The Neuroscience and Physiology of Memory

What Is Memory?

1. There are several forms of memory, each with different cognitive properties and brain substrates.
2. Memory involves four operations: encoding, storage, consolidation, and retrieval.
3. Imperfections in memory (amnesia, confabulation) reveal how normal memory works.

• Eric Kandel, Principles of Neural Science, 6th ed.

Taxonomy of Memory

By Time Course

• Bradley and Daroff's Neurology in Clinical Practice

By Content: Explicit vs. Implicit

• Episodic memory: personal events ("what I did last Tuesday") - requires "mental time travel"
• Semantic memory: factual world knowledge ("Paris is the capital of France") - distributed across lateral temporal and association cortices

• Procedural memory (skills and habits): processed in the striatum
• Classical/operant conditioning: amygdala (emotional responses), cerebellum (motor responses)
• Priming: improved recall from prior exposure; survives even in profound amnesia
• Habituation/sensitization: depends on basic reflex pathways

• Kandel, Principles of Neural Science, pp. 1341-1342

Brain Structures: The Medial Temporal Lobe System

• Frontal lobes = the "filing clerk" that decides what to retrieve and from where
• Medial temporal lobes = the "recent memory filing cabinet" where new memories are stored
• Subcortical white matter = the pathway the filing clerk must travel to reach the cabinet

Consolidation: From Short-Term to Long-Term

Synaptic Consolidation (Hours)

• Early LTP (E-LTP): protein synthesis-independent; lasts minutes to hours. The synapse becomes "tagged" via a protein synthesis-independent mechanism.
• Late LTP (L-LTP): requires intracellular signaling cascades and new protein synthesis in soma and dendrites; lasts days to years. The tagged synapse must capture plasticity-related proteins (PRPs) to stabilize.

1. High-frequency presynaptic activity (or theta-burst stimulation, 4-8 Hz) depolarizes the postsynaptic membrane
2. NMDA receptors (glutamate-gated, voltage-dependent) become unblocked - Na⁺ and Ca²⁺ flow in
3. Calcium rise activates CaMKII (calcium-calmodulin-dependent kinase II), which autophosphorylates
4. Cytoskeletal reconfiguration and AMPA receptor insertion strengthen the synapse
5. Gene activation and new protein synthesis produce structural synaptic changes (dendritic spine growth)

"The key to memory is alteration in the strength of selected synaptic connections... the alteration involves the synthesis of proteins and the activation of genes. This occurs during the change from short-term working memory to long-term memory."

• Ganong's Review of Medical Physiology, 26th ed.

Systems Consolidation (Weeks to Years)

Reconsolidation: Memory Is Not Fixed

• Existing memories can be strengthened or updated during reconsolidation
• Fear memories can be weakened or erased by pharmacologic or behavioral interventions during this window

• Miller's Anesthesia, 10th ed.

The Amygdala and Emotional Memory

Summary Table: Brain Regions and Memory Functions

Synaptic Plasticity

What It Is

"Changes in the strength and efficiency of synaptic signaling, termed synaptic plasticity, underlie one of the most important neurochemical foundations of learning and memory."

• Kaplan & Sadock's Comprehensive Textbook of Psychiatry

Overview: Three Major Categories

Short-Term Synaptic Plasticity

• Neuroscience: Exploring the Brain, 5th ed.

Long-Term Potentiation (LTP)

The Hebbian Principle

Three Key Properties (Kandel)

1. Cooperativity - A single weak input cannot induce LTP (can't expel Mg²⁺ from NMDA channel). Only convergent activation of many inputs simultaneously achieves the strong depolarization required. This ensures only significant events trigger memory formation.
2. Associativity - A weak input paired with a strong one achieves LTP in both, because the strong input provides the depolarization. This is the cellular analog of Pavlovian conditioning - a neutral stimulus gains meaning when paired with a meaningful one.
3. Synapse specificity - Only activated synapses undergo LTP, even when neighboring synapses on the same cell receive strong stimulation. This allows a single neuron to store vast amounts of independent information across its thousands of synapses.

