue: this section follows a chapter on "Stimulants and Cannabis" and appears to be part of a larger textbook or course module on substance use.

📚 What the excerpt contains

📚 Resource format

• The excerpt is a short section header followed by a list of supplementary materials.
• It does not include lecture notes, definitions, or explanations of opioids or psychedelics.
• The only content is:
  • A section title: "Opioids and Psychedelics"
  • A subheading: "Additional Video and Readings"
  • One video reference with a note that interactive elements are excluded from this text version.

🎥 Video reference

• Title: "Health Meets Psychedelics"
• Speaker: Burton Tabaac
• Platform: TEDxUCLA (a TEDx Talks presentation)
• Access note: the excerpt states "One or more interactive elements has been excluded from this version of the text. You can view them online here: [URL]"
• The excerpt does not summarize the video's content or key arguments.

🔍 What is missing

🔍 No substantive information

• The excerpt does not explain what opioids or psychedelics are.
• It does not describe pharmacology, mechanisms of action, therapeutic uses, risks, or legal status.
• It does not compare opioids and psychedelics or discuss their relationship.
• Don't confuse: this is a resource pointer, not a content section—readers must access the video or readings to learn about the topic.

📖 Context from surrounding text

• The excerpt follows a section on "Stimulants and Cannabis" that also lists "Additional Video and Readings."
• The page numbering ("154 | Stimulants and Cannabis" and "Opioids and Psychedelics") suggests this is part of a structured textbook or online course.
• The earlier visible text discusses the Brain Disease Model of Addiction (BDMA), but the opioids/psychedelics section does not continue that discussion.

🧭 Overview

🧠 One-sentence thesis

Sleep is a vital biological function characterized by decreased activity, sensory decoupling, and distinct brain wave patterns that cycle through multiple stages each night, driven by circadian rhythms and neurochemical signals that regulate when we sleep and wake.

📌 Key points (3–5)

• Sleep is essential for health: lack of ~7 hours per night correlates with increased risk for heart disease, stroke, diabetes, depression, and even cancer; sleep deprivation also impairs immune function and cognitive performance.
• Sleep cycles through distinct stages: NREM1 (light sleep) → NREM2 (theta waves, sleep spindles) → NREM3 (deep/slow-wave sleep) → REM (paradoxical sleep with rapid eye movement and dream recall), repeating roughly every 90 minutes.
• Three theories explain why we sleep: recuperation (body repair and waste clearance), evolutionary adaptation (species-specific survival strategies), and brain plasticity (memory consolidation and learning).
• Circadian rhythms are ~24-hour cycles: driven by internal molecular clocks (PER/TIM proteins) and entrained by environmental zeitgebers like light; free-running rhythms are slightly longer than 24 hours.
• Common confusion—REM vs deep sleep: REM sleep has high-frequency brain activity resembling wakefulness and is linked to procedural memory/dreams, while NREM3 (deep sleep) has slow, synchronized waves and supports declarative memory and physical restoration.

🛌 Defining sleep and its characteristics

🛌 What sleep is

Sleep is characterized by: (1) a decrease in physical activity, (2) a decoupling from external inputs, and (3) changes in brain wave activity.

• Decreased physical activity: the body uses ~10% less energy during sleep; movement is greatly reduced compared to waking, though some people may talk, grind teeth, or even sleepwalk (somnambulism—about 15% of people).
• Sensory decoupling: the brain's threshold for detecting stimuli is heightened, so sensory inputs are dampened; this is why someone may need to shake you or speak loudly to wake you.
• Brain wave changes: EEG technology (1924 onward) revealed that the sleeping brain is not simply "low activity"—at times it resembles the awake brain in activity level.

📊 Measuring sleep with polysomnography

• A polysomnogram records multiple physiological measures: heart rate, blood pressure, oxygen levels, respiration, muscle activity, eye movement, and brain waves (EEG).
• EEG is the gold standard for identifying sleep stages based on cortical neuron firing patterns.

🌀 Stages of sleep and the sleep cycle

🌀 Two main phases: REM and NREM

• REM sleep (rapid eye movement): eyes dart rapidly; respiration and heart rate increase; vivid visual dreams are more likely if awakened during REM.
• NREM sleep (nonREM): subdivided into three stages (NREM1, NREM2, NREM3) based on EEG patterns; eyes do not move rapidly; physiological activity generally decreases.

🧠 Awake state (baseline)

• Beta waves (13–30 Hz): high-frequency, low-amplitude; dominate when a person is concentrating or mentally active (e.g., reading a textbook).

💤 NREM1 (light sleep / drowsiness)

• Alpha waves (8–13 Hz) increase as beta waves decrease; later, theta waves (4–8 Hz) become more prevalent.
• Muscles still somewhat active; eyelids may open/close; person may still respond to questions.
• This is the transition from wakefulness to sleep.

💤 NREM2 (intermediate sleep)

• Theta waves predominate; about 50% of a healthy adult's night is spent here.
• K-complexes: large-amplitude events occurring about once per minute (largest amplitude in healthy human EEG).
• Sleep spindles: high-frequency bursts (~1 second, low beta range) that may help with memory or block perception of outside noises to maintain sleep.

💤 NREM3 (deep sleep / slow-wave sleep)

• Delta waves (1–4 Hz): large-amplitude, low-frequency; cortical neurons fire in synchrony.
• Physiological activity reaches its lowest point: heart rate, respiration, blood pressure, and metabolism all minimal.
• Hardest stage from which to wake someone.

💤 REM sleep (paradoxical sleep)

• High-frequency, low-amplitude brain activity—similar to the awake state, hence "paradoxical."
• Eyes move rapidly; vivid dreams with visual imagery are common.
• Early in the night, REM periods are short; later cycles have longer REM and almost no deep sleep.

🔄 The sleep cycle (hypnogram)

• A hypnogram plots time (x-axis) vs. sleep stage (y-axis); awake at top, deep sleep at bottom.
• Typical progression: NREM1 → NREM2 → NREM3 → back through NREM2 → NREM1 → REM, repeating roughly every 90 minutes (ultradian rhythm).
• Early night: more time in NREM3 (deep sleep), little REM.
• Late night: more time in REM, almost no NREM3.

