Seth M. Tomchik, Ph.D. - US grants

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Memory impairment is a core deficit accompanying many neuropsychiatric disorders. This proposal will examine a central signaling pathway involved in learning and some mental illnesses, revealing how cAMP/PKA signaling is activated during learning across the arrays of neurons that encode memories. These experiments will provide insight into how memories are formed, shedding light on the biological basis of memory impairment and investigating potential targets for treatment of memory disorders.

Neurofibromatosis type 1 is one of the most common monogenic developmental disorders, affecting ~1 in 3,500 individuals worldwide. Some form of cognitive or neuropsychiatric dysfunction is present in approximately 50-80% of individuals with NF1, and these are often considered the major causes of lifetime morbidity. The neurofibromin protein (Nf1) directly inhibits Ras signaling, but also affects several other signaling cascades (possibly indirectly). The complexity of the signaling cascades implicated in neurofibromatosis 1, combined with the lack of drugs to target Nf1 directly, highlights the pressing need for new approaches to target NF1 phenotypes. Uncovering genetic modifers of neurofibromatosis 1-related cellular dysfunction would provide potential new targets for treating this disorder. This project will focus on hyperactivity and repetitive behaviors in Drosophila loss of function nf1 mutants. The large effect size of these behavioral deficits will enable their use it as a readout to unravel both the in vivo molecular and circuit functions of the neurofibromin protein in a powerful genetic model organism. Specific aims will investigate how Nf1 loss of function affects hyperactivity/repetitive behaviors, test the signaling and genetic interactions underlying Nf1 function, probe its role in a putative signaling complex with a novel lipid signaling interaction partner, and decipher the effects of loss of Nf1 on neuronal circuit excitability and function.

Project Summary Learning and memory are modulated by dopaminergic circuits, which convey valence and/or arousal signals. This proposal will examine how discrete dopaminergic circuits modulate learning and memory and neuronal plasticity in memory-encoding brain regions in Drosophila. Specifically, it will disentangle the roles of dopaminergic circuits that convey positive valence signals, negative valence signals, and valence-independent arousal signals. In vivo imaging experiments will examine how these dopaminergic neurons drive discrete patterns of plasticity in the mushroom body and downstream valence-coding output neurons that mediate approach and avoidance behavior. Complementary behavioral and optogenetic manipulation experiments will decipher how each of these neuronal subsets modulates arousal, valence, and memory strength. These studies will apply the large genetic toolkit and experimental throughput of the fly toward developing a more comprehensive understanding of how learning and memory alter the flow of information through the brain, to ultimately engage novel behaviors (e.g., conditioned approach/avoidance) following learning. Understanding how memories are encoded in the brain and disrupted in brain disorders is a prerequisite to the rational design of treatments for memory impairment. Results of the present studies will provide guideposts for future research into the molecular biology of memory formation across multiple model organisms, as dopaminergic circuits regulate arousal and memory across taxa. The project will support our long-term goal of understanding of memory down to the single-cell and subcellular levels, contributing to the knowledge base necessary for the rational development of novel treatments for memory impairment.

Project Summary Neural regulation of sleep and metabolic homeostasis are critical to many aspects of human health. Despite extensive epidemiological evidence linking sleep dysregulation with obesity, diabetes, and metabolic syndrome, little is known about the neural and molecular basis for the integration of sleep and metabolic state. The genetic and functional basis of sleep is highly conserved from fruit flies to mammals. While the application of genetic approaches in flies have been used to identify novel genes and neural circuit mechanisms regulating sleep, the field has predominantly focused on sleep duration, rather than the physiological effects of sleep. This proposal employs a novel assay for simultaneously measuring sleep and metabolic rate in single flies. Preliminary data reveals that mutation of Neurofibromin 1 (Nf1), a gene that has been linked to sleep and metabolic dysregulation in humans, abolishes sleep-dependent modulation of metabolic rate in flies. The proposed experiments seek to identify the neurons required for sleep-metabolism interactions and determine the effects of Nf1 on the activity of neural circuits regulating sleep and metabolic function. Further, genetic experiments will be performed to identify the protein domains within NF1, and downstream signaling pathways, that are required for sleep-metabolism interactions. The completion of this work will yield insights into the cellular and neural circuit basis for the integration of sleep and metabolic rate, and establish flies as a model for investigating these interactions. Given the robust conservation of sleep and metabolism between flies and mammals, these results will provide a platform for investigation of how these processes are regulated, with the potential to provide insight into the association between sleep loss and metabolism-related disease.