• Kandel, Principles of Neural Science, 6th ed., p. 1397

Molecular Mechanism of LTP

1. Glutamate binds to AMPA receptors → Na⁺ influx → membrane depolarization
2. Sufficient depolarization expels Mg²⁺ from NMDA receptor channel
3. NMDA receptor opens → large Ca²⁺ influx (the critical trigger)
4. Ca²⁺ binds calmodulin → activates CaMKII (and PKC)
5. CaMKII phosphorylates existing AMPA receptors → increased Na⁺ conductance
6. CaMKII drives insertion of additional AMPA receptors from an intracellular pool into the postsynaptic membrane
7. More AMPA receptors = larger future EPSPs = stronger synapse

Spike Timing-Dependent Plasticity (STDP)

• Neuroscience: Exploring the Brain, 5th ed.

Two Phases: E-LTP and L-LTP

• CaMKIV (nuclear) and PKA (cAMP-dependent) → phosphorylate CREB
• CREB recruits RNA polymerase II → transcription of plasticity genes (Arc, Homer, ΔFosB)
• New proteins cause dendritic spine enlargement (thin → mushroom-shaped spines) and structural synapse growth

Long-Term Depression (LTD)

• High Ca²⁺ (from strong, high-frequency stimulation) → activates CaMKII → LTP
• Low Ca²⁺ (from weak, low-frequency stimulation, partial Mg²⁺ relief) → activates calcineurin (a Ca²⁺-dependent phosphatase with a higher affinity for Ca²⁺ than CaMKII) → dephosphorylates AMPA receptors → receptor endocytosis (removal from membrane) → LTD

• Kandel, Principles of Neural Science, 6th ed.

Homeostatic Plasticity

"Unlike Hebbian plasticity, homeostatic plasticity is unlikely to drive information storage but rather helps maintain longer-term function in response to local changes in excitation and inhibition."

• Kaplan & Sadock's Comprehensive Textbook of Psychiatry

Clinical and Disease Relevance

Summary

SYNAPTIC ACTIVITY
       |
   Ca²⁺ concentration in postsynaptic cell
       |
   HIGH Ca²⁺          LOW Ca²⁺
       |                    |
   CaMKII active        Calcineurin active
       |                    |
  AMPA ↑ (LTP)         AMPA ↓ (LTD)
  Spine enlargement    Spine shrinkage
  Protein synthesis    Receptor endocytosis
  (if L-LTP)

Lipoprotein Structure, Classification, and Metabolism

What Are Lipoproteins?

• A hydrophobic core packed with triglycerides (TG) and cholesterol esters (CE)
• A hydrophilic surface shell of phospholipids and unesterified (free) cholesterol
• Apolipoproteins embedded in the surface, which determine particle identity, dictate enzyme interactions, and serve as ligands for receptors

Classification of Lipoproteins

Apolipoproteins: The Key Regulatory Proteins

• Tietz Textbook of Laboratory Medicine, 7th ed.

The Three Major Metabolic Pathways

Pathway 1: Exogenous (Dietary) Pathway - Chylomicrons

1. Dietary fats are digested in the intestinal lumen and absorbed in the proximal small intestine
2. Cholesterol and fatty acids are esterified in enterocytes; longer-chain FAs (>12C) are incorporated into TGs
3. Microsomal TG transfer protein (MTP) packages TGs with ApoB-48, phospholipids, cholesteryl esters, retinyl esters, and vitamin E to form nascent chylomicrons
4. Secreted into intestinal lymph → thoracic duct → systemic circulation
5. In blood, chylomicrons acquire ApoC-II and ApoE from HDL
6. ApoC-II activates LPL (anchored to endothelium of capillaries in adipose, heart, skeletal muscle by GPHBP1 protein) → TGs hydrolyzed → free fatty acids released to muscle (oxidation) and adipose (storage)
7. Excess surface phospholipids, cholesterol, and apolipoproteins transfer to HDL
8. Chylomicron remnants (enriched in cholesterol, carrying ApoB-48 + ApoE) are rapidly cleared by the liver via LRP and LDL receptor-related receptors (ApoE is the critical ligand)
9. Half-life of chylomicrons < 1 hour; absent after 12-h fast