Don't confuse: the 90-minute sleep cycle (ultradian) with the 24-hour circadian rhythm—they operate on different timescales.

🧬 Why do we sleep? Three theories

🧬 Recuperation theory (body repair and waste clearance)

The recuperation theory: being awake is physically demanding; sleep allows the body to reset, repair, and clear metabolic waste.

Evidence 1: Glymphatic system and beta-amyloid clearance

• During sleep, extracellular space expands by ~60%, allowing cerebrospinal fluid (CSF) to penetrate deeper and wash out cellular waste products.
• Beta-amyloid (a protein byproduct) accumulates in Alzheimer's disease; the glymphatic system clears it during sleep.

Evidence 2: Immune function

• Sleeping <6 hours per night increases susceptibility to colds, flu, gastroenteritis.
• Each hour of sleep over 6 hours boosts vaccine effectiveness by ~50%.

Evidence 3: Growth hormone (GH) release

• Growth hormone promotes cellular repair, muscle/bone growth, and protein synthesis.
• The largest GH burst occurs early in the night during NREM3; plasma GH concentration may be 10× baseline.

Case study: Peter Tripp (1959)

• Radio DJ stayed awake for 201 hours; developed severe paranoia, hallucinations (spiders, rodents), and stripped naked in the street.
• Long-term effects may have included job loss and divorce (though causality is uncertain).
• Guinness Book of World Records no longer allows prolonged wakefulness records due to health risks.

Exception: short sleepers (~1% of people)

• Some individuals feel refreshed with <6 hours of sleep and have similar health outcomes to normal sleepers.
• They have very short sleep latencies (fall asleep in minutes), spend more time in deep sleep and REM, and minimize NREM1/NREM2.

🧬 Evolutionary adaptation theory (species-specific survival)

Sleep patterns evolved to maximize survival for each species' ecological niche.

• Humans: highly dependent on vision; darkness is dangerous (risk of falling, predators, poisonous food), so inactivity at night is adaptive; sleep reduces metabolism and energy needs.
• Dolphins: prey animals that sleep with one brain hemisphere at a time (unihemispheric sleep) to remain vigilant for predators.
• Small prey (e.g., squirrels): remain very still and hidden at night to avoid predators.
• Alpha predators (e.g., tigers): no predators to fear, so they can sleep up to 20 hours per day.

Weakness of this theory: sleep makes almost all animals vulnerable to predation (decreased sensory detection), so it's unclear why evolution would favor such a risky state unless sleep provides critical benefits.

🧬 Brain plasticity theory (memory and learning)

Sleep allows the brain to consolidate memories and undergo critical neural changes.

• Declarative memory (facts) benefits more from NREM3 (slow-wave sleep).
• Procedural memory (motor skills) is enhanced by REM sleep.
• Mechanism: brain activity during sleep may move memories from "temporary" storage to stable, long-term storage.

Evidence: newborn sleep

• Newborns sleep ~17 hours per day (~70% of the time).
• Their brains are experiencing massive amounts of new sensory input (light, sound, touch) and must rapidly learn to respond to the environment.
• High sleep need supports this rapid learning and memory formation.

Don't confuse: these three theories are not mutually exclusive—sleep likely serves all three functions (repair, adaptation, and learning).

⏰ Circadian rhythms and the 24-hour clock

⏰ What is a circadian rhythm?

Circadian rhythm: any behavioral or physiological measure that intrinsically cycles on a ~24-hour pattern (from Latin circa = "around" + diem = "day").

• Examples: sleep-wake cycle, blood pressure (peaks at 11 AM), body temperature (dips in evening), hunger hormones, attention (highest in morning).
• Ultradian rhythm: cycles faster than 24 hours (e.g., 90-minute sleep cycles).
• Infradian rhythm: cycles longer than 24 hours (e.g., 4-week menstrual cycle).

⏰ Discovery: the Mimosa pudica plant (1729)

• French scientist Jean-Jacques d'Ortous de Mairan studied a plant that opened its leaves in daytime and closed at night (heliotropism).
• When placed in complete darkness, the plant still opened and closed on a 24-hour schedule.
• Conclusion: the plant has an internal 24-hour clock, not just a response to light.
• This laid the foundation for chronobiology (the study of day-night periodic phenomena).

⏰ Circadian rhythms exist even in short-lived organisms

• Cyanobacteria (blue-green algae) reproduce every ~6 hours but still exhibit 24-hour patterns of nitrogen fixation aligned with light-dark cycles.

🌍 Jet lag and entrainment

• Jet lag: psychological (difficulty concentrating, mood swings) and physical (fatigue, insomnia, GI distress) symptoms caused by a mismatch between internal circadian clock and external environment.
• Example: flying from Chicago to Cairo (7-hour time difference)—your internal clock says "sleep at 11 PM Chicago time," but the sun is rising in Cairo.
• Entrainment: circadian rhythms can adjust to new environments over a few days.
• Zeitgebers (German for "time givers"): environmental cues (e.g., light, social activity) that help the brain reset its clock.
• Melatonin supplements late at night in a new time zone can speed up entrainment.

🌍 Free-running circadian rhythm (no zeitgebers)

• Michel Siffre (1972): French cave explorer spent 6 months in a Texan cave with no sunlight; his circadian cycle became unpredictable—some "days" were 36 hours awake + 12 hours asleep.
• Scientific study: people in an underground bunker with constant lighting had a free-running cycle of ~26 hours (i.e., they fell asleep and woke ~2 hours later each day).
• International Space Station: astronauts experience 16 sunrises/sunsets per day (90-minute orbit); NASA uses artificial 24-hour lighting (bright blue LEDs in "daytime," dim red-shifted light in "evening") to prevent jet lag.

🧬 Molecular basis: PER and TIM proteins (fruit flies)

• Period gene discovered in Drosophila (1980s): mutations caused flies to sleep on 29-hour, 19-hour, or unpredictable cycles.
• Timeless gene codes for TIM protein; period gene codes for PER protein.
• Mechanism:
  • PER and TIM form a dimer (pair) that enters the nucleus and represses transcription of both genes (negative feedback loop).
  • Light degrades TIM during the day → PER alone cannot repress transcription → more PER and TIM are made.
  • At night, TIM accumulates (no light to degrade it) → PER-TIM dimer forms → transcription is repressed.
  • Cycle repeats every ~24 hours.
• Nobel Prize (2017): Hall, Rosbash, and Young won for discovering this molecular clock mechanism.

