A fundamental challenge of modern neuroscience is to define how memories are encoded within the brain. Classically, long-lasting plasticity in synaptic transmission has been proposed to be the cellular substrate for memory, shaping the flow of information through neural pathways. However, the sparse distributed neural networks thought to encode a memory trace have, until now, defied delineation. Consequently, the link between synaptic plasticity, sensory ensembles and learned behaviors remains elusive. Here I propose to use the olfactory system of the fruit fly, Drosophila melanogaster, as a unique paradigm to bridge the critical interface between synapses and behavior. I present a novel neural tracing technique that uses photoconvertible fluorophores and precise electroporation of dyes to label synaptically connected neurons for anatomic and functional analysis. I propose to apply this innovative tracing approach to map the associative olfactory circuits in the fly brain and discern how odor associations are encoded by synaptic connections and neural ensembles. I will then use in-vivo functional imaging and electrophysiolgical recordings in a tethered fly preparation to directly correlate the plasticity of individual synapses with learned olfactory behaviors. As a complement to these high-resolution circuit-mapping techniques, I propose genetic strategies to catalog the transcriptional changes selectively induced in neurons participating in a memory trace and provide insight into the molecular machinery that mediates experience-dependent changes in neural circuit function. Together, these experiments will offer an integrative understanding of neural plasticity mechanisms, from molecules and synapses to circuits and behavior, and lay the foundation for the development of rational therapeutic treatments to treat dementias and other memory disorders with molecular precision.
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