Physiology of Learning and Memory

1. Definitions

• Costanzo Physiology 7th Edition, p. 118
• Ganong's Review of Medical Physiology, 26th Ed., p. 289

2. Classification of Learning

3. Forms of Memory

3a. Explicit (Declarative) Memory

• Involves conscious awareness
• Depends on the hippocampus and medial temporal lobes for consolidation
• Two subtypes:
  • Semantic memory: factual knowledge (words, rules, language) - stored in lateral/anterior temporal cortex and prefrontal cortex
  • Episodic memory: personal autobiographical events - hippocampus, medial temporal lobe, neocortex

3b. Implicit (Nondeclarative) Memory

• Does not require conscious awareness
• Does not require hippocampal processing
• Four subtypes:
  1. Procedural (skills and habits): striatum, cerebellum, motor cortex
  2. Priming and perceptual (recognition facilitated by prior exposure): neocortex
  3. Associative learning (classical conditioning): amygdala, cerebellum
  4. Nonassociative learning (habituation, sensitization): reflex pathways

Key clinical illustration - Patient H.M.: In 1953, bilateral surgical removal of the hippocampus and amygdala controlled seizures but produced severe anterograde amnesia - H.M. could not form new long-term declarative memories. His procedural memory remained intact, proving dissociation of memory systems.

4. Memory by Time Stage

5. Synaptic Plasticity: The Cellular Basis of Learning

5a. Hebb's Rule

5b. Short-Term Plasticity

5c. Long-Term Potentiation (LTP)

Step-by-step NMDA receptor mechanism of LTP:

1. At rest, the presynaptic neuron releases glutamate which binds to both AMPA and NMDA receptors on the postsynaptic membrane.
2. At resting membrane potential, Mg²⁺ physically blocks the NMDA receptor channel, so only AMPA receptors conduct (Na⁺/K⁺ flow, small EPSP).
3. During high-frequency tetanic stimulation, repeated activation of AMPA receptors produces sufficient postsynaptic depolarization to expel Mg²⁺ from the NMDA channel.
4. With Mg²⁺ unblocked, glutamate binding to NMDA receptors allows Ca²⁺ influx into the postsynaptic cell.
5. Elevated intracellular Ca²⁺ activates Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) and other kinases.
6. CaMKII phosphorylates existing AMPA receptors (increasing their conductance) and triggers insertion of additional AMPA receptors into the postsynaptic membrane.
7. The result: more AMPA receptors at the synapse → larger EPSPs for the same presynaptic input → LTP.

This requires coincident pre- and postsynaptic activity - making the NMDA receptor a true "coincidence detector" and the cellular implementation of Hebb's rule.

Key properties of LTP:

• Cooperativity: Multiple weak inputs arriving simultaneously can together produce LTP (spatial summation relieves Mg²⁺ block), allowing formation of associations
• Input specificity: Only active synapses are potentiated (not silent neighboring synapses)
• Associativity: A weak input can be potentiated if it is active at the same time as a strong input

5d. Long-Term Depression (LTD)

5e. Glutamate Receptor Trafficking

6. Memory Consolidation: Molecular Mechanisms

1. CaMKII (calcium/calmodulin-dependent protein kinase II): Becomes persistently active after Ca²⁺ activation, maintaining synaptic potentiation even after Ca²⁺ returns to baseline.
2. cAMP and PKA (Protein Kinase A): Sensitization in Aplysia (the classic invertebrate model, studied by Nobel laureate Eric Kandel) showed serotonin → cAMP rise → PKA activation → increased glutamate release. This short-term mechanism.
3. CREB (cAMP Response Element Binding protein): With repeated stimulation, PKA translocates to the nucleus, phosphorylates CREB, which activates gene transcription. This triggers new protein synthesis, which is required for long-term memory consolidation.
4. Structural plasticity: Long-term memory involves actual growth of new synaptic connections (new dendritic spines, enlarged postsynaptic densities) - a physical remodeling of neural circuits. This is why long-term memory is stable: it is encoded in anatomy, not just chemistry.
5. Synaptic tagging and capture: A strongly stimulated synapse is "tagged" with a signal that allows it to capture plasticity-related proteins (synthesized in the cell body) even if it was only weakly stimulated. This mechanism allows events separated in time to become associated in memory.

7. Neural Circuits and Brain Regions

8. Cellular Representation of Memory - The Engram

9. Homeostatic Plasticity (Metaplasticity)

1. Synaptic scaling: Chronic low activity causes global up-scaling of all synaptic strengths to restore excitability; chronic overactivity causes down-scaling
2. Firing rate homeostasis: Neurons adjust their intrinsic excitability to maintain a target firing rate
3. Metaplasticity: The history of prior activity determines how easily LTP or LTD can be induced in the future (the threshold for plasticity itself is plastic)

10. Memory and Disease: Alzheimer Disease

• Early loss: Episodic memory (hippocampal-dependent) is first affected
• Pathology: Intracellular neurofibrillary tangles (hyperphosphorylated tau protein) + extracellular amyloid plaques (β-amyloid peptides from APP cleavage)
• Genetics: APP (chr 21), Presenilin-1 (chr 14), Presenilin-2 (chr 1), ApoE4 allele
• Mechanism: Amyloid and tau disrupt synaptic function, destroy hippocampal circuits, and progressively impair the molecular machinery of LTP

Summary Concept Map

LEARNING (behavior change by experience)
    └─► SYNAPTIC PLASTICITY
           ├─ Habituation (↓Ca²⁺, ↓transmitter release)
           ├─ Sensitization (↑cAMP → PKA → ↑transmitter release)
           └─ LTP (NMDA receptor-dependent Ca²⁺ influx → CaMKII
                   → ↑AMPA receptors → persistent ↑synaptic strength)

MEMORY (retention of learning)
    ├─ EXPLICIT (hippocampus required)
    │     ├─ Semantic (temporal cortex, PFC)
    │     └─ Episodic (hippocampus, MTL, neocortex)
    └─ IMPLICIT (no hippocampus needed)
          ├─ Procedural (striatum, cerebellum)
          ├─ Priming (neocortex)
          ├─ Classical conditioning (amygdala, cerebellum)
          └─ Habituation/Sensitization (reflex circuits)

CONSOLIDATION: Short-term → Long-term
    CaMKII → PKA → CREB → Gene transcription
    → Protein synthesis → Structural synaptic growth

• Ganong's Review of Medical Physiology, 26th Edition, Chapter 15
• Costanzo Physiology, 7th Edition, Chapter 3
• Neuroscience: Exploring the Brain, 5th Edition, Chapter 25
• Eric Kandel - Principles of Neural Science, 6th Edition, Chapters on Learning & Memory