Thermogenesis is the principal mechanism through which mammals dissipate energy. Pioneering work dating back to the 1930s demonstrated that neurons within the hypothalamus are sensitive to ambient and local deviations in temperature, and that in turn, these neurons could outcome a potent change in body temperature. A basic goal of neuroscience has been to identify the neural substrates underlying thermoregulation. Significant progress has been made on understanding how hypothalamic cell types regulate thermogenesis and thermogenesis related processes such as shivering; however, what populations outside of the hypothalamus regulate temperature and how they accomplish this feat is incompletely understood. Mentored work will focus on establishing the dorsal raphe nucleus (DRN) as a critical regulator of thermogenesis. In particular, we plan to delineate the neural circuits embedded within the DRN that regulate energy expenditure through changes in thermogenesis. Preliminary data using whole-brain activity mapping, demonstrate activation of GABAergic DRN neurons in heat environment. Furthermore, through a combination of chemogenetic approaches, we proof that activation of these neurons directly regulate thermogenesis through autonomic and/or behavioral mechanisms. Together, through a combination of functional, molecular, and anatomic approaches, we will dissect whether the DRN bidirectionally controls thermogenesis and its specific upstream and downstream neurocircuitry in thermal regulation. Previous identified roles in feeding regulation for this region together with these results opens a new horizon in obesity treatment. On the independent phase, I plan to identify the molecular identity of neurons in premotor areas of the CNS responsible for a thermogenic response. My overarching hypothesis is that one subset of premotor neurons in the CNS drives a coordinated response to control thermogenesis through sympathetic nervous system mediated outflow to specific peripheral tissues. Furthermore, after corroborating that direct modulation of these neurons modulates body temperature, the proposed research will focus on defining if there is neuronal molecular heterogeneity in these premotor areas regarding the sympathetic nervous system mediated coordinated thermogenic response. I will take an interdisciplinary approach, using a combination of novel, state-of-the-art molecular technologies, such as optogenetics, neuronal tracing, calcium imaging and molecular phenotyping, together with metabolic assessments. This work will ultimately identify how the CNS orchestrates a thermogenic response. The proposed work will set the grounds for my own laboratory on central nervous system (CNS) mediated regulation of thermogenesis. Altogether, this work seeks to better understand thermogenesis regulation and establish the framework of my career as an independent investigator. Additionally, future molecular profiling studies of these neurons will allow us to perform cell-type specific targeted pharmacology mimicking the metabolic outcomes of cold exposure to ultimately treat obesity. !

Public Health Relevance

The proposed project aims to elucidate which brain nuclei underlie the response to changes in whole body thermogenesis. This work will improve our understanding on thermogenesis identifying the molecular identity of neurons in premotor areas driving a thermogenic response, which could lead to the development of novel, cell type specific efficacious therapies for treating obesity. Furthermore, direct manipulation of identified neuronal subtypes will provide unprecedented information of how the coordinated sympathetic nervous system mediated thermogenesis response is produced.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Career Transition Award (K99)
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Kidney, Urologic and Hematologic Diseases D Subcommittee (DDK)
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Cooke, Brad
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Rockefeller University
New York
United States
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