Analyses of the Distributed Representation of Associative-Learning in an Identified Circuit Using a Combination of Single-Cell Electrophysiology and Multicellular Voltage-Sensitive Dye Recordings

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PROJECT SUMMARY/ABSTRACT Although significant advances have been made in elucidating the cellular, biophysical and molecular mechanisms of learning and memory, much less is known about the ways in which mnemonic processes are embedded in neuronal networks. The overall goal of this proposal is to provide insights into the design principles that govern the implementation of memories within the complex environment of a neural circuit. Studies will focus on an established in vitro analogue of operant conditioning (QC) in a relatively complex circuit, which is amenable to population-wide, cellular, and biophysical analyses. A combination of intra- and extracellular electrophysiological techniques, voltage-sensitive dye (VSD) imaging, dimensionality reduction analysis, and computational modeling will identify and characterize loci of non-synaptic and synaptic plasticity. In addition, the project will examine the extent to which plasticity loci are shared between short- and long-term memory. Aim 1 will use intracellular recording techniques to examine loci of QC-induced plasticity. Previous correlates of OC in this model system were restricted to increases in intrinsic excitability or electrical synapses of key neurons in the circuit. Our recent results indicate QC also decreases the strength of an inhibitory synapse and the excitability of a key neuron in the circuit. Aim 1 will examine other prime candidates of QC-induced synaptic and non-synaptic plasticity, which have an established role in mediating the behavior. In addition, we will use intracellular techniques to examine regions of the circuit that our recent VSD recordings have shown to exhibit QC-induced changes in activity. Computational modeling will assess the ways in which loci work unilaterally or synergistically to mediate the OC phenotype. Aim 2 will use a combination of intracellular recordings, VSD imaging, and dimensionality reduction approaches to expand the search for additional sites of QC-induced plasticity and search for low-dimensional 'signatures' of OC. The combined results from Aims 1 and 2 will provide for an assessment of the scope of plasticity mechanisms associated with OC that is unprecedented in any system. A further important question will be addressed by Aim 3, which will determine the extent to which sites for short-term memory persist during long-term memory and, conversely, which sites of plasticity may be unique to long-term memory. The present proposal will help develop a comprehensive understanding of the ways in which memories are encoded in a relatively complex circuit, elucidate design principles of memory encoding, and provide guidance for similar analyses in more complex systems.