The Human Brain: Interactive Reference Guide

86B

Neurons in the Human Brain

100T+

Synaptic Connections

600 m²

Blood-Brain Barrier Surface Area

How to Use This Guide

Navigate between sections using the tabs above. Each section contains expandable cards with detailed peer-reviewed research. Click any card header marked with + to expand it. Citations link to original papers. This guide covers four major domains:

Brain Anatomy

Major regions, structures, functions, damage effects, and neural communication

Sleep Science

Sleep stages, circadian rhythms, memory consolidation, glymphatic clearance

Dementia

Alzheimer's, vascular, Lewy body, FTD, biomarkers, treatments

Neuroplasticity

LTP/LTD, BDNF, neurogenesis, enhancing and impairing factors

Interactive Brain Map

Click a region to learn about it. Colors indicate functional groups.

Frontal Lobe

Functions: Executive function, planning, decision-making, motor control, speech production (Broca's area), personality, working memory, impulse control.

Key structures: Primary motor cortex, prefrontal cortex (DLPFC), Broca's area, anterior cingulate cortex. Comprises ~30% of the cerebral cortex.

Neurotransmitters: Dopamine GABA Glutamate Acetylcholine

Damage effects: Impaired executive function, personality changes, loss of impulse control, motor impairment, apraxia, abulia.

Parietal Lobe

Functions: Sensory integration (touch, temperature, pain), spatial awareness, navigation, proprioception, visual-spatial processing, selective attention.

Key structures: Primary somatosensory cortex (S1), posterior parietal cortex, precuneus, superior and inferior parietal lobules.

Neurotransmitters: Glutamate GABA Acetylcholine

Damage effects: Contralateral sensory loss, neglect syndrome, spatial disorientation, agraphesthesia, astereognosis.

Temporal Lobe

Functions: Auditory processing, language comprehension (Wernicke's area), memory formation, face/object recognition, emotional memory.

Key structures: Primary auditory cortex (Heschl's gyrus), Wernicke's area, hippocampus, amygdala, fusiform face area.

Neurotransmitters: Glutamate GABA Acetylcholine Serotonin

Damage effects: Wernicke's aphasia, auditory agnosia, memory impairment, prosopagnosia (face blindness), temporal lobe seizures.

Occipital Lobe

Functions: All visual processing — color perception, motion detection, depth perception, pattern recognition.

Key structures: Primary visual cortex (V1), V2 (form), V4 (color), V5/MT (motion). Organized retinotopically across six cortical layers.

Neurotransmitters: Glutamate GABA Acetylcholine

Damage effects: Homonymous hemianopia, cortical blindness (bilateral), visual agnosia, achromatopsia (V4), akinetopsia (V5), Anton syndrome.

Cerebellum

Functions: Motor coordination, balance, movement timing, motor learning, and increasingly recognized cognitive roles: working memory, language, visuospatial processing, emotional regulation.

Key structures: Purkinje cells, granule cells, deep cerebellar nuclei (dentate, interposed, fastigial), vermis, hemispheres, crus I/II.

Neurotransmitters: GABA Glutamate Dopamine

Damage effects: Cerebellar ataxia, intention tremor, dysmetria, nystagmus, dysarthria, cognitive and emotional impairment.

Frontiers: The cerebellum and cognitive neural networks (2023)

Brainstem

Three divisions:

Midbrain: Visual/auditory reflexes (superior/inferior colliculi), dopamine production (substantia nigra, VTA), eye movement, pain modulation.

Pons: Bridge between cerebrum and cerebellum, REM sleep generation, houses locus coeruleus (norepinephrine) and raphe nuclei (serotonin).

Medulla: Breathing, heart rate, blood pressure, swallowing, protective reflexes. Damage can be fatal.

Key neurotransmitters: Dopamine Norepinephrine Serotonin Acetylcholine

Limbic System

Hippocampus: Memory formation, spatial navigation, pattern separation/completion. First region affected in Alzheimer's. Supports adult neurogenesis in dentate gyrus.

