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Memory and Learning - Physiology Notes (MBBS 1st Year Exam)

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1. DEFINITIONS

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2. TYPES OF LEARNING

A. Non-associative Learning

• Habituation: Repeated neutral stimulus causes progressively diminishing response. The organism "learns" the stimulus is not important.
  • Mechanism: decreased neurotransmitter release from presynaptic terminal due to decreased intracellular Ca2+ (gradual inactivation of Ca2+ channels)
  • Example: New city-dweller gradually ignores street noise
• Sensitization: Augmented postsynaptic response after a habituated stimulus is paired with a noxious stimulus (opposite of habituation)
  • Mechanism: presynaptic facilitation; Ca2+-mediated change in adenylyl cyclase → greater cAMP production
  • Can be short-term or long-term

B. Associative Learning

• Classical conditioning (Pavlovian): Temporal relationship between a conditioned stimulus (CS) and unconditioned stimulus (UCS) is repeatedly paired → CS alone eventually elicits the unconditioned response. Example: Pavlov's dog - bell (CS) paired with food (UCS) → salivation to bell alone.
• Operant conditioning: Response to a stimulus is reinforced positively or negatively, changing the probability of that response.

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3. FORMS OF MEMORY

A. Explicit (Declarative) Memory

• Associated with consciousness/awareness
• Dependent on hippocampus and medial temporal lobes for retention
• Subtypes:
  • Semantic memory - facts, words, rules, language → stored in lateral and anterior temporal cortex, prefrontal cortex
  • Episodic memory - personal events → stored in hippocampus, medial temporal lobe, neocortex

B. Implicit (Non-declarative) Memory

• Does not involve awareness
• Does not require hippocampal processing
• Subtypes:

Exam tip: Skills like riding a bicycle begin as explicit memory but become implicit once thoroughly learned.

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4. SHORT-TERM vs. LONG-TERM MEMORY

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5. NEURAL BASIS OF MEMORY

• Second messenger systems contribute to changes in neural circuitry
• Alterations in membrane ion channels correlate with learning
• Conversion from short-term to long-term memory requires protein synthesis and gene activation

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6. SYNAPTIC PLASTICITY AND LTP

Posttetanic Potentiation

• Enhanced postsynaptic potentials after a brief tetanizing stimulation of presynaptic neuron
• Lasts up to 60 seconds
• Mechanism: Ca2+ accumulates in presynaptic neuron overwhelming intracellular binding sites

Long-Term Potentiation (LTP) ⭐ (HIGH YIELD)

• Definition: Rapidly developing, persistent enhancement of postsynaptic potential response after brief high-frequency (tetanic) stimulation of presynaptic neuron
• Lasts days to weeks (much more prolonged than posttetanic potentiation)
• The most important cellular mechanism of learning and memory

1. Presynaptic neuron releases glutamate
2. Glutamate activates NMDA receptors on postsynaptic membrane
3. NMDA receptors = ligand-gated Ca2+ channels (open when activated)
4. High-frequency stimulation → more Ca2+ accumulates in postsynaptic cell
5. High intracellular Ca2+ → activates calcium-calmodulin-dependent protein kinase
6. → Increased responsiveness of synapse (increased synaptic strength)
7. Long-term: involves protein synthesis and growth of pre- and postsynaptic neurons

Note: LTP can also be NMDA receptor-independent; in those cases, initiation still requires increase in intracellular Ca2+ in either pre- or postsynaptic neuron.

Long-Term Depression (LTD)

• Opposite of LTP - decreased synaptic strength
• Also involves NMDA receptors and Ca2+ signaling

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7. BRAIN STRUCTURES IN MEMORY (Summary)

The Famous Case of HM (Patient Henry Molaison) - Classic Exam Vignette

• Underwent bilateral hippocampal and amygdala removal for seizure control (1953)
• Result: Anterograde amnesia - could not form NEW long-term memories
• Short-term memory was intact
• Remote (pre-surgical) long-term memories were intact
• Procedural memory was normal (could learn new motor skills but not remember learning them)
• Lesson: The hippocampus is required for encoding NEW declarative memories, not for their storage or retrieval once consolidated

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8. AMNESIA

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9. ALZHEIMER DISEASE (Memory Pathology)

1. Intracellular neurofibrillary tangles (paired helical filaments of hyperphosphorylated tau protein)
2. Extracellular amyloid (senile) plaques - core of β-amyloid peptides surrounded by altered nerve fibers and reactive glial cells
3. Brain atrophy - narrowing of gyri, widening of sulci, enlarged ventricles, reduced brain weight

• Aβ peptides (40-42 amino acids) stick to AMPA receptors and Ca2+ channels → increased Ca2+ influx
• Initiate inflammatory response → intracellular tangles
• Most toxic form: Aβ1-42

• Acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine): increase ACh availability; delay symptom worsening ~12 months in ~50% patients
• Memantine (NMDA receptor antagonist): prevents glutamate-induced excitotoxicity; used in moderate-to-severe Alzheimer disease

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10. QUICK RECALL TABLE - Mechanisms at a Glance

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11. KEY EXAM POINTS (One-Liners)

• Learning = acquisition; Memory = retention/storage
• Fundamental mechanism of learning = synaptic plasticity
• LTP = high-frequency stimulation → NMDA → Ca2+ → kinase → persistent synaptic enhancement
• Hippocampus = needed for encoding declarative memory (not storage)
• Explicit memory = hippocampus dependent; Implicit = hippocampus independent
• Semantic memory = facts; Episodic memory = events (both are explicit)
• Procedural memory = cerebellum + striatum (implicit)
• Alzheimer plaques = β-amyloid; Tangles = tau protein
• Anterograde amnesia = cannot form new memories (HM case)
• Retrograde amnesia = loss of old memories before injury
• Short-term → Long-term memory conversion requires protein synthesis
• Memantine blocks NMDA receptors (used in moderate-severe Alzheimer)
• "Use it or lose it" - effortful mental activity slows onset of cognitive dementia

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