SCAN 05 / 17
A T2-weighted analog. fMRI BOLD signals in vivo correlate ~hemodynamic delay 4–6 s after neural activity.
~86,000,000,000 neurons. ~10¹⁵ synapses. The 1.4-kg organ that thinks about itself, often poorly.
Santiago Ramón y Cajal, 1888: the brain is built of discrete cells, not a continuous net. Camillo Golgi's silver stain made them visible; Cajal interpreted them. Shared 1906 Nobel.
A typical neuron: dendrites receive signals; the cell body integrates them; the axon transmits an action potential to the terminals; synaptic vesicles release neurotransmitters across the cleft.
Voltage-gated Na⁺ channels open at threshold (~−55 mV). Sodium rushes in; the membrane depolarizes to ~+30 mV in < 1 ms. Na⁺ channels inactivate; K⁺ channels open; potassium leaks out; the membrane repolarizes.
Hodgkin and Huxley quantified all of this in squid giant axons in 1952 — Nobel 1963. Their equations:
still teach computational neuroscience today.
At the chemical synapse — most synapses in the human brain — depolarization of the presynaptic terminal opens voltage-gated Ca²⁺ channels; Ca²⁺ triggers vesicle fusion via SNARE proteins; neurotransmitter diffuses ~20 nm across the cleft; postsynaptic receptors open ion channels.
Excitatory: glutamate (~80 % of cortical synapses), AMPA & NMDA receptors. Inhibitory: GABA, GABAA (Cl⁻) and GABAB (G-protein) receptors. Modulatory: dopamine, serotonin, acetylcholine, noradrenaline.
A T2-weighted analog. fMRI BOLD signals in vivo correlate ~hemodynamic delay 4–6 s after neural activity.
Donald Hebb, 1949: synaptic strength changes with correlated pre- and post-synaptic activity. Cellularly demonstrated by Bliss & Lømo in 1973: long-term potentiation (LTP) of dentate gyrus synapses by tetanic stimulation, lasting hours, days, weeks.
The molecular machinery: NMDA receptors as coincidence detectors (require both glutamate AND postsynaptic depolarization to relieve Mg²⁺ block); Ca²⁺ entry triggers AMPA receptor insertion via CaMKII; with sustained activity, gene expression and morphological growth (spine enlargement, new spines).
Inverse: long-term depression (LTD), driven by lower Ca²⁺. Together: bidirectional learning rule, basis of synaptic theories of memory.
Photons → rhodopsin/opsins in rods/cones → bipolar/ganglion cells → optic nerve → LGN → V1 retinotopy.
Pressure waves → cochlear hair cells → tonotopic organ of Corti → auditory nerve → A1.
Mechanoreceptors (Merkel, Meissner, Pacinian, Ruffini), thermoreceptors, nociceptors → dorsal columns → S1 homunculus.
~400 olfactory receptor genes, combinatorial code; 5+ taste qualities (sweet, salty, sour, bitter, umami) via TRPM/T1R/T2R.
1852–1934. Neuron doctrine; exquisite drawings.
1857–1952. Synapse coined; reflexes.
1952. Action potential mathematized.
1959–. Visual cortex orientation columns.
Henry Molaison. Bilateral hippocampectomy revealed memory systems.
Place cells, grid cells. Nobel 2014.
Aplysia LTP; molecular memory. Nobel 2000.
Optogenetics, CLARITY tissue clearing.
Galvani: frog legs twitch on metal — animal electricity.
Phineas Gage's iron rod; frontal lobe and personality.
Broca's patient "Tan"; speech in left frontal cortex.
Cajal & Golgi work out neuronal architecture.
Hans Berger records the first human EEG.
Hodgkin–Huxley equations.
Patient HM's bilateral medial-temporal lobectomy maps memory.
LTP discovered.
fMRI BOLD signal — Kwong, Ogawa.
Optogenetics: Boyden, Deisseroth express channelrhodopsin in neurons.
BRAIN Initiative (US), Human Brain Project (EU).
Janelia/Google MICrONS: ~1 mm³ of mouse cortex synapse-resolved (~ 10⁸ synapses).
Equilibrium potential for an ion across a membrane. K⁺: ~−90 mV; Na⁺: +60 mV.
Resting potential weighted by ion permeabilities.
Wilfred Rall, 1959. Passive signal spread along dendrites.
Main excitatory NT. AMPA fast, NMDA slow + Ca²⁺. Excitotoxicity in stroke.
Main inhibitory NT. Benzodiazepines, alcohol, anesthetics potentiate GABAA.
Reward prediction error; movement (Parkinson's). VTA, substantia nigra.
Mood, sleep, gut. SSRIs target reuptake. Raphe nuclei.
Neuromuscular junction; cortical attention/arousal. Lost in Alzheimer's.
Locus coeruleus. Arousal, fight-or-flight, attention.
Anandamide, 2-AG. Retrograde messengers; CB1, CB2 receptors.
Oxytocin, vasopressin, opioids, substance P. Slower, longer-lasting.
"If our brains were simple enough for us to understand, we would be too simple to understand them."
David Chalmers (1995) distinguished the "easy" problems of consciousness — explaining attention, integration, reportability — from the "hard" problem: why is there subjective experience at all? Why does any of this feel like anything?
Several theories compete:
In 2023, an "adversarial collaboration" between IIT and GNW returned mixed verdicts. The hard problem itself remains unresolved.
Aβ plaques, tau tangles. ~55 M cases globally. Lecanemab/donanemab (2023–24) modestly slow progression.
Substantia nigra dopamine loss; α-synuclein aggregates. L-DOPA, deep brain stimulation.
~280 M cases. SSRIs & SNRIs first-line; ketamine/esketamine for treatment-resistant.
~24 M cases. Dopamine D2 hyperactivity (mesolimbic) and hypoactivity (prefrontal); glutamate/NMDA hypofunction theories.
2nd cause of death globally. Ischemic vs hemorrhagic. tPA < 4.5 h, thrombectomy < 24 h.
Hypersynchronous discharges. ~50 M cases. Antiepileptic drugs, vagus nerve stim, resective surgery.
Neuralink, Synchron, BrainGate. Speech decoding from cortical electrodes; human trials underway.
Drosophila full-brain (FlyWire, 140k neurons, 50M synapses, 2024). Mouse cubic mm done; primate scaling.
Cerebral organoids; assembloids; neural-network-grown wetware. Ethical questions accumulating.
Psilocybin, MDMA, ketamine, LSD: serotonergic 5-HT2A modulation; clinical phase III for PTSD, depression.
Brain's waste-clearance pathway, mostly during sleep. Cerebrospinal fluid flow along perivascular spaces.
GLP-1 agonists, senolytics, intermittent fasting. Cognitive reserve. Klotho protein.
Plus Robert Sapolsky's Stanford behavioural biology course and "2-Minute Neuroscience" by Neuroscientifically Challenged.