Amygdala: Emotional processing (especially fear), threat detection, emotional memory. Different subregions process different emotions. Right amygdala: sensory-mediated fear; left: cognitive-mediated fear.

Thalamus: Sensory relay station (all senses except smell), attention modulation, sleep-wake regulation. Reticular nucleus acts as gatekeeper.

Hypothalamus: Homeostasis (temperature, appetite, thirst), hormone control via pituitary, circadian rhythm (SCN), sleep-wake, stress response, autonomic regulation.

Specialization of amygdala subregions (2024) • Hippocampus and Alzheimer's (PMC)

Blood-Brain Barrier (BBB)

A highly selective semi-permeable membrane between blood and brain tissue, with ~600 m² surface area. Composed of tightly-joined endothelial cells, pericytes, and astrocyte end-feet.

What Can Pass

Can Pass Freely	Requires Active Transport	Cannot Pass
O&sub2;, CO&sub2;, some hormones Fat-soluble molecules <400 Da	Glucose (GLUT1), amino acids, nucleotides, ions	Most drugs, large proteins, water-soluble molecules, pathogens

Four-Part Barrier System

Physical barrier: Tight junctions (Claudin-5, Occludin) prevent paracellular diffusion
Active transport: Carriers move essential nutrients into brain
Efflux transport: Pumps remove hydrophobic molecules and drugs
Cell migration regulation: Controls immune cell passage

BBB Breakdown Causes

Infection, stroke, TBI, seizures, hypertension, diabetes, aging, and neurodegeneration (Alzheimer's, Parkinson's) can compromise the BBB.

Nature: BBB structure, regulation & drug delivery (2023)

Brain Regions & Structures

Cerebral Cortex: The Four Lobes

Region	Primary Function	Key Neurotransmitters	Damage Effects
Frontal Lobe	Executive function, motor control, speech, personality	Dopamine GABA	Impaired judgment, personality changes, motor deficits
Parietal Lobe	Sensory integration, spatial awareness, proprioception	Glutamate GABA	Sensory loss, neglect syndrome, spatial disorientation
Temporal Lobe	Auditory processing, language, memory, face recognition	Glutamate Serotonin	Wernicke's aphasia, amnesia, prosopagnosia
Occipital Lobe	All visual processing	Glutamate GABA	Visual field deficits, cortical blindness, agnosia

Basal Ganglia

Deep brain nuclei critical for motor control, decision-making, habit formation, and reward processing.

Key Structures

Striatum: Caudate (cognition), Putamen (motor), Nucleus accumbens (reward)
Globus Pallidus: External (GPe) and Internal (GPi) segments
Substantia Nigra: Pars compacta (dopamine) and Pars reticulata (output)
Subthalamic Nucleus: Excitatory input to GPi

Motor Pathways

Direct Pathway (facilitates movement)

Cortex→ Striatum→ GPi/SNr→ Thalamus→ Cortex

Indirect Pathway (inhibits movement)

Cortex→ Striatum→ GPe→ STN→ GPi/SNr→ Thalamus

Clinical Relevance

Parkinson's disease: Loss of 80%+ dopamine neurons in substantia nigra causes tremor, rigidity, bradykinesia. Huntington's: Striatal neuron degeneration causes involuntary movements and cognitive decline.

PLOS Biology: Basal ganglia computational roles (2024)

Corpus Callosum

The brain's largest white matter structure: 200+ million axons connecting left and right hemispheres.

Regions

Rostrum: Connects prefrontal regions
Genu: Connects prefrontal and anterior regions
Body: Connects frontal, parietal, temporal lobes
Splenium: Connects occipital and temporal lobes

Split-Brain Effects

When severed (callosotomy), each hemisphere operates independently: intermanual conflict, left-hand agraphia, alien hand syndrome, sensory integration deficits.

PNAS: Corpus callosum in interhemispheric connectivity

Neural Communication: Synaptic Transmission

Action Potential Phases

Resting State (-70 mV)

Na+/K+ ATPase maintains resting potential. Na+ channels closed.

