Neuroscience of Memory: From Historical Theories to LTP
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Historical Perspectives on Memory
| Descartes | Semon | Ramon y Cajal | Wundt | Ebbinghaus | Thorndike | Pavlov | Watson, Skinner | Karl Lashley |
|---|---|---|---|---|---|---|---|---|
|
| Synaptic theory: Synapses are where computation happens | First psychology laboratory, 1879 |
| Instrumental conditioning, 1898 | Classical conditioning, 1920s | Rejection of the study of the nervous system |
|
Phrenology and Molecular Theories
Phrenology: Personality determined by different amounts of cortical regions.
Molecular Theory of Memory:
- McConnell: Light and shock conditioning in worms. Suggested RNA molecules store memories (not shown in mammals).
- Agranoff: Protein synthesis in long-term memory. Injected puromycin into fish brains; protein synthesis inhibition leads to loss of medium-term memory with immediate injection.
Only long-term memory requires protein synthesis; earlier intervention has a greater effect on LTM.
Declarative vs. Non-Declarative Memory
Declarative: Facts and past events.
Non-declarative: How-to and performance.
Case Study: HM
Medial temporal lobe damage resulting in:
- Anterograde amnesia for declarative memory.
- Normal procedural learning and mirror tracing.
- Temporally graded retrograde amnesia.
Hippocampal Function and Circuitry
The rat hippocampus occupies a larger proportion of total brain volume than in humans, while rats have a smaller cerebral cortex.
- Highly organized trisynaptic loop circuit.
- HC Lesions: Impair context but not tone fear conditioning. Subjects still freeze to auditory CS tone. Temporally graded retrograde amnesia for context fear.
- Slide Preparation: Brain tissue kept alive on a slide; stimulation electrodes at the Schaffer collateral pathway cause action potentials that release Glutamate on CA1.
- Temporally Graded RA: Declarative and episodic memory may be stored in the HC and transferred to the cortex.
- Cell Layers: Dentate gyrus and Cornu Ammonis (CA3, CA1). Dentate granule cells are areas for adult neurogenesis. LTP depends on NMDA.
Synaptic Plasticity: Hebb and LTP
Hebb: Plasticity; cells that wire together, fire together. Hebbian potentials strengthen connections (e.g., classical conditioning).
LTP (Long-Term Potentiation): High-frequency stimulation (100Hz) causes larger EPSPs in CA1. Induced by pairing pre- and postsynaptic stimulations.
LTD (Long-Term Depression): Low-frequency stimulation (1Hz) causes smaller EPSPs in CA1.
- Hebbian LTP: Stimulation of axons and postsynaptic cells causes LTP, distinct from stimulating only the input at 100Hz.
LTP properties at CA1: 
Weak stimulation of pathway 2 does not trigger LTP, but can be induced for both when paired with a strong stimulus.
LTD Induction and Molecular Mechanisms
LTD induction depends on NMDA receptor activation and protein phosphatases. LTD requires NMDA (blocked by AP5) and is inhibited by okadaic acid (inhibitor of PP1, PP2A).
- Coincidence Receptor: Mg2+ is removed and glutamate binds.
- LTP Pathway: Release of Glu → Ca2+ influx → Ca2+ calmodulin → CaMKII → AMPA receptors (more vesicles in presynaptic terminal, retrograde signals like nitric oxide).
- Phosphorylation: LTP increases phosphorylation at Thr286; LTD decreases it.
- Simplified Model: AMPARs bind neurotransmitters, opening channels for Na+. Increased sensitivity to Glu and NO for retrograde signaling leads to more vesicles.
- LTP Expression: Small stimulation results in failure rate; LTP reduces failures. This indicates a presynaptic response, as it increases the probability of vesicle release.
- Postsynaptic Response: More current per synaptic release due to more AMPA receptors.
- CaMKII: When open, it is active and autophosphorylates, staying active until inhibited by protein phosphatases.
- CaMKII and substrate GluR1 are phosphorylated after LTP and dephosphorylated after LTD.