Don't confuse: the molecular clock (PER/TIM proteins) operates at the cellular level, but it drives organism-level behaviors like sleep-wake cycles.

💊 Neurochemicals that regulate sleep

💊 Overview

• Many neurotransmitters affect sleep: glutamate (heightened when awake and during REM), GABA (sedative; positive allosteric modulators are sleep aids), norepinephrine (increases alertness via sympathetic nervous system).
• We focus on three key molecules: adenosine, melatonin, and histamine.

💊 Adenosine (sleepiness signal)

Adenosine: a signaling molecule involved in inflammation, immune response, heart rate modulation, and—importantly—sleep regulation.

• Adenosine is part of ATP (adenosine triphosphate), the cellular energy currency.
• Throughout the day, as the body uses energy, adenosine accumulates → signals to the brain that we are sleepy.
• Caffeine is an adenosine receptor antagonist: it blocks adenosine signaling, staving off sleepiness and increasing alertness.
• Other adenosine antagonists: theobromine and theophylline (found in tea and chocolate), chemically similar to caffeine.

Half-life of caffeine: ~5 hours

• If you drink coffee at 2 PM and go to bed at midnight, the caffeine in your bloodstream is equivalent to drinking ¼ cup of coffee right before bed.
• After 5 half-lives, a substance is effectively eliminated.

💊 Melatonin (sleep-promoting hormone)

Melatonin: an endogenous hormone produced by the pineal gland that helps regulate the sleep-wake cycle; increased levels signal the body to prepare for sleep.

How light suppresses melatonin:

• Photosensitive retinal ganglion cells detect daylight and send signals via the retinohypothalamic tract (RHT) to the suprachiasmatic nucleus (SCN) in the hypothalamus.
• The SCN sends inhibitory projections to the pineal gland.
• Daytime: RHT strongly activates SCN → SCN inhibits pineal gland → low melatonin.
• Nighttime: less light → weaker RHT signal → less SCN inhibition → pineal gland produces more melatonin.

Blue light is most potent at suppressing melatonin:

• Shorter wavelengths (violet-blue) activate the RHT more efficiently than longer wavelengths (yellow-red).
• Digital devices (computers, phones) emit blue light from LEDs.
• Sleep hygiene tip: eliminate digital device exposure ~1 hour before bedtime to optimize melatonin production.

💊 Histamine (wakefulness signal)

Histamine: a neurotransmitter in the brain that acts as a pro-wakefulness signal (opposite of adenosine and melatonin).

• In the body, histamine mediates itch, inflammation, and immune activation.
• Antihistamines (histamine antagonists) are used for allergies but cause drowsiness as a side effect (because they block the wakefulness signal in the brain).
• Newer "non-drowsy" antihistamines are designed to minimize this effect.

Don't confuse: adenosine and melatonin both promote sleepiness, but they work through different mechanisms—adenosine accumulates with energy use, while melatonin is regulated by light exposure via the SCN.

🧠 Brain structures involved in sleep

🧠 Overview

• Sleep and wake behaviors are driven by deep brain structures (phylogenetically older areas), not just the cortex.
• These areas communicate broadly throughout the brain; we focus on the hypothalamus here.

🧠 Hypothalamus and encephalitis lethargica

• Constantin von Economo (1917): described patients with encephalitis lethargica (sleeping sickness).
• Two symptom patterns:
  1. Progressive lethargy → drowsiness → extended sleep → coma.
  2. Severe insomnia (difficulty falling asleep).
• Autopsy findings:
  • Patients with persistent sleepiness had damage to the posterior hypothalamus.
  • Conclusion: the posterior hypothalamus is involved in promoting wakefulness.
• (The excerpt cuts off here, so we cannot describe the full role of the hypothalamus or other brain structures.)

Don't confuse: the hypothalamus is not the only brain area controlling sleep—it is part of a network, but the excerpt does not provide details on other structures (e.g., brainstem, thalamus).

---

Note: The excerpt ends mid-sentence in the hypothalamus section, so the full explanation of brain structures involved in sleep is incomplete. The material provided covers sleep stages, theories of sleep function, circadian rhythms, neurochemicals, and the beginning of brain structures.

🧭 Overview

🧠 One-sentence thesis

The hippocampus and related medial temporal lobe structures are essential for forming new declarative memories, while procedural memories depend on other brain regions like the striatum and cerebellum, and memory formation involves synaptic strengthening through processes like long-term potentiation.

📌 Key points (3–5)

• Patient HM's legacy: Surgical removal of the medial temporal lobe (including hippocampus) left him unable to form new declarative memories but preserved procedural memory, revealing that different memory types depend on different brain structures.
• Memory types distinction: Declarative (explicit) memories include facts and personal episodes; procedural (implicit) memories include motor skills and conditioned associations—these are neurologically separable.
• Common confusion: Anterograde amnesia (inability to form new memories after injury) vs. retrograde amnesia (loss of past memories); HM had both, with temporally graded retrograde amnesia (older memories better preserved).
• Cellular basis of memory: Hebb's principle "cells that fire together, wire together" explains how repeated synaptic activity strengthens connections, creating memory traces (engrams) distributed across brain networks.
• Consolidation during sleep: Memory consolidation occurs predominantly during sleep—declarative memories during non-REM sleep, procedural memories during REM sleep.

🧠 Memory types and Patient HM

🧠 Who was Patient HM

• Born Henry Molaison in 1926; suffered severe epilepsy from childhood.
• In 1953, neurosurgeon William Scoville performed experimental surgery removing ~8 cm of medial temporal lobe bilaterally, including the hippocampus.
• Surgery reduced seizures but caused profound anterograde amnesia: inability to form new discrete memories.
• Example: Could not remember what he ate minutes after a meal; forgot people he met repeatedly.
• Intelligence, language, and word recall remained intact; loved crossword puzzles.
• Died in 2008 at age 82.