Threshold (-55 mV)

Stimulus depolarizes membrane to threshold. All-or-nothing response triggered.

Depolarization (+30 mV)

Voltage-gated Na+ channels open. Rapid Na+ influx drives membrane positive.

Repolarization

Na+ channels inactivate. Delayed K+ channels open, K+ efflux returns membrane to negative.

Hyperpolarization

Brief undershoot below resting potential before stabilization.

Refractory Period

Absolute (no new AP possible) then relative (higher stimulus needed).

Propagation Speed

Type	Mechanism	Speed
Unmyelinated	Continuous conduction along axon	~0.5 m/s
Myelinated	Saltatory conduction (jumps between Nodes of Ranvier)	~100 m/s

Synaptic Transmission Steps

AP reaches terminal→ Ca²+ influx→ Vesicle fusion→ NT release→ Cross 20-40nm cleft→ Receptor binding→ EPSP or IPSP

Ionotropic receptors: Directly open ion channels (fast). Metabotropic receptors: Activate G-proteins and intracellular cascades (slow but modulatory).

StatPearls: Physiology, Synapse • Cell Comm. & Signaling: Stimulus-response timing (2024)

Major Neurotransmitter Systems

Overview: Excitatory vs Inhibitory Balance

The brain maintains a dynamic balance between excitation (primarily glutamate, ~75% of excitatory transmission) and inhibition (primarily GABA, ~30% of CNS synapses). Disruption of this balance underlies seizures, anxiety, neurodegeneration, and many psychiatric conditions.

Glutamate

75% excitatory

GABA

30% of synapses

Dopamine

Modulatory

Serotonin

Most widespread

Acetylcholine

Sparse, wide

Norepinephrine

Locus coeruleus

Dopamine (DA)

Synthesis: Tyrosine → L-DOPA → Dopamine

Functions: Movement initiation, reward/pleasure, motivation, reinforcement learning, attention, working memory, cognitive flexibility.

Major Pathways

Pathway	From → To	Function
Nigrostriatal	Substantia nigra → Striatum	Movement control
Mesolimbic	VTA → Nucleus accumbens	Reward, motivation
Mesocortical	VTA → Prefrontal cortex	Cognition, emotion
Tuberoinfundibular	Hypothalamus → Pituitary	Hormone regulation

Dysfunction

Low DA Parkinson's, depression, ADHD High DA Schizophrenia (mesolimbic excess)

Serotonin (5-HT)

Synthesis: Tryptophan → 5-HTP → Serotonin

Functions: Mood regulation, sleep-wake cycles, appetite, sexual function, aggression/impulsivity control, pain modulation, anxiety regulation.

Major Pathways

Dorsal raphe: Projects widely to cortex, limbic system, striatum. Median raphe: Projects to hippocampus, prefrontal cortex. Most widespread neurotransmitter system.

Receptor Types

5-HT1 through 5-HT7 families with multiple subtypes at pre- and post-synaptic locations.

Dysfunction

Low 5-HT Depression, anxiety, OCD, suicidality High 5-HT Serotonin syndrome (with SSRIs)

Glutamate (Glu)

Synthesis: Glucose → α-ketoglutarate → Glutamate

Functions: Primary excitatory NT (~75% of excitatory transmission). Learning, memory (via LTP), synaptic plasticity, brain development, cognitive function.

Receptor Types

Receptor	Type	Role
AMPA	Ionotropic	Fast excitatory transmission
NMDA	Ionotropic (voltage-dependent)	Ca²+ permeable, memory formation, LTP
Kainate	Ionotropic	Modulates transmission
mGluR	Metabotropic	Intracellular signaling cascades

Dysfunction

Excess Excitotoxicity, stroke damage, neurodegeneration, ALS Low/hypofunction Cognitive impairment, schizophrenia

GABA

Synthesis: Glutamate → GABA (via glutamate decarboxylase)

Functions: Primary inhibitory NT. Dampens excessive neural activity, anxiety reduction, sleep facilitation, muscle relaxation, seizure prevention.

