Defining the differential roles of Glutamatergic and GABAergic projections from the Lateral Preoptic Area to the Lateral Habenula in Reward, Aversion, and Drug-Seeking Behavior.

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Project Summary/Abstract Drug addiction is a complex neurological disorder which produces aberrant function in limbic circuits and limbic-associated structures. One specific portion of the basal forebrain—the lateral preoptic area—serves as an important relay between limbic structures and the lateral habenula, a region that has been implicated in addiction and depression. Under the primary mentorship of Drs. Marisela Morales and Geoffrey Schoenbaum, the present Pathway to Independence award will allow me to obtain training in electron microscopy and in vivo calcium imaging in order to elucidate the role of the preopto-habenular projection in the processing of rewarding and aversive stimuli, and eventually the role that this circuitry plays in cocaine addiction. In the mentored phase of this grant, I will use a combination of viral tracers and immuno-electron microscopy in order to determine the targets of the lateral preoptic area glutamatergic and GABAergic axons that establish synapses on lateral habenula neurons and to determine how individual differences in postsynaptic receptors contribute to individual differences in the processing of rewarding and aversive stimuli. Subsequently, fiber photometry calcium imaging will be used in order to determine how the terminals of lateral preoptic glutamatergic and GABAergic neurons in the lateral habenula process rewarding or aversive outcomes and their associated cues. In the independent phase, I will combine these cutting-edge techniques with my prior training in order to simultaneously record the axon terminals of lateral preoptic neurons in the lateral habenula using fiber photometry and the responses of the postsynaptic cells in the lateral habenula using single-unit electrophysiological recordings in order to establish a role for the preopto-habenular pathway in cocaine self-administration, punishment-imposed abstinence, and cued reinstatement. In summary, the research proposed in this Pathway to Independence Award will elucidate the ultrastructural architecture and functional mechanisms of a novel circuit that participates in cocaine self-administration while simultaneously providing me with the tools to establish an independent research program capable of producing high impact studies that bridge anatomical data with cutting-edge techniques for examining circuit function.