📚 Declarative (explicit) memory

Declarative memories (explicit memories): pieces of information that can be consciously declared or stated explicitly; "knowing what."

Two subtypes:

Type	Definition	Examples from excerpt
Semantic memory	Factual information	"Jupiter is the largest planet"; "Rosalind Franklin discovered DNA structure"
Episodic memory	Personal life events; "mental time travel"	"I ordered pizza last night"; "I put my wallet on the table"

• HM lost ability to form new semantic memories: performed at chance (50%) on words added to dictionary after 1953 (e.g., "granola," "jacuzzi").
• HM could not create new autobiographical memories: gave only vague, generic answers about adult birthday parties.
• Don't confuse: HM's childhood memories remained intact, showing the hippocampus stores memories temporarily before they relocate to cortex.

🔧 Procedural (implicit) memory

Procedural memories (implicit memories): unconscious memories that cannot be explicitly stated; "knowing how."

• Includes motor skills (sometimes called "muscle memory," though muscles don't store memory).
• Also includes priming effects and conditioned associations.

Mirror tracing task:

• HM drew a star while watching his hand in a mirror.
• Improved dramatically over days: ~10× faster after practice.
• Retained skills up to one year later.
• Yet each day he forgot the experimenter (Dr. Brenda Milner) and needed task re-explained.
• Conclusion: Procedural learning intact despite declarative memory loss.

Associative memory (Pavlovian conditioning):

• Example: Dog learns to associate whistle (conditioned stimulus, CS) with food (unconditioned stimulus, US), eventually salivating to whistle alone (conditioned response, CR).
• This type of procedural memory was preserved in HM.

🧩 Working memory

Working memory: temporarily storing information while simultaneously manipulating it; "short-term memory on overdrive."

• Digit span test: Remember numbers, repeat in reverse order; series lengthens until errors occur.
• Corsi block tapping test: Experimenter taps blocks in sequence; subject taps in reverse order.
• HM struggled immediately after surgery but performed normally years later.

🔄 Retrograde vs. anterograde amnesia

• Anterograde amnesia: Cannot create new memories after injury (HM's primary deficit).
• Retrograde amnesia: Cannot recall memories from before injury.
• HM had temporally graded retrograde amnesia: memories from 2 years before surgery mostly lost; childhood memories intact.
• Interpretation: Hippocampus stores memories short-term (perhaps ~2 years), then memories relocate to cortex for permanent storage.

🏗️ Brain structures for memory

🐚 Hippocampus (HPC)

Hippocampus: seahorse-shaped structure in medial temporal lobe; part of the limbic system (evolutionarily ancient network involved in emotions and memory).

Anatomy:

• Trisynaptic circuit: Three main synaptic connections.
  1. Entorhinal cortex (layers 2–3) → perforant pathway → dentate gyrus granule cells
  2. Dentate gyrus → mossy fibers → CA3 pyramidal cells
  3. CA3 → Schaffer collaterals → CA1 (hippocampal output) → entorhinal cortex (layers 5–6)
• Neurotransmitters: mainly glutamatergic; modulated by GABA, acetylcholine, norepinephrine, serotonin.

Function: Spatial memory

• Involved in navigation and creating mental maps.
• Example: Finding a new classroom; walking across campus.
• Hippocampal damage causes spatial memory deficits.

Behavioral tests (rodents):

• Morris water maze: Opaque pool with hidden platform; rodents learn platform location using environmental cues; time to find platform decreases with learning. HPC lesions impair performance.
• Radial arm maze: Central platform with 8+ arms; one arm has food; rodents learn which arm is rewarded. Alzheimer's model organisms perform poorly.

🔴 Amygdala

• Almond-shaped structure in medial temporal lobe, adjacent to hippocampus.
• Subdivisions: basolateral amygdala (BLA; fear and reward) vs. central nucleus (CeA; physiological/emotional response).

Function: Emotional memories

• Both positive and negative emotions.
• Example: Smell of grandmother's cooking → happy childhood memory; smell of vomit → nausea from food poisoning.

Fear conditioning (foot-shock paradigm):

• Rodent in chamber with metal-rod floor; sound/light cues paired with painful foot shock.
• If learning occurs, rodent freezes when cues presented alone.
• Amygdala lesions prevent freezing; hippocampal lesions have no effect.
• Used as model for post-traumatic stress disorder.

👁️ Inferotemporal cortex (IT)

• Part of ventral visual stream.
• Stores visual memory components.

Fusiform gyrus:

• Involved in facial recognition.
• Prosopagnosia (fusiform damage): can perceive face parts but cannot match features to specific person.

Parahippocampal place area (PPA):

• Activated by place-related images: landscapes, buildings, room interiors.
• Not activated by faces or objects.

Visual memory capacity:

• After viewing 10,000 images briefly, people identified previously seen images ~83% of the time.

🧩 Prefrontal cortex (PFC)

• Part of frontal lobe; involved in decision-making and personality.
• Important for short-term and working memory.
• PFC damage (stroke, tumor, aneurysm) impairs working memory tasks like digit span test.
• Frontotemporal dementia (PFC degradation) causes working memory difficulty.
• Strong connections with hippocampus; involved in hippocampal-dependent memory formation.

🎯 Striatum

• Part of basal ganglia.
• Stores habit memories.
• Habits preserve cognitive bandwidth but reduce behavioral flexibility.

Related disorders:

• Obsessive-compulsive disorder (OCD): Intrusive thoughts → repetitive actions (e.g., excessive handwashing).
• Rodent model: excessive self-grooming → fur pulling, skin injury.
• Drug addiction: Compulsive drug use involves habitual motor sequences (e.g., opening cigarette pack, flicking lighter).

🎪 Cerebellum

• Posterior and ventral to cerebrum; phylogenetically ancient.
• Involved in procedural memories, especially motor skills.
• Learning new motor skills requires changes in cerebellar circuit strength.

🔬 Special neuron populations

Place cells (hippocampus):

• Pyramidal cells that fire when animal is in specific location.
• No topographical arrangement (adjacent locations ≠ adjacent neurons).
• Help create spatial map.

Grid cells (entorhinal cortex):

• Fire periodically at intersections of hexagonal "grid" in open environment.
• Multiple overlapping grids give animal sense of surroundings.
• Discovery earned 2014 Nobel Prize in Physiology or Medicine.