Receptor Types

GABA-A: Ionotropic, fast (enhanced by benzodiazepines, barbiturates). GABA-B: Metabotropic, slow. GABA-C: Retinal-specific.

Dysfunction

Low GABA Anxiety, seizures, insomnia, tremors Imbalance Associated with autism spectrum disorders

Acetylcholine (ACh)

Synthesis: Acetyl-CoA + Choline → ACh (via choline acetyltransferase)

Functions: Attention, arousal, memory formation/consolidation, REM sleep promotion, motor control (neuromuscular junction), autonomic regulation.

Pathways

Basal forebrain (nucleus basalis): Projects to cortex, hippocampus. Mesopontine tegmentum: Sleep-wake, REM sleep. Sparse but widespread projections.

Dysfunction

Low ACh Alzheimer's disease, age-related cognitive decline. Cholinesterase inhibitors are first-line AD treatment.

StatPearls: Physiology, Acetylcholine

Norepinephrine (NE)

Synthesis: Tyrosine → L-DOPA → Dopamine → Norepinephrine

Functions: Arousal, alertness, attention, stress response, fear/anxiety, mood, energy, pain modulation.

Primary Source

Locus coeruleus (LC): Small pontine nucleus, sole source of brain NE. Projects to cortex, hippocampus, thalamus, amygdala, cerebellum. Critical for sleep-wake gating: high during wake, low NREM, nearly silent during REM.

Dysfunction

Low NE Depression, ADHD, fatigue High NE Anxiety, hypertension

Sleep Science & Circadian Rhythms

Sleep Architecture

Sleep cycles through 4 stages in ~90-minute cycles (4-6 per night). SWS dominates early; REM dominates later.

Stage	Brain Waves	Duration	Key Features
N1 (Light)	Low-voltage mixed frequency (alpha → theta)	1-7 min	Sleep onset, easily awakened
N2 (Intermediate)	Sleep spindles (12-16 Hz) + K-complexes	45-55% of total sleep	True sleep onset, memory consolidation begins
N3 (Deep/SWS)	High-amplitude delta waves (0.5-4.5 Hz)	Predominates early cycles	Restorative, memory consolidation, glymphatic clearance peak
REM	Desynchronized (low-voltage, mixed), theta bursts	20-25% total (lengthens each cycle)	Dreaming, muscle atonia, emotional memory processing

StatPearls: Physiology, Sleep Stages

Two-Process Model of Sleep

Process S (Homeostatic / Sleep Pressure)

Adenosine accumulates in basal forebrain during wakefulness. Binds A1/A2A receptors, suppressing wake-promoting neurons and activating sleep-promoting neurons. Creates sleep pressure proportional to time awake. Dissipates during sleep.

Process C (Circadian)

Generated by suprachiasmatic nucleus (SCN), ~24.5-hour intrinsic period. Light-entrained via retinohypothalamic tract. Promotes wakefulness during day, sleep at night. Opposes adenosine buildup during daytime.

Combined Effect

Daytime: Circadian drive opposes rising adenosine, maintaining wakefulness. Evening: circadian drive wanes + high adenosine = sleep onset. During sleep: adenosine clears, cycles become lighter toward morning.

PMC: Adenosine, caffeine, and sleep-wake regulation

Brain Regions in Sleep Regulation

Region	Role	Primary NT
SCN (hypothalamus)	Central circadian clock (~10,000 neurons/side)	Glutamate (input)
VLPO (preoptic area)	Sleep promotion, inhibits arousal systems	GABA, galanin
Lateral hypothalamus	Wakefulness (orexin neurons)	Orexin/hypocretin
Locus coeruleus	Arousal; silence enables REM	Norepinephrine
Raphe nuclei	Mood/sleep modulation	Serotonin
Pineal gland	Melatonin synthesis (darkness signal)	Melatonin
Reticular activating system	Arousal, sleep-wake transitions	Multiple

LC sleep gating (2024): Infraslow fluctuations in locus coeruleus activity gate the NREM-REM cycle. High LC = prevents REM; low LC = allows NREM→REM transition.

