Intro Neuroscience I — Study Guide

U1 · Neuroscience perspective + brain anatomy

Levels of analysis

Molecular → cellular → systems → behavioral → cognitive. Each level constrains the others.

Central nervous system (CNS)

Brain + spinal cord. Encased in bone (cranium + vertebral column), bathed in CSF.

Peripheral nervous system (PNS)

Cranial + spinal nerves + autonomic ganglia outside CNS.

Major brain divisions

Telencephalon (cerebrum, basal ganglia) · diencephalon (thalamus, hypothalamus) · mesencephalon (midbrain) · metencephalon (pons, cerebellum) · myelencephalon (medulla).

Cerebral cortex lobes

Frontal (motor + executive), parietal (somatosensation, spatial), temporal (auditory + memory + face), occipital (visual). Insula, cingulate sit deeper.

Anatomical planes

Sagittal (left-right), coronal/frontal (front-back), horizontal/axial (top-bottom). Rostral=anterior, caudal=posterior.

Gray vs white matter

Gray = cell bodies + dendrites + synapses. White = myelinated axon tracts.

Ventricles

Lateral (×2) → third → cerebral aqueduct → fourth → central canal. Choroid plexus produces CSF.

U2 · Neurons + glia

Neuron doctrine

Cajal: nervous system = discrete cells communicating across gaps (synapses). Defeated Golgi's reticular theory.

Soma

Cell body containing nucleus + organelles. Site of protein synthesis (Nissl bodies = stacks of rough ER).

Dendrite

Branched input region; receives synapses; spines on excitatory contacts.

Axon

Output process. Single per neuron. Initiates action potential at axon hillock; conducts to terminals.

Axon hillock / initial segment

High density of voltage-gated Na⁺ channels — site of AP initiation.

Neuron classifications

By shape: unipolar, bipolar, multipolar. By function: sensory (afferent), motor (efferent), interneuron.

Astrocyte

Star-shaped glia. K⁺ buffering, glutamate uptake (EAAT), tripartite synapse, BBB end-feet, lactate shuttle to neurons.

Oligodendrocyte

CNS myelinator; one cell wraps multiple axons.

Schwann cell

PNS myelinator; one cell wraps one axon segment.

Microglia [Chivero focus]

CNS-resident immune cells. Phagocytose debris + dead cells; respond to injury + infection. Activated states: M1 pro-inflammatory vs M2 anti-inflammatory. Drive neuroinflammation in HIV, methamphetamine, neurodegeneration.

Ependymal cells

Ciliated cells lining ventricles + central canal. Choroid plexus produces CSF.

Blood-brain barrier (BBB)

Tight junctions between brain capillary endothelial cells (claudin-5, occludin, ZO-1) + astrocyte end-feet + pericytes. Excludes most polar/large molecules.

U3 · Membrane potential

Ion gradients (typical mammalian neuron)

Inside: high K⁺ (~140 mM), low Na⁺ (~10 mM), low Cl⁻ (~10 mM), low Ca²⁺ (~100 nM). Outside: opposite.

Resting membrane potential

~−65 mV (range −60 to −80 mV in different neurons). Set primarily by K⁺ permeability through leak channels.

Nernst equation

E_ion = (RT/zF) ln([out]/[in]). At 37°C: E_K ~ −85 mV, E_Na ~ +60 mV, E_Cl ~ −65 mV, E_Ca ~ +120 mV.

Goldman-Hodgkin-Katz equation

V_m = (RT/F) ln[(P_K[K]_o + P_Na[Na]_o + P_Cl[Cl]_i) / (P_K[K]_i + P_Na[Na]_i + P_Cl[Cl]_o)]. Weighted by permeabilities.

Why is V_m close to E_K?

Resting membrane is most permeable to K⁺ (open leak K⁺ channels). V_m drifts toward whichever ion has the highest permeability.

Na⁺/K⁺-ATPase

Maintains gradients: 3 Na⁺ out + 2 K⁺ in per ATP. Electrogenic — contributes ~−5 to −10 mV directly.

Equilibrium vs steady state

At E_ion, no net flux for that ion (reversal potential). Resting V_m is steady state — pumps balance leakage.

U4 · Action potential

Action potential definition

All-or-none rapid depolarization (~100 mV swing) lasting ~1-2 ms; propagates without decrement along axon.