Concept cells ("Jennifer Aniston neurons"; temporal cortex):

• Fire in response to highly specific concepts (e.g., Jennifer Aniston, Luke Skywalker, Tower of Pisa).
• Respond to multiple modalities: pictures, text, spoken words.
• May encode broader concepts (e.g., "Star Wars characters").
• Example: Luke Skywalker neuron fires for Mark Hamill photo, "LUKE SKYWALKER" text, spoken name, and possibly Yoda/Darth Vader (related concepts).

🔬 Cellular and molecular mechanisms

🔄 Three stages of memory processing

1. Encoding:

• Brain circuits store information.
• Not all sensory input is encoded (energetically costly).
• Salient stimuli (e.g., predator cues) or strongly attended information (e.g., repeated phone number) encoded more strongly.
• Novel information building on existing knowledge encodes more easily.

2. Consolidation:

• Makes memory more permanent.
• Hebb's principle (1949): "Cells that fire together, wire together."
• Repeated synaptic activity strengthens connections; inactive connections weaken.
• Memory trace (engram): specific circuit of neurons representing a memory.

Reverberation:

• Networks of neurons fire repeatedly.
• Each activation strengthens the network, making future activation easier.
• Memory traces shift from subcortical structures (hippocampus, amygdala) to neocortex over time.
• HM's temporally graded retrograde amnesia supports this: hippocampus needed for ~2 years, then cortex stores permanently.

Sleep consolidation:

• Declarative memory enhanced during non-REM sleep.
• Procedural memory enhanced during REM sleep.
• Research method: deprive participants of specific sleep phases using EEG signatures.
• Dreaming may relate to consolidation, but role is unclear.

3. Retrieval:

• Brings back specific engram.
• Applies to both declarative and procedural memories.

Free-recall vs. cued-recall:

• Free-recall: Write down words from memorized list (~33% success).
• Cued-recall: Prompted with category titles (~75% success).
• Higher cued-recall scores show encoding/consolidation differs from retrieval.

Reconsolidation:

• When engram is retrieved, it is replayed and reconsolidated.
• Some aspects emphasized, others lost.
• Leads to false memories: memories not true to reality.
• Eyewitness testimonies are unreliable.
• Good memories may seem better; negative aspects dampened.
• Dysregulation may cause PTSD symptoms (negative emotions exaggerated).

⚡ Long-term potentiation (LTP)

Bliss and Lomo (1973):

• First published evidence of plasticity using electrophysiology.
• Experiment on anesthetized rabbit hippocampus.
• Stimulating electrode on perforant pathway axons; recording electrode on dentate gyrus cells.
• Single pulse → field excitatory post-synaptic potential (fEPSP).

High-frequency stimulation (HFS):

• 100 stimulations/second for 3 seconds.
• Result: Enhanced fEPSP amplitude in response to single stimulus.
• LTP persisted up to one year in experiments.
• In humans, some synaptic connections may remain potentiated for entire lifetime.

Long-term potentiation (LTP): prolonged increase in synaptic strength.

Long-term depression (LTD): prolonged decrease in synaptic strength.

• Both LTP and LTD are important for healthy brain function.
• Both excitatory and inhibitory synapses can undergo LTP or LTD.

Molecular basis (glutamate receptors):

• AMPA receptors: Standard ionotropic glutamate receptors; glutamate binding → cation (mostly Na+) influx → depolarization.
• NMDA receptors: More complex; also cation-permeable and excitatory, but with specific functional differences (excerpt ends before full explanation).

📊 Plasticity summary

Plasticity: change in synaptic strength, which may increase or decrease and persist from minutes to a lifetime.

• Synaptic changes are the substrate of learning.
• Individual memory likely distributed across multiple brain areas.
• Memory = specific pattern of activity across certain synaptic connections.

🩺 Clinical notes

💤 Hypermnesia (sidebar)

• Solomon Shereshevsky: rare case of near-perfect recall of any memory, even years later.
• Could memorize pages of text in any language; recall events from 10–12 years prior.
• Today would be described as autistic with strong multimodal synesthesia.
• Had deficits: executive function, face recognition, abstract idea interpretation.
• Case study published 1968 by psychologist A. R. Luria in "The Mind of a Mnemonist."

🧠 Note on memory distribution

• Single memory likely stored as mosaic across several brain areas.
• Examples not fully detailed in excerpt: orbitofrontal cortex (positive emotional memories), sensory cortices (stimulus-specific memories).

🧭 Overview

🧠 One-sentence thesis

Emotions are complex neurophysiological states distributed across multiple brain structures, and understanding their neural mechanisms—from early theories about physiological responses to modern knowledge of structures like the amygdala and hypothalamus—helps explain emotional processing, memory, and disorders.

📌 Key points (3–5)

• What emotions are: complex neurophysiological states that contribute to internal feelings and guide behavior, existing on a spectrum and experienced simultaneously.
• Historical theories of emotion origin: James-Lange (physiological changes precede emotion), Cannon-Bard (simultaneous independent activation), and two-factor theory (physiological response + cognitive label).
• Common confusion—theories of emotion: James-Lange says body changes cause emotion; Cannon-Bard says perception triggers both body and emotion independently; two-factor says physiology + context/cognition together determine emotion.
• Key brain structures: amygdala (emotional valence and memory), hypothalamus (endocrine responses), pituitary gland (hormone release), and the Papez circuit (distributed emotional processing).
• Universal facial expressions: Ekman's research suggests humans across cultures use similar facial expressions for basic emotions (anger, contempt, disgust, fear, happiness, sadness, surprise).

🧪 Historical theories of emotion origin

🧪 James-Lange theory

James-Lange theory of emotion: the body's physiological changes precede the onset of an emotional response.

• Contrary to common sense, which says stimulus → emotion → body response.
• James-Lange says: stimulus → body response → emotion.
• Example: seeing a lion → sympathetic nervous system activation (heart rate up, respiration up) → then you feel fear.

🧪 Cannon-Bard theory

Cannon-Bard theory of emotion: perception of an emotionally charged stimulus prompts simultaneous but independent activation of both the autonomic nervous system and the emotional response.