Nature Neurosci: LC fluctuations gate NREM-REM cycle (2024)

Memory Consolidation During Sleep

Systems Consolidation: Hippocampus → Cortex Transfer

During slow-wave sleep, hippocampal neurons replay recently learned activity patterns. This replay occurs during sharp-wave ripples (~150-250 Hz), coordinated with thalamocortical spindles (~12-16 Hz) and cortical slow oscillations (~0.5-3 Hz). This triple coupling gradually transfers memory traces from hippocampus-dependent to distributed cortical storage.

Sleep Stage Contributions

Stage	Memory Type	Mechanism
SWS (N3)	Declarative (facts, events)	Hippocampal replay, ripple-spindle-SO coupling
REM	Procedural (skills) + Emotional	High ACh, theta activity, amygdala-PFC dialogue
N2	Motor memory	Sleep spindle density correlates with consolidation

Synaptic Homeostasis Hypothesis (SHY)

Proposed by Tononi & Cirelli: waking learning strengthens synapses globally, increasing metabolic demands and saturating capacity. During NREM sleep, net synaptic depression (downscaling) occurs, driven by dramatic drops in NE, ACh, 5-HT, histamine, and orexin. This renormalizes synapses while preserving the strongest (most important) connections.

Neuron: Sleep serving systems memory consolidation • PMC: Sleep and the Price of Plasticity

Glymphatic System: Brain Waste Clearance

How It Works

CSF circulates through perivascular channels driven by aquaporin-4 water channels in astrocyte end-feet, flushing interstitial fluid and metabolic waste from the brain.

60%

Interstitial space increase during sleep

SWS

Peak clearance during slow-wave sleep

Aβ + Tau

Key proteins cleared during sleep

Sleep Deprivation Impact

Sleep deprivation impairs CSF-to-blood clearance of amyloid-beta and tau. Chronic poor sleep accelerates accumulation of these neurotoxic proteins, creating a bidirectional relationship: poor sleep → neurodegeneration → worse sleep.

2024-2025 Human Evidence

Biomarker studies confirm sleep-active enhancement of overnight glymphatic clearance in humans. DTI-ALPS imaging reveals reduced glymphatic function in insomnia patients, with dose-response relationship: worse sleep quality = worse clearance.

PMC: Sleep Drives Metabolite Clearance from the Adult Brain • Physiology: Targeting Sleep for Glymphatic Clearance (2024)

Sleep Disorders Neuroscience

Narcolepsy

Type 1: Selective autoimmune loss of 70-90% of orexin-producing neurons in lateral hypothalamus. Genetic vulnerability: HLA-DQB1*0602 allele (90% of cases). Causes excessive daytime sleepiness, cataplexy, sleep paralysis, hypnagogic hallucinations.

Insomnia

Brain imaging reveals distinct patterns: decreased amygdala-insula connectivity, decreased striatum-thalamus connectivity, and increased amygdala-sensorimotor connectivity. Reduced glymphatic clearance indices on DTI-ALPS. Associated with accelerated brain aging.

Obstructive Sleep Apnea (OSA)

Repeated oxygen desaturations cause cumulative brain damage via intermittent hypoxia. REM sleep hypoxia linked to white matter hyperintensities. Entorhinal cortex thinning (early Alzheimer's region). CPAP treatment for 12 months can nearly reverse some white matter damage.

