The Role of cAMP/PKA Signaling in Neural Circuits Underlying Memory Formation

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Abstract Candidate A fundamental function of nervous systems is to acquire, categorize, and store sensory information, using it to form predictions about the world that influence future behavior. I am interested in how these processes occur at the molecular, cellular, and neuronal circuit levels. In pursuit of these questions, I have acquired training in psychology, sensory physiology, and learning and memory. My undergraduate education was in psychology, with an emphasis on psychobiology. During my graduate and early postdoctoral training, I studied how the nervous system acquires and processes sensory information using electrophysiology and imaging approaches. Currently, I am studying associative learning in the laboratory of Dr. Ronald Davis, using an experimental approach to study the cellular signaling pathways that are activated during olfactory learning. Intracellular signaling events are imaged in intact brains using genetically-encoded optical reporters, combined with focal application of neurotransmitters to circumscribed regions of the brain. I plan to acquire additional training in behavioral analysis, molecular biology, in vivo imaging, and in vivo photostimulation through the training laid out in this proposal. This training will provide a solid scientific foundation and facilitate launching a productive independent research laboratory within two years. My lab will focus on several broad research areas over the long term: I) the ways in which learning modifies subcellular signaling cascades within neurons; II) how learning alters the response properties across the arrays of neurons that encode memories; III) how the changes in neuronal responsivity alter animal behavior - delineating the circuits that are involved in learning, decision making, and behavioral modification; IV) how these molecular and cellular signaling pathways are altered in mental illnesses. If we can successfully answer these questions, our understanding of the mental health and behavior will be significantly advanced. Environment Scripps Florida is an ideal environment in which to carry out the proposed research and training. The Davis lab has a long and outstanding track record in neurogenetics and behavioral analysis, maintaining ongoing projects on topics ranging from Drosophila learning and memory to the genetics of bipolar disorder in humans. Dr. Davis' group has pioneered genetic techniques to control gene expression spatially and temporally, and has established techniques for in vivo imaging of the adult Drosophila brain. Scripps Florida provides state-of- the-art facilities and resources, supporting high-caliber research across many areas of biology and chemistry. Communication and mutual assistance between labs is outstanding, and collaboration across traditional research disciplines is common practice. Finally, there are frequent scientific seminars, career development workshops, and strong support for postdoctoral researchers. Research Memory impairment is a core deficit accompanying many neuropsychiatric disorders. The cAMP/PKA signaling pathway is critical for memory acquisition and various forms of synaptic plasticity. It also appears to be involved in some mental illnesses, as it has been implicated in bipolar disorder, major depressive disorder, and schizophrenia. Therefore, understanding this pathway is critical for understanding learning and memory as well as mental health and illness. This proposal focuses on the role of cAMP/PKA signaling in learning, with the following specific aims: I) characterize how cAMP elevation translates into PKA activity during associative learning; II) investigate the roles of several candidate adenylyl cyclases in learning; III) examine the effects of elevating cAMP on stimulated and unstimulated neuronal pathways to determine how parallel arrays of neurons encode associative memories; IV) test whether cAMP elevation is sufficient for the formation of aversive memories. To accomplish these aims, behavioral analysis and knock-down of gene expression (RNAi) will be paired with newly-developed live imaging and photostimulation methods, taking advantage of the genetic power of Drosophila melanogaster. This research will extend from the mentored phase (aims I and II) into the independent phase of my career (aims III and IV). The results of these experiments will help reveal how cAMP/PKA signaling functions across arrays of neurons that mediate the acquisition and behavioral expression of memory. Elucidating the fundamental mechanisms with which neurons and circuits encode and retrieve memories will be a major focus of my independent research, and will be extended to understand how these processes are disrupted in neuropsychiatric disorders.