• Criticized James-Lange with two key observations:
  • Cats with removed sympathetic nervous systems still showed fear/aggression responses (hissing, clawing).
  • Physiological changes (exercise, fever, cold) can occur without strong emotional states.
• Don't confuse: Cannon-Bard says emotion and body response happen at the same time, not one causing the other.
• Emphasized role of hypothalamus and thalamus in triggering autonomic and emotional responses.

🧪 Two-factor theory

Two-factor theory of emotion: people use a combination of the physiological response and a cognitive label to determine the emotion most appropriate for a given circumstance.

• Explains why the same physiological state (elevated heart rate) can be fear, elation, or love depending on context.
• Cognitive label comes from:
  • Prior knowledge ("lions eat meat, so I should be afraid").
  • Environmental cues (observing others running and screaming).
• Schachter and Singer experiment: gave epinephrine to patients, then exposed them to a confederate acting either euphorically or angrily; patients who didn't know what to expect from the drug were more influenced by the confederate's emotional display.
• Example: same physiological arousal interpreted as fear (lion context) or excitement (good news context).

🧠 Early neuroanatomical findings

• Decorticate preparation: removing the cortex in cats led to sham rage (hyper-aggressive response to harmless stimuli), suggesting the cortex normally inhibits powerful emotions.
• Papez circuit: hypothalamus, cingulate gyrus, thalamus, hippocampus (later added amygdala); emotional responding is distributed across many areas, not localized to one.
• Kluver-Bucy syndrome: bilateral temporal lobe removal in monkeys caused loss of fear/anger, visual agnosia, hypersexuality, and hyperorality (inappropriate mouth use like licking nonfoods).

😊 Faces and universal emotions

😊 Darwin's evolutionary view

Darwin suggested that similar emotional responding is found across different cultures and to some extent even in nonhumans; the main purpose of emotive expression is to communicate survival cues between individuals.

• Relaxed expression conveys safety; fearful expression promotes alertness (danger nearby).
• We also gain survival information from non-human behaviors (hissing snake, snarling lion).

😊 Ekman's universal facial expressions

Universal facial expressions: all humans, regardless of culture, use similar facial expressions for basic emotions.

• Ekman identified seven basic categories: anger, contempt, disgust, fear, happiness, sadness, surprise.
• Tested in remote Papua New Guinea village (isolated from other cultures); people made the same facial responses to emotional circumstances.
• Ekman 60 faces (EK-60F) test: photographs of actors portraying six major emotions; used to assess facial emotion recognition.
  • People with major depressive disorder or borderline personality disorder have lessened ability to detect happiness.
  • Seeing emotional faces results in similar emotion in the viewer.
  • People with dementia or Parkinson's see emotions as less intense.

😊 Facial Action Coding System (FACS)

FACS: a system that uses facial anatomy to differentiate features characteristic of different expressions.

• Example: happy face = flexing zygomaticus major and orbicularis oculi muscles (upward turn of mouth corners, rising cheeks).
• Distinguishes genuine smiles (Duchenne smile: simultaneous muscle action) from fake smiles (non-Duchenne: mouth corners turn without much change to upper face).
• Also scores head movement, eye movement, and larger physical movements.

🧠 Key brain structures in emotion

🧠 Amygdala

Amygdala: a limbic structure that contributes heavily to processing the valence of emotional experiences.

• Almond-shaped, part of temporal lobe.
• Subdivided into basolateral amygdala, central nucleus, cortical nucleus.
• Strongly implicated in emotional memory formation (positive or negative valence).
• Autobiographical memories more often have emotional content than semantic memories.
• Lesion effects:
  • Monkeys with amygdala lesions showed no fear response to hissing snake, no anger to provocative stimuli (Kluver-Bucy syndrome).
  • Used as last-resort treatment for temporal lobe epilepsy or pathological aggressiveness (rarely used today due to high complication/mortality rates).
• Fear conditioning paradigm: rodent learns tone/light predicts foot-shock, freezes when stimuli presented; amygdala lesion → less freezing (impaired emotional memory acquisition). Used as model for PTSD.

🧠 Hypothalamus

Hypothalamus: an almond-shaped structure at the base of the brain that initiates endocrine responses in the rest of the body, such as hormone production.

• Major output pathway from the amygdala.
• Modulates homeostasis, hunger, circadian regulation.
• Signals the pituitary gland to produce/release hormones.

🧠 Pituitary gland

Pituitary gland: a pea-sized endocrine organ that protrudes from the base of the brain, strongly involved in production and release of neurohormones.

• Neurohormones: signaling molecules produced by nerve cells that travel through bloodstream to influence organs throughout the body.
• Subdivided into posterior and anterior regions (excerpt only covers posterior in detail).

🧠 Posterior pituitary gland (neurohypophysis)

• Does not synthesize neurohormones; axonal projections from hypothalamus run through it.
• Hormones secreted into hypophyseal portal system (leaky capillaries) → diffuse into bloodstream.
• Two main hormones:

Hormone	Function	Role in emotion/behavior
Oxytocin (OT)	Prosocial behaviors (trust, compassion, empathy)	Increases in new couples, released during orgasm (romantic attachment), triggers milk letdown (mother-child bond); promotes antisocial behaviors against out-groups
Vasopressin (AVP/ADH)	Social behaviors, osmolarity regulation, blood vessel constriction	Contributes to social behaviors; regulates water retention and blood pressure

• OT disorders: believed to contribute to autism spectrum disorder and psychopathy (social impairment).
• OT therapy: nasal OT studied for psychiatric conditions, but no strong clinical effects despite success in animal models.
• Don't confuse: OT and AVP are biochemically similar (nine amino acid peptides, differ by only two residues) but have distinct functions.

🧠 Papez circuit

• Collective term for structures involved in emotional processing: hypothalamus, cingulate gyrus, thalamus, hippocampus, and (later added) amygdala.
• Emotional responding is distributed across many areas, not localized to one structure.
• Papez observed unusual aggression in animals with injury to these structures.

🧬 Affective neuroscience and applications

🧬 What affective neuroscience is

Affective neuroscience: seeks to understand the neural mechanisms that underlie emotion.