Threshold

~−55 mV. Voltage-gated Na⁺ channel opening exceeds K⁺ leak → positive feedback → AP.

Voltage-gated Na⁺ channel

Three states: closed (resting), open (activated), inactivated (ball-and-chain). Inactivation explains absolute refractory period.

Voltage-gated K⁺ channel

Slower activation (delayed rectifier). Repolarizes membrane → afterhyperpolarization. No fast inactivation.

Phases of AP

(1) Rising: Na⁺ in. (2) Overshoot: peaks ~+30 to +40 mV. (3) Falling: Na⁺ inactivates, K⁺ out. (4) Undershoot/AHP: V_m below rest until K⁺ closes.

Absolute refractory period

~1 ms; Na⁺ channels inactivated, no AP possible regardless of stimulus.

Relative refractory period

~2-4 ms; some Na⁺ channels still inactivated + AHP — stronger stimulus required.

Saltatory conduction

AP "jumps" between nodes of Ranvier in myelinated axons. ~10-50× faster than unmyelinated of same diameter.

Conduction velocity factors

↑ axon diameter → ↑ velocity (less internal resistance). Myelin → much faster (saltatory).

Tetrodotoxin (TTX)

Pufferfish toxin; blocks voltage-gated Na⁺ channels → no AP. Classic experimental tool.

U5 · Synaptic transmission

Electrical synapse

Gap junction (connexons) between cells. Bidirectional, fast, no delay. Coupling for synchronized firing.

Chemical synapse — sequence

(1) AP arrives at terminal. (2) Voltage-gated Ca²⁺ channels open. (3) Ca²⁺ triggers vesicle fusion via SNAREs + synaptotagmin. (4) NT released into cleft. (5) Binds postsynaptic receptors. (6) Termination by reuptake/enzyme/diffusion.

Vesicle fusion proteins

v-SNARE synaptobrevin (VAMP) + t-SNAREs syntaxin + SNAP-25 form 4-helix bundle. Ca²⁺ sensor: synaptotagmin.

EPSP

Excitatory postsynaptic potential — depolarizing (e.g., glutamate → cation influx through AMPA/NMDA).

IPSP

Inhibitory postsynaptic potential — hyperpolarizing (e.g., GABA → Cl⁻ influx through GABA_A; or K⁺ efflux through GABA_B-coupled GIRK).

Spatial vs temporal summation

Spatial: multiple synapses simultaneously. Temporal: rapid trains from one synapse. Both bring the soma toward AP threshold.

Ionotropic vs metabotropic receptor

Ionotropic = ligand-gated ion channel (fast, ms). Metabotropic = GPCR → 2nd messenger (slow, seconds, modulatory).

Long-term potentiation (LTP)

Sustained increase in synaptic strength. Classic NMDA-dependent LTP in hippocampal CA1: Ca²⁺ through NMDA → CaMKII → AMPA insertion. Cellular basis of memory.

Long-term depression (LTD)

Sustained decrease in synaptic strength. Modest Ca²⁺ rise → phosphatases → AMPA internalization.

U6 · Neurotransmitters

Glutamate

Major excitatory NT in CNS. Receptors: AMPA (fast Na⁺/K⁺), NMDA (Ca²⁺, Mg²⁺ block, voltage-dependent), kainate, mGluRs.

GABA

Major inhibitory NT in CNS. Synthesized from glutamate by GAD. Receptors: GABA_A (Cl⁻ ionotropic), GABA_B (GPCR → K⁺ open + Ca²⁺ close).

Glycine

Inhibitory in spinal cord + brainstem. Cl⁻ channel. Strychnine antagonist.

Acetylcholine (ACh)

NMJ + autonomic + brain (cholinergic basal forebrain). Receptors: nicotinic (ionotropic, Na⁺/K⁺) + muscarinic (GPCR).

Dopamine (DA)

Motivation, reward, motor (substantia nigra → striatum). 5 receptor subtypes (D1-D5), all GPCRs. Implicated in Parkinson, addiction, schizophrenia.

Norepinephrine (NE)

Arousal, attention, autonomic. Locus coeruleus (CNS). α + β adrenergic receptors (GPCRs).

