Dissection of a neural circuit proposed to underlie hot flush generation

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Abstract Thermoregulation is the ability of homeothermic animals to maintain a steady core body temperature by rapidly responding to changes in the environment. Despite its fundamental nature, our understanding of the neural circuitry underlying thermoregulation is limited. The lack of effective treatments for many disorders of thermoregulation, from hot flushes to various drug- induced hyper- and hypothermias, reflects a lack of knowledge about how and where temperature signals from the environment are converted into compensatory responses. Perhaps the most common disorder of thermoregulation is the development of hot flushes, or periodic and often overwhelming sensations of heat, sweating, and flushing affecting millions of individuals, primarily but not exclusively menopausal women. Here I propose experiments designed to dissect thermoregulatory circuits in the mouse brain while simultaneously testing a proposed model of hot flush generation. The exact mechanism of hot flush generation is currently unknown, though it is associated with a drop in estrogen levels. A leading hypothesis implicates a population of neurons in the arcuate nucleus of the hypothalamus (ARC) co-expressing Kisspeptin, Neurokinin B, and Dynorphin (KNDy) that become hypertrophic in response to estrogen withdrawal and that are thought to project to the preoptic area of the hypothalamus (POA). The POA is well established as the thermoregulatory center of the brain, but the molecular identity of POA neurons underlying temperature regulation is largely unknown. This research proposal has three aims designed to elucidate the molecular identity of neurons comprising a thermoregulatory circuit in mice. Identification of cell-specific neural substrates for thermoregulation will hopefully uncover targets (e.g., receptors) that help to foster the development of novel therapeutics for conditions of dysfunctional thermoregulation and to further our understanding of exactly how temperature signals are converted into compensatory responses. Such knowledge has broad implications not only in thermoregulatory disorders, but also in disorders of general energy balance including those associated with diet.