APPROACHES TO THE BIOLOGY OF MEMORY

1. APPROACHES TO THE BIOLOGY OF MEMORY • Scale of analysis: • Micro: intra, intercellular • Medio: cell assemblies and neural networks • Macro: Coordinated brain systems • Focus of Analysis: • Content: particular memories, “kinds” of memories • Process: mechanisms of encoding, persistence, retrieval • Goal of analysis: • Reductionism: from cognition to biochemistry • Cognitive neuroscience: building bridges between levels of discourse

2. THE NEURONAL BASES OF MEMORY • A (re)view of neuronal conduction • Potential memory mechanisms • More (or fewer) neurons • More (or fewer) synapses • Efficiency of synapses • Surface area of synapses • Changes in other cell areas

3. Activation and Alteration of Synapses • Kandel’s work with Aplysia (Sea Hare) • Habituation of gill-withdrawal reflex • Presynaptic membrane is altered • Fewer calcium ions • Fewer vesicles move to cleft • Less neurotransmitter is released • Smaller postsynaptic potential shift • Smaller motor nerve stimulation • Diminished gill withdrawal

4. LONG-TERM POTENTIATION • How LTP is produced • 100 Hz stimulation of synapse • Increases response to later stimulation • Can last hours in vitro, days in vivo • Seen most readily in hippocampus • One scenario of how it works • Postsynaptic membrane changes • Increase in calcium ions (Ca+) • More glutamate receptors activated(N-methyl-D-aspartate, or NMDA) • Glutamate uptake increases • Increases postsynaptic activity • Requires co-occurrence of neurotransmitter & depolarization

5. LTP Changes Dendritic Morphology

6. Images of Dendritic Changes after LTP

7. Genetically enhancing LTP • NMDA receptors have two subunit types • NR2B gives more sustained “current” • Proportion of NR2B greater in young mice • Genetically enhancing NR2B ratio • Increases NMDA-mediated current • Gives greater LTP in vitro, vivo • Improves learning and retention on a wide range of tasks (Tang, et al., 1999)

8. LONG-TERM DEPRESSION (!) • Weak, slow stimulation reduces EPSP • Distinct from “decay” of LTP • Effect is dependent on “history” • Same stimulus can give LTP or LTD depending on timing • 5-15 ms prior to PSAP > LTP • 5-15 ms after PSAP > LTD • A “negative feedback” mechanism for continued plasticity?

9. cyclic AMP-response element binding protein (CREB) and LTP • Repeated LTP stimulation • Synthesis of CREB via genetic activation of postsynaptic nucleus • Thought to be (one) basis of longer-term memory and retention • Other neuronal changes with learning • Enriched, complex environments give increased synaptic counts • Some recent evidence for increases in neuron population with learning • The outlook • Rapid progress • Proliferation of types and loci of LTPand of “memory molecules”

10. FRONTIERS IN THE MICROBIOLOGY OF MEMORY • The search for “memory drugs” • Potential sites of action • Interesting and uninteresting effects • Current evidence is modest at best • Consolidation and the hippocampus • Animal models of consolidation • The problem of time-course • Correlations with independence of hippocampal function • Reconsolidation • Protein-synthesis blocker (anisomysin) after ”retrieval” creates amnesia (Nader, Schafe & LeDoux, 2000) • “The notion that recurrent vulnerability windows exist in LTM has remarkable practical potential, for example the deletion of anguishing post-traumatic memories by post-retrieval intervention. Some psychotherapists, of course might claim that this is exactly what they are trying to do already” (Dudai, 2002)

11. Gron, et al. (2005) • Donepizil (Acetylcholine esterase inhibitor, used for Alzheimer’s) • 30 days of treatment in healthy adults • Battery of standard clinical tests of cognition, including memory, pre and post • Drug vs. placebo seen only in episodic memory tests, visual and verbal:

12. Types of Neurons