• Expanded with functional imaging methods (EEG, fMRI) to measure brain activity during emotion-provoking stimuli.
• Goal: develop biology-supported therapies for disorders like depression (dysregulated sadness), PTSD (dysregulated fear), addiction (dysregulated desire).

🧬 Challenges in defining emotion

• Emotions exist on a spectrum.
• Multiple emotions experienced simultaneously.
• Each emotion perceived uniquely by different people.
• Everyone has slightly different interpretation/understanding of an emotion.
• Emotions can be pleasant (joy), negative (disgust), or mixed (nostalgia); short-lasting (surprise) or persistent (vengefulness).

🧭 Overview

🧠 One-sentence thesis

Psychiatric disorders like schizophrenia arise from complex interactions between genetic vulnerabilities and environmental factors, manifesting through dysregulation of neurotransmitter systems (especially dopamine), abnormal brain development, and disruptions in neural circuits that control cognition, emotion, and behavior.

📌 Key points (3–5)

• What causes these disorders: Neither purely genetic nor purely environmental—both contribute; no condition is 100% penetrant (having affected relatives raises risk but doesn't guarantee onset).
• Diagnosis challenges: Symptoms exist on a spectrum and frequently overlap; the DSM-5 provides criteria but remains imperfect.
• Animal model limitations: Face validity (looks similar), construct validity (same biological origin), and predictive validity (predicts treatment success) are rarely all present; many human symptoms (e.g., delusions) cannot be modeled or measured in animals.
• Common confusion—positive vs. negative symptoms: Positive symptoms are excesses (hallucinations, delusions); negative symptoms are deficits (flat affect, avolition, cognitive impairments).
• Why it matters: Better understanding of disease mechanisms enables development of more effective therapies; current treatments are often incomplete or ineffective.

🧬 Understanding brain disorders

🧬 Genes and environment both matter

Penetrance: the degree to which a particular gene or set of genes will manifest a specific trait or condition.

• None of these psychiatric conditions are dictated exclusively by genetics.
• Having two parents or an identical twin with the condition elevates baseline risk but is not a guarantee.
• Environmental triggers (prenatal drug exposure, childhood adversity, nutritional deficiency) may lead to sudden onset.
• Certain environmental factors may be protective.
• Example: Low socioeconomic status is associated with increased schizophrenia risk, possibly due to prenatal malnutrition or food insecurity.

📋 Diagnosis is complex

• Almost everything in biology exists on a spectrum, including brain disorders.
• Symptoms frequently overlap between different conditions.
• The DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th edition) provides diagnostic criteria compiled by the American Psychiatric Association.
• It's an imperfect set of criteria but represents a starting point for understanding these complicated conditions.

🐁 Animal models have limitations

Three types of validity researchers consider:

Validity type	Definition	Example
Face validity	Animal model looks similar to human condition behaviorally or physically	Rat exposed to predator shows anxiety and avoidance like human PTSD
Construct validity	Model starts with same pathological brain changes as in humans	Genetically modified animal with poly-glutamine repeats mimicking Huntington's disease origin
Predictive validity	Model predicts whether therapy will work in humans	Antidepressant reverses depression in both mouse model and humans

• Humans and non-humans are very different; same disease origin doesn't always produce same symptoms.
• Impossible to create mouse models of some complex human conditions (dissociative identity disorder, dyslexia).
• Even when models exist, they're often imperfect or incomplete, modeling only some deficits.
• Can only study disorders with clearly and easily quantifiable behavioral components.

🧠 Schizophrenia (SZ)

📊 Who gets schizophrenia

• Affects just under 1% of people.
• Affects men slightly more often than women; affects all races.
• Strong association with low socioeconomic status (neonatal nutritional deficiency, food insecurity may be risk factors).
• Other risk factors: prenatal drug exposure, heavy drug use during early adolescence, childhood adversity.
• Diagnosis typically made in late adolescent years through thirties (brain still undergoing maturation).
• After this age, risk decreases significantly; later onset correlates with better health outcomes.
• Don't confuse: People with SZ have neurotypical range of intelligence (e.g., John Nash, Nobel Prize-winning economist, was diagnosed with SZ in 1959).

➕ Positive symptoms (excesses)

👂 Hallucinations

Hallucinations: perceiving something that is not there (as opposed to illusions, which are misinterpretations of things that are there).

• Usually auditory hallucinations; visual hallucinations more rare.
• Voices may be consistent or change over time.
• Nature influenced by culture: cultures with ancestor reverence may hear grandparents' voices; religious cultures may hear deities.

🧠 Delusions

Delusions: untrue beliefs that cannot be changed despite overwhelming evidence.

• Can come and go spontaneously.
• Types include:
  • Paranoid delusion: belief of being spied on (by government, aliens).
  • Persecutory delusion: persistent thought that the world is out to harm them.
  • Delusions of grandeur: tremendously high self-esteem, believing they are royalty or God's reincarnation.

➖ Negative symptoms (deficits)

😐 Expression deficits

• Flat affect: patient does not show or express emotion in situations where you would expect to see them.
• Alogia: decrease in use of language; vague, lacking in content, or repetitive language.

🚫 Motivation and interest deficits

• Anhedonia: loss of sensation of pleasure and inability to expect upcoming pleasure.
• Avolition: decrease in goal-directed activity; may stop seeing friends, cease interest in social gatherings, leading to worsened relationships.

🤸 Motor disturbances

• Basal ganglia and cerebellar structural deficits found in SZ (both involved in motor control).
• Catatonia: holding body in highly unusual position for prolonged period.
• Stereotypy: repetitive, purposeless behaviors (persistent rocking, self-caressing).

🧩 Cognitive deficits

• Shortcomings in episodic memory.
• Difficulty performing attention-related behavioral tasks.

🔬 Causes and mechanisms of schizophrenia

🧪 Dopamine hypothesis

Dopamine hypothesis: abnormal dopamine signaling may be an underlying root cause of SZ.

• In healthy people, dopamine is important for motor control and motivation—both changed in SZ patients.
• One of the earliest theories of SZ.
• Modern genetics studies show polymorphisms in dopamine D2 receptor are risk factors.
• Example: Introducing high doses of amphetamine (increases dopaminergic signaling) induces temporary schizophrenic-like state in animals.