Wiley: Orexin Deficiency in Narcolepsy (2025) • UCI: REM Sleep Apnea and Brain Changes

Dementia & Neurodegeneration

Types of Dementia: Comparison

Type	Key Pathology	Brain Regions	Distinguishing Features
Alzheimer's	Amyloid-beta plaques + tau tangles	Hippocampus first, then parietal/temporal cortex	Progressive memory loss, most common (~60-70%)
Vascular	Cerebrovascular damage, small strokes	White matter, wherever strokes occur	Stepwise decline, executive dysfunction
Lewy Body	α-synuclein aggregates (Lewy bodies)	Neocortex, limbic, brainstem	Visual hallucinations, parkinsonism, REM sleep disorder
Frontotemporal	Tau or TDP-43 aggregates	Frontal and temporal lobes	Personality changes, language deficits, preserved memory early

Alzheimer's Disease: Molecular Mechanisms

Amyloid Cascade (Updated View)

APP is cleaved by beta- and gamma-secretase to produce amyloid-beta peptides that aggregate into plaques. However, only ~1/3 of biomarker-confirmed AD cases comply with amyloid cascade predictions. The hypothesis remains "a working hypothesis, no less but certainly no more" as of 2024.

Tau Pathology

Tau undergoes hyperphosphorylation, misfolds into paired helical filaments, aggregates into neurofibrillary tangles. Tau correlates more strongly with cognitive symptoms than amyloid. Propagates in prion-like fashion through connected brain regions. New biomarker: plasma eMTBR-tau243 specifically reflects tangle pathology.

Neuroinflammation

Microglia over-activate via NF-κB pathway (triggered by Aβ oligomers through TLR4). Activated microglia transform astrocytes into neurotoxic A1 astrocytes. 2024 discovery: ISR pathway in microglia drives lipid synthesis causing synaptic loss.

Mitochondrial Dysfunction

Early and prominent feature: excessive ROS, calcium dysregulation, ATP depletion, impaired dynamics/transport, reduced mitophagy. PET/MRI shows mitochondrial stress at early disease stages.

Cell Death & Disease: Amyloid-β and Tau (2025) • Frontiers: Amyloid cascade hypothesis status (2024)

Brain Structural Changes in Dementia

Hippocampal Atrophy Timeline

Preclinical (5+ years before symptoms)

Progressive CA1 subfield atrophy detectable. Neuronal loss, not just tau deposition, drives structural changes.

MCI Stage

Hippocampal atrophy accelerates. Memory deficits emerge.

Dementia Stage

Continued accelerated atrophy. Pronounced amnestic syndrome.

Default Mode Network Disruption

The DMN (medial parietal, medial prefrontal, hippocampus) shows decreased functional connectivity along the continuum from normal aging → MCI → AD. Altered DMN connectivity predicts future dementia even in cognitively normal individuals at risk.

Synaptic Loss

Correlates most strongly with cognitive decline. Mild dementia: 15-25% synapse loss. Advanced: 20-50% loss. Driven by oligomeric Aβ toxicity, tau synaptotoxicity, and microglial-derived lipid damage.

Nature Mental Health: DMN and early dementia detection (2024)

2024 Lancet Commission: 14 Modifiable Risk Factors (~45% of cases)

Early Life

Low education

Mid-Life (greatest impact window)

Hearing loss
Hypertension
Obesity
Traumatic brain injury
Excessive alcohol
NEW Elevated LDL cholesterol

Late Life

Smoking
Depression
Physical inactivity
Diabetes
Social isolation
Air pollution
NEW Vision loss

Genetics: APOE4

Strongest genetic risk factor. 2024 reconceptualization: APOE4 homozygosity may be a distinct genetic form of AD, not merely a risk factor. Homozygotes develop symptoms ~age 65 (7-10 years earlier). A rare R251G mutation, when co-inherited with APOE4, neutralizes risk entirely.

Lancet: Dementia prevention 2024 Commission • Nature Med: APOE4 homozygosity as genetic AD form (2024)

Biomarkers & Diagnosis

Blood-Based Biomarkers (Revolution)

p-tau217: Most promising plasma biomarker. Better diagnostic accuracy than primary care doctors using traditional methods. Accessible, cost-effective, non-invasive.

Other markers: p-tau181, p-tau205, MTBR-tau243, GFAP (astrocyte), NfL (neuronal injury).