Serotonin (5-HT)

Mood, sleep, appetite. Raphe nuclei. ~14 receptor subtypes (mostly GPCR; 5-HT3 ionotropic).

Histamine

Wakefulness. Tuberomammillary nucleus. H1-H4 receptors.

Endocannabinoids

Retrograde messengers (anandamide, 2-AG). Activate presynaptic CB1 → reduce NT release.

Nitric oxide (NO)

Gas messenger, diffuses freely. Made by nNOS; activates soluble guanylyl cyclase → cGMP.

Neuropeptides

Larger NT (e.g., substance P, enkephalin, oxytocin, neuropeptide Y). Synthesized in soma, transported in dense-core vesicles, GPCR signaling.

U7 · Sensory + Somatosensory system

Sensory transduction

Conversion of stimulus energy into electrical signals (receptor potential).

Receptor classes

Mechanoreceptors (touch, hearing), thermoreceptors, photoreceptors, chemoreceptors, nociceptors (pain).

Receptive field

Region of stimulus space (skin area, retinal location) that affects a sensory neuron's firing.

Adaptation

Slowly adapting (SA) receptors fire continuously to maintained stimulus; rapidly adapting (RA) fire on changes.

Touch receptors of glabrous skin

Meissner (RA, fluttering touch) · Pacinian (RA, vibration deep) · Merkel (SA, pressure + form) · Ruffini (SA, skin stretch).

Dorsal column–medial lemniscus pathway

Fine touch, vibration, proprioception. 1st neuron → ipsilateral dorsal columns → gracile/cuneate nucleus (medulla) → DECUSSATES → medial lemniscus → VPL thalamus → S1 cortex.

Spinothalamic (anterolateral) pathway

Pain, temperature, crude touch. 1st neuron synapses in dorsal horn → DECUSSATES at spinal level → ascends contralaterally → VPL thalamus → S1.

Sensory homunculus

Distorted body map in S1 with overrepresentation of hands + face. Penfield's stimulation studies.

U8 · Pain & nociception

Aδ fibers

Thinly myelinated, fast (5-30 m/s); sharp, well-localized "first" pain.

C fibers

Unmyelinated, slow (0.5-2 m/s); dull, throbbing "second" pain; longer-lasting.

TRPV1

Capsaicin + heat (>43°C) receptor on nociceptors. Cation channel.

Gate control theory (Melzack-Wall)

Aβ touch fibers activate dorsal horn inhibitory interneurons → "gate" partially closes pain transmission. Why rubbing reduces pain.

Periaqueductal gray (PAG)

Midbrain center for descending pain modulation; activates raphe + locus coeruleus → spinal inhibition. Endogenous opioid system.

Endogenous opioids

Endorphins, enkephalins, dynorphins. Bind μ, δ, κ opioid receptors → presynaptic + postsynaptic inhibition of pain pathway.

Hyperalgesia vs allodynia

Hyperalgesia = exaggerated pain to noxious stimulus. Allodynia = pain from normally non-painful stimulus (light touch).

U9 · Vision

Eye optics

Cornea (~⅔ refraction) + lens (variable). Pupil = aperture; iris controls. Retina at back has receptors.

Photoreceptors

Rods (high sensitivity, low resolution, peripheral, scotopic) · cones (low sens, high res, central, photopic, color). 3 cone types (S/M/L; "blue/green/red").

Phototransduction

Dark: cGMP holds CNG channel open → Na⁺/Ca²⁺ in → photoreceptor depolarized → glutamate released. Light: rhodopsin → transducin → PDE → ↓ cGMP → channel closes → hyperpolarization → ↓ glutamate.

Retinal cell layers

Photoreceptor → bipolar → ganglion (output). Horizontal + amacrine = lateral interactions. Light enters from ganglion side.

Center-surround receptive field

ON-center: light in center excites, surround inhibits. OFF-center: opposite. Computed by horizontal cell lateral inhibition.

Retinal ganglion cell axons

Optic nerve → optic chiasm (decussation of nasal fibers) → optic tract → LGN of thalamus → V1 (primary visual cortex).

Magnocellular vs parvocellular

M: large, fast, motion + low contrast. P: small, slow, color + form, high acuity. Parallel processing.

Dorsal vs ventral stream

Dorsal "where/how" = parietal, motion + spatial. Ventral "what" = temporal, object + face recognition.