🧠 Atypical cortical neuron network development

• Healthy brain: cortical neurons produce cyclic patterns at 40 Hz (gamma oscillations) from combination of excitatory and inhibitory neurons.
• In SZ: decrease in dendritic spine density on excitatory neurons + simultaneous decrease in GABA-ergic signaling → unpredictable gamma oscillations.

🐭 Animal models used

• Hyperdopaminergic model: High-dose amphetamine produces cognitive deficits but no changes in memory or other negative symptoms.
• NMDA antagonist model: Ketamine or PCP administration; can cause changes in rodent social behaviors.
• Neurodevelopmental models: Pregnant dam exposed to MAM compound or strong immune response causes atypical development and behavioral deficits in offspring.
• Limitation: Many human SZ symptoms (paranoid delusions, auditory hallucinations) impossible to detect and quantify in non-humans.

💊 Treatment of schizophrenia

💊 Dopamine-based therapies

• D2 antagonists decrease hallucinations and delusions in some patients.
• Effectiveness correlates with ability to block D2 receptor.
• Clozapine (atypical antipsychotic, dopamine receptor antagonist) can decrease SZ symptoms.

⚠️ Treatment limitations

• Around one-third of patients discontinue treatment regimen.
• Around one-fifth report adverse side effects: extrapyramidal motor symptoms, sedation, weight gain.

🧲 Emerging therapies

• Transcranial magnetic stimulation: Targeted cortex activation can decrease severity of auditory hallucinations; mild improvements in negative symptoms.
• Smoking observation: ~65% of North Americans with SZ smoke (vs. 25% in general population); may be self-medicating to activate dopamine- or acetylcholine-sensitive networks, or to reverse anhedonia.

🧩 Related brain structures and systems

🧠 Stress and the HPA axis

HPA axis (hypothalamic-pituitary-adrenal axis): series of organs that result in the stress response.

• Hypothalamus releases corticotropin-releasing hormone (CRH).
• CRH triggers anterior pituitary to release adrenocorticotropic hormone (ACTH).
• ACTH travels to adrenal cortices (on kidneys) and triggers cortisol production.
• Cortisol initiates stress response characterized by mild sympathetic nervous system activity.

🧠 Insula and disgust

Insula (insular cortex): the lobe of cortex buried deep within the lateral fissure; contributes to interoception (detecting internal body state).

• Involved in recall of many emotional stimuli, especially those with sensory component.
• Strongly implicated in emotion of disgust.
• Responds to unpleasant smells and social cues related to disgust.
• Atypical insula activity implicated in behavioral disorders: substance use disorders, PTSD, suicide attempts.
• Example: Insensitivity to disgust can lead to squalor-dwelling conditions (hoarding, cognitive decline), heightened health risks from unsanitary conditions.

😨 Fear and the amygdala

• Fear response is quick onset and quick dissipation.
• Triggered by perceived threat regardless of whether genuine (most spiders are harmless).
• Greatly modified by knowledge and experience.
• Likely evolutionarily ancient and protective.
• Patient SM case: Born with Urbach-Wiethe disease causing bilateral amygdala calcification; cannot experience fear but can feel other emotions (humor, disgust, anger); found scary stimuli non-fearful; no PTSD despite traumatic experiences.

🧭 Overview

🧠 One-sentence thesis

The excerpt introduces depressive and bipolar disorders through embedded videos and readings, highlighting that bipolar disorder involves two extreme mood states and that ketamine represents a novel, fast-acting antidepressant targeting glutamate rather than traditional neurotransmitter systems.

📌 Key points (3–5)

• Bipolar disorder definition: characterized by two extremes—elation and depression—splitting life between different realities.
• Ketamine as breakthrough treatment: the first new antidepressant medication in decades, approved in March 2019 by the FDA.
• How ketamine differs: targets the neurotransmitter glutamate instead of traditional systems, works in hours (not weeks), and effects persist for weeks from a single dose.
• Common confusion: ketamine vs. previous antidepressants—older generations targeted different neurotransmitters and took much longer to show effects.

🎭 Understanding bipolar disorder

🎭 What bipolar disorder means

Bipolar: 'two extremes.'

• The disorder affects many millions worldwide.
• Life is split between two different realities:
  • Elation (elevated mood)
  • Depression (low mood)
• The excerpt emphasizes this fundamental duality as the defining feature.
• Example: A person experiences periods of extreme high energy and optimism alternating with periods of profound sadness and hopelessness.

🔍 Root causes and treatment

• The excerpt references that the video describes "root causes and treatments for bipolar disorder."
• Specific mechanisms are not detailed in this excerpt; the content directs to external video resources for full explanation.

💊 Ketamine: A new approach to depression

💊 What makes ketamine novel

• FDA approval: March 2019—the first new antidepressant medication approved in decades.
• This represents a significant breakthrough after a long period without new medication classes.

🧪 How ketamine works differently

Feature	Previous antidepressants	Ketamine
Target neurotransmitter	Not glutamate (traditional systems)	Glutamate
Time to effect	Weeks	Just a few hours
Duration	Requires ongoing dosing	Effects persist for weeks from a single dose

• Key distinction: Unlike previous generations of antidepressants, ketamine targets the neurotransmitter glutamate.
• Don't confuse: Traditional antidepressants work through different neurotransmitter systems and require continuous use over weeks to show benefits; ketamine acts rapidly and maintains effects longer from a single administration.

⚡ Speed and persistence of effects

• Rapid onset: A single dose can work in just a few hours.
• Sustained benefit: The effects persist for weeks after that single dose.
• This combination of speed and duration represents a major advantage over traditional treatments.
• Example: A patient receives one ketamine dose and experiences symptom relief within hours, with improvement lasting several weeks before another dose might be needed.

📚 Additional resources referenced

📚 Readings and videos

The excerpt lists several educational resources:

• Video on what bipolar disorder is (Ted Talks)
• Video on how ketamine treats depression (Brainfacts.org)
• Reading on mood disorders (Noba Project)
• Research article on molecular basis of major depressive disorder (2020)
• Clinical article on diagnosis and management of bipolar disorders (2023)

These are reference materials for deeper study; the excerpt itself does not contain their content.