Pathway 2: Endogenous (Hepatic) Pathway - VLDL → IDL → LDL

1. Liver assembles nascent VLDL: packages TGs (from de novo lipogenesis or fatty acids) with ApoB-100, cholesteryl esters, phospholipids via MTP → secreted into plasma
2. Nascent VLDL acquires ApoC-II, ApoC-III, ApoE from circulating HDL
3. LPL hydrolyzes VLDL TGs at capillary surfaces → FFAs released to tissues → VLDL shrinks to IDL (VLDL remnant)
4. IDL contains ApoB-100 + ApoE → approximately half is taken up directly by the liver (via LDL receptor and LRP, using ApoE as ligand)
5. Remaining IDL is further hydrolyzed by hepatic lipase (HL) → most apolipoproteins (including ApoE) transferred to HDL, leaving only ApoB-100 → LDL is formed
6. LDL circulates with a half-life of ~2-3 days, delivering cholesterol to:
   • Liver (~70%) via LDL receptor (LDLR) - ApoB-100 is the ligand
   • Peripheral tissues (lymphocytes, fibroblasts, adrenal glands, etc.) via endocytosis

• When cell cholesterol is adequate → LDLR synthesis is suppressed (SREBP pathway inactive)
• When cell cholesterol is low → LDLR expression increases → more LDL uptake
• This is the target of statins (inhibit HMG-CoA reductase → lower intracellular cholesterol → upregulate LDLR → lower plasma LDL)
• Familial hypercholesterolemia = loss-of-function mutations in LDLR → markedly elevated LDL

Pathway 3: Reverse Cholesterol Transport - HDL

1. Nascent HDL (disc-shaped, lipid-poor) is secreted by the liver and intestine, carrying ApoA-I
2. ABCA1 transporter on macrophages and other peripheral cells effluxes free cholesterol and phospholipids onto ApoA-I → forming nascent HDL discs (defective in Tangier disease)
3. LCAT (lecithin-cholesterol acyltransferase), activated by ApoA-I, esterifies free cholesterol → cholesteryl esters sink into the core → HDL matures into spherical HDL3 → HDL2
4. CETP (cholesterol ester transfer protein) transfers CE from HDL to VLDL/chylomicrons in exchange for TGs (allowing indirect return of cholesterol to liver)
5. SR-BI (scavenger receptor class B) on hepatocytes takes up CE selectively from HDL without degrading the particle ("selective uptake")
6. Phospholipid transfer protein (PLTP) transfers phospholipids between lipoproteins; hepatic lipase and endothelial lipase (EL) remodel HDL, generating smaller particles

Lipoprotein(a) - Lp(a)

• Structure: LDL-like particle with ApoB-100 covalently linked (via single disulfide bond) to Apo(a) - a large protein with kringle domains homologous to plasminogen
• Synthesized in the liver; plasma levels are >90% genetically determined (by LPA gene kringle copy number)
• Pathogenic mechanisms:
  1. Atherogenic (like LDL, deposits cholesterol in arterial wall)
  2. Thrombogenic: Apo(a) competitively inhibits fibrinolysis by interfering with plasminogen activation
• Levels >125 nmol/L (or >50 mg/dL) are an independent ASCVD and aortic stenosis risk factor
• Not reduced by statins (may modestly increase); niacin reduces it ~20-30%; PCSK9 inhibitors reduce ~25%; antisense oligonucleotides (pelacarsen) and small interfering RNA (olpasiran) reduce Lp(a) by >80% - now in phase 3 trials
• Harrison's Principles of Internal Medicine, 22nd ed.; Lp(a) in clinical practice - CCJM 2026

Friedewald Formula and Clinical Measurement

Summary: The Flow of Lipid Traffic

DIETARY LIPIDS             HEPATIC LIPIDS
     |                          |
Chylomicrons            Nascent VLDL
(ApoB-48)               (ApoB-100)
     |                          |
   LPL (ApoC-II)             LPL (ApoC-II)
     |                          |
Chylomicron               IDL (VLDL remnant)
remnants → Liver       Liver (50%) + HL
(ApoE → LRP)               |
                           LDL
                        (ApoB-100 → LDLR)
                           |
                    Peripheral tissues
                           |
                   HDL (reverse transport)
                    ApoA-I → ABCA1 → LCAT
                           |
                    Liver (SR-BI, CETP)