U10 · Audition + vestibular

Outer ear

Pinna, ear canal → tympanic membrane (eardrum).

Middle ear

Ossicles malleus → incus → stapes (oval window). Impedance matching air → fluid (×22 amplification).

Cochlea

Spiral fluid-filled tube (3 chambers: scala vestibuli, scala media, scala tympani). Basilar membrane runs length.

Organ of Corti

On basilar membrane. Inner hair cells (sensory; ~3,500) + outer hair cells (motile, amplify; ~12,000). Tectorial membrane on top.

Tonotopic organization

Base of cochlea = high frequency; apex = low frequency. Maintained through auditory pathway up to A1 cortex.

Mechanotransduction

Stereocilia bending → tip-link tension → mechanically gated cation channel opens → K⁺ + Ca²⁺ in → depolarize hair cell → glutamate to spiral ganglion neurons.

Auditory pathway

Hair cell → spiral ganglion → cochlear nucleus → superior olive (sound localization) → inferior colliculus → MGN of thalamus → A1 (Heschl's gyrus).

Sound localization

Interaural time difference (ITD; low freq, medial superior olive) + interaural level difference (ILD; high freq, lateral superior olive).

Vestibular system

Semicircular canals (3, angular acceleration via cupula + ampulla) + otolith organs (utricle + saccule, linear accel + gravity via otoconia on macula). Hair cells transduce.

U11 · Chemical senses

Olfactory receptor neurons

Bipolar neurons in nasal epithelium. Cilia have GPCR olfactory receptors → G_olf → AC → cAMP → CNG channel → depolarization.

OR gene family

~400 functional ORs in humans (largest gene family). Each ORN expresses one OR.

Olfactory glomerulus

All ORNs expressing the same OR converge on ~2 glomeruli in olfactory bulb. Mitral cells → piriform cortex (no thalamus relay!).

5 taste modalities

Sweet, salty, sour, bitter, umami. Sweet/bitter/umami via GPCRs (T1R, T2R) → α-gustducin. Salty + sour via ion channels (ENaC, TRP).

Taste pathway

Taste bud → CN VII (anterior 2/3 tongue), IX (posterior 1/3), X (epiglottis) → solitary nucleus (medulla) → VPM thalamus → gustatory cortex (insula).

U12 · Motor systems intro

Lower motor neuron (LMN)

Final common pathway: cell body in ventral horn or brainstem motor nuclei → axon → muscle. Lesion → flaccid paralysis, atrophy, fasciculations.

Upper motor neuron (UMN)

Originates in motor cortex; descends via corticospinal tract; synapses on LMN. Lesion → spastic paralysis, hyperreflexia, Babinski sign.

Motor unit

One LMN + all muscle fibers it innervates. Size principle: smaller units recruited first.

Stretch reflex (myotatic)

Muscle spindle (Ia afferent) → monosynaptic excitation of homonymous motor neuron + reciprocal inhibition of antagonist via Ia interneuron. Knee jerk.

Golgi tendon organ reflex

Ib afferent senses tension → inhibits its own motor neuron. Protects against overload.

Withdrawal reflex

Polysynaptic; flexor activation + crossed extension contralateral.

Corticospinal tract

M1 → internal capsule → cerebral peduncle → medulla pyramids → DECUSSATES → lateral corticospinal tract → ventral horn LMN. Lateral = limbs; ventral = trunk.

Basal ganglia

Caudate, putamen, globus pallidus, subthalamic, substantia nigra. Direct (D1, GO) + indirect (D2, NO-GO) pathways. Parkinson = SNc dopamine loss; Huntington = caudate degeneration.

Cerebellum

Coordination, balance, motor learning. Three peduncles. Purkinje cell GABAergic output to deep cerebellar nuclei. Lesions → ataxia, dysmetria.

U13 · Glia & neuroinflammation — Chivero focus

Microglia origin

Yolk-sac-derived; resident macrophages of CNS. Distinct from infiltrating monocytes.

Microglial activation states

"M1" pro-inflammatory (TNFα, IL-1β, ROS) vs "M2" anti-inflammatory/restorative (IL-10, TGF-β). Spectrum, not binary.