Imaging

Amyloid PET: Detects plaque burden. Best for early-stage assessment. Tau PET: Correlates more closely with dementia progression. Predicts clinically relevant decline.

Digital Biomarkers (Emerging)

Gait analysis (walking velocity, stride variability), speech analysis, wearable data. AI/ML applied to multimodal data provides superior prediction.

PMC: P-tau217 as Reliable Blood Marker

Treatment Landscape (2023-2025)

Anti-Amyloid Antibodies

Lecanemab (Leqembi): FDA approved July 2023. Donanemab (Kisunla): FDA approved July 2024. Both show measurable but modest cognitive slowing. Safety concern: ARIA (amyloid-related imaging abnormalities), 4.35x higher than placebo, especially in APOE4 carriers.

Tau-Targeting Therapies (In Development)

E2814 + Lecanemab combo trial: Launched 2024, results expected 2027. BMS-986446: Anti-MTBR-tau antibody, Phase 2, FDA Fast Track designation. Growing focus given tau's stronger correlation with symptoms than amyloid.

Emerging Approaches

TREM2 agonists (microglial modulation)
NLRP3 inflammasome inhibitors
ISR pathway inhibitors (prevent microglial lipid-driven synapse loss)
Mitochondrial function restoration

Nature Rev Neurol: Tau-targeting therapies (2023)

Neuroplasticity & Learning

Types of Neuroplasticity

Structural Plasticity

Synaptogenesis: Formation of new synapses through axon/dendrite remodeling
Neurogenesis: New neuron generation (confirmed in human hippocampus to 10th decade of life)
Dendritic remodeling: Changes in spine density, diameter, morphology

Functional Plasticity

LTP: Synaptic strengthening after high-frequency stimulation
LTD: Synaptic weakening after low-frequency stimulation
Synaptic scaling: Homeostatic adjustment of all synaptic strengths

LTP: The Molecular Mechanism of Learning

Step-by-Step

1. Coincidence Detection

NMDA receptors require BOTH glutamate binding AND postsynaptic depolarization. Mg²+ block is voltage-dependent.

2. Calcium Influx

Ca²+ enters through NMDARs. High Ca²+ (>1 μM) triggers LTP; low Ca²+ (<0.5 μM) triggers LTD.

3. Kinase Activation

CaMKII activated, phosphorylates AMPA receptor GluA1 subunits at Ser831. Increases conductance and surface expression.

4. AMPA Receptor Insertion

New AMPA receptors inserted into postsynaptic membrane via exocytosis. Synaptic strength increases.

5. Gene Expression

CaMKII/ERK phosphorylate CREB. CREB activates transcription of Arc, c-fos, BDNF. Converts short-term to long-lasting memory.

6. Structural Change

New protein synthesis stabilizes enlarged dendritic spines. Permanent synaptic strengthening.

LTD: The Opposing Process

Low-frequency stimulation produces modest Ca²+ influx, activating calcineurin and PP1 (phosphatases). These dephosphorylate AMPA receptors, triggering clathrin-mediated endocytosis (removal). LTP and LTD compete through AMPA receptor insertion vs. removal.

Frontiers: NMDA-Dependent LTP and LTD • Sci Reports: AMPA trafficking competition (2020)

BDNF: The Plasticity Growth Factor

Brain-derived neurotrophic factor binds TrkB receptors, activating PI3K/Akt and MAPK/ERK cascades. Promotes neuronal survival, synaptic plasticity, neurogenesis, and enhances LTP through NMDA/AMPA receptor trafficking.

How to Increase BDNF

Aerobic exercise: Both moderate (60-70% max HR) and high-intensity (≥80% max HR) increase BDNF
Sleep: Adequate sleep maintains BDNF levels
Meditation: Mindfulness practice increases BDNF
Enriched environments: Novel, complex stimulation upregulates BDNF
Omega-3 fatty acids: Support BDNF production

IJMS: BDNF as Transformative Target (2024)

Epigenetic Mechanisms

Experience physically modifies DNA accessibility without changing the genetic code, creating a molecular record of learning.

