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

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

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

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

LTP Changes Dendritic Morphology

Images of Dendritic Changes after LTP

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)

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?

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 LTP and of “memory molecules”

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)

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:

Types of Neurons