Obesity and diabetes are unusually prevalent disruptions of energy homeostatic mechanisms which have significant consequences for the health and quality of life of afflicted individuals and impose an enormous financial burden on our nation's health care system. The long-term objective of this research is to understand the central neural circuits through which the brain influences energy expenditure, a key component of energy homeostasis and body weight regulation. Treating such dysregulatiohs of energy homeostasis would be aided by an understanding of the functional organization and neurotransmitters within the central neural pathways that are activated by metabolic signals. The proposed research plan is a logical extension of the results from the initial funding period to directly test a series of specific hypotheses represented in our model of the central neural circuits through which metabolic signals, acting within the hypothalamus, influence brown adipose tissue (BAT) thermogenesis and heart rate by changing the activity of specific populations of brainstem sympathetic premotor neurons. These studies will provide, for the first time, the unique opportunity to define each of the synaptic integration sites in the pathways by which hypothalamic neurons regulate sympathetically-mediated energy expenditure. The proposed studies to elucidate the organization, function and pharmacology of the longitudinally- organized, core pathway for the metabolically-regulated sympathetic activation of BAT thermogenesis and heart rate will combine data from anatomical tracing and immunocytochemical experiments with those from studies examining the effects on sympathetic outflows from microinjection of substances into specific brain regions to guide subsequent electrophysiological recordings from single neurons at sites in the hypothalamus, pons and medullary raphe pallidus. The three specific aims will focus on the relevant anatomical connections, the evoked physiological responses and the behavior of functionally-identified neurons in (1) the dorsomedial hypothalamus, (2) the ventromedial periaqueductal gray and (3) the medial preoptic hypothalamus, respectively, to test clearly defined hypotheses on their functional roles in the activation of RPa neurons that leads to increased energy expenditure and heart rate evoked during the response to leptin or melanocortin agonist administration. Understanding the pharmacology within this pathway driving the sympathetic responses during fever could provide a foundation for developing strategies to alter sympathetically-mediated energy expenditure in support of a reduction in energy storage depots.
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