DNA Methylation

Methyl groups added to CpG sites by DNA methyltransferases (silences genes). Removed by TET enzymes. Learning causes dynamic methylation changes at memory genes. Reversible and modifiable by experience.

Histone Modifications

Acetylation (HATs): Opens chromatin → gene transcription. Deacetylation (HDACs): Closes chromatin → silencing. Learning induces histone acetylation at CREB target genes. HDAC inhibitors enhance memory in animal models.

Neuropsychopharmacology: Epigenetic regulation of brain plasticity (2025)

Factors That Enhance Neuroplasticity

Factor	Mechanism	Key Evidence
Exercise	Increases BDNF, neurogenesis, angiogenesis, hippocampal volume	Meta-analysis of 49 RCTs: moderate-to-large effect on depressive symptoms, improved cognition
Sleep	Synaptic homeostasis, memory consolidation, glymphatic clearance	SWS drives systems consolidation; REM handles integration and emotional processing
Enriched Environments	Upregulates BDNF, enhances neurogenesis, increases dendritic complexity	Compensates for stress-induced cognitive deficits; synergistic with stress reduction
Meditation	Increases cortical thickness (PFC), hippocampal grey matter, white matter connectivity	2024 systematic review: structural and functional brain changes even with web-based training
Music Training	Auditory cortex plasticity, motor-auditory integration, enhanced white matter	25% greater cortical activation for trained tones; structural changes with 1 year training
Nutrition	Omega-3s support BDNF; antioxidants protect neurons; proper nutrition maintains plasticity	DHA/EPA improve learning, memory, cognitive function, cerebral blood flow

Factors That Impair Neuroplasticity

Factor	Mechanism	Reversibility
Chronic Stress	Cortisol causes 10-15% hippocampal volume reduction, impairs neurogenesis. Paradoxically enhances amygdala (maladaptive)	Partially reversible: dendritic regrowth possible within 6-12 months of stress reduction
Aging	Reduced neurogenesis, synaptic density, metabolic activity. Requires greater stimulation for reorganization	Foundational mechanisms persist. Cognitive reserve (lifelong learning) is protective
Neuroinflammation	Overactivated microglia produce excess cytokines, cause excessive synaptic pruning via PI3K dysregulation	Potentially treatable with anti-inflammatory interventions
Substance Abuse	Hijacks reward system with supranormal dopamine. Drug-induced synaptic plasticity in reward circuitry	After 14 months abstinence, dopamine transporters return to near-normal
Sleep Deprivation	Alters LTP/LTD mechanisms, increases cortical excitability, inhibits neurogenesis, weakens hippocampal ripples	Some effects may be irreversible with chronic deprivation. Prevention > treatment

Clinical Applications & Recent Advances

Stroke Rehabilitation

Stroke triggers heightened neuroplasticity in perilesional and remote regions. Critical window: first 3-6 months. Task-specific training, constraint-induced movement therapy, and virtual reality leverage this reorganization capacity.

Brain-Computer Interfaces (2024-2025)

BCIs decode motor intention and provide closed-loop feedback, promoting neuroplasticity. Recent trials show medium-to-large effect size (SMD 0.79) for upper limb stroke recovery. BCI-based language training shows sustained aphasia recovery.

Adult Neurogenesis: Debate Resolved (2025)

Single-cell RNA sequencing confirms human hippocampal neurogenesis persists to the 10th decade of life. Neural stem cells, neuroblasts, and immature neurons all present. Dkk3 protein increases with age but its deletion restores neurogenesis in old mice and reverses cognitive decline.

Transcranial Stimulation

TMS/tES produces multi-scale plasticity: short-term electrocortical changes, intermediate neurotrophin release (BDNF), and long-term synaptic remodeling. Theta burst stimulation (TBS) is more efficient than conventional rTMS.

Nature Neurosci: Human adult hippocampal neurogenesis (2025) • Frontiers: BCI for stroke rehabilitation (2025)