NLRP3 inflammasome

Cytosolic multiprotein complex. Two-signal activation: priming (TLR → NF-κB → upregulates components) + activation (DAMPs/PAMPs → assembly). Recruits ASC + procaspase-1 → cleaves IL-1β + IL-18 + gasdermin D → pyroptosis. Chivero's research target.

HIV-Tat in neuroinflammation

HIV-1 Trans-activator of transcription crosses BBB; activates microglia; primes NLRP3; contributes to HAND (HIV-associated neurocognitive disorder) even on suppressive ART. Chivero's research.

Methamphetamine + microglia

Meth crosses BBB, activates microglia + induces oxidative stress + NLRP3 priming. Synergistic with HIV in dual-exposed individuals. Chivero's research.

Astrocyte tripartite synapse

Astrocyte processes ensheath synapses; take up glutamate (EAAT1/2), release gliotransmitters (glutamate, ATP, D-serine). Buffer K⁺.

Reactive astrocytosis

Astrocytes upregulate GFAP, hypertrophy, form glial scar after injury. A1 (neurotoxic) vs A2 (neuroprotective) phenotypes.

Microglial pruning

Complement-tagged synapses (C1q, C3) phagocytosed by microglia during development + aging + Alzheimer.

Neurodegeneration + microglia

Alzheimer (TREM2, complement), Parkinson (α-syn-activated), ALS, MS — chronic microglial activation contributes to pathology.

U14 · Pharmacology & drugs of abuse

Agonist vs antagonist

Agonist binds + activates receptor. Antagonist binds + blocks. Inverse agonist reduces constitutive activity.

Allosteric modulator

Binds non-orthosteric site → potentiates (PAM) or inhibits (NAM) agonist effect. Benzodiazepines = PAM at GABA_A.

Mesolimbic dopamine pathway

VTA → nucleus accumbens (NAc) + PFC. Final common reward circuit; activated by virtually all addictive drugs.

Cocaine

Blocks DAT, NET, SERT → ↑ synaptic monoamines. Strong reinforcer via NAc DA.

Amphetamine + methamphetamine

Reverses DAT (efflux), enters vesicles displacing DA. Massive ↑ extracellular DA. Neurotoxic at high doses (oxidative stress, microglia).

Opioids

μ receptor agonists → presynaptic Ca²⁺ ↓ + postsynaptic K⁺ ↑ → inhibition. Analgesia + euphoria + respiratory depression.

Alcohol

Enhances GABA_A + inhibits NMDA → sedation. Chronic → withdrawal hyperexcitability + addiction.

Nicotine

Nicotinic ACh receptor agonist; α4β2 on VTA DA neurons → NAc reward.

Cannabis (THC)

CB1 agonist; presynaptic; reduces NT release. Affects memory (hippocampus), motor (basal ganglia), reward.

Tolerance

Reduced response after repeated exposure. Pharmacodynamic (receptor downregulation) + pharmacokinetic (faster metabolism).

Sensitization

Increased response with repeated exposure (especially psychomotor stimulants).

Addiction circuits

VTA → NAc + amygdala + PFC; loss of top-down PFC control + amygdala stress dysregulation. Chivero's lab studies SUD-microglia interactions.

U15 · Methods + integration

EEG

Scalp electrodes record summed dendritic potentials. Excellent temporal (ms), poor spatial. Frequency bands: δ, θ, α, β, γ.

fMRI

BOLD signal — blood oxygenation. Good spatial (~mm), poor temporal (~seconds). Indirect measure of activity.

Patch clamp

Glass pipette suction onto cell membrane → record currents from individual ion channels (single-channel) or whole cell.

Intracellular vs extracellular recording

Intra: pipette inside cell; measures V_m + APs + synaptic potentials. Extra: outside; only spikes resolved.

Optogenetics

Express channelrhodopsin (ChR2, Na⁺ in, excitation) or halorhodopsin (Cl⁻ in, inhibition) → light-triggered control of neurons in vivo.

Chemogenetics (DREADDs)

Designer GPCRs (hM3Dq, hM4Di) activated by clozapine-N-oxide → minute-scale modulation.

Calcium imaging

GCaMP fluoresces with Ca²⁺. Bulk or single-cell readout of activity over time.

Lesion studies

Loss of function via surgical, chemical, or pharmacological ablation → infer normal role.