PROJECT SUMMARY Estrogen withdrawal at menopause is associated with a suite of metabolic, vascular, and neuroendocrine changes that impact health and quality of life. The most specific symptoms associated with menopause are vasomotor symptoms, which include hot flashes and night sweats. It is thought that vasomotor symptoms are caused by fluctuating estrogen levels at the time of the menopausal transition. However, it is unclear how these changes affect temperature regulation in the brain. Our preliminary data identify a thermoregulatory role for neurons that express estrogen receptor alpha (ER) in the medial preoptic area (MPO) of the hypothalamus, a potent temperature sensor and regulator. We hypothesize that ER signaling in the MPO modulates the activity of thermoregulatory neural circuits. To test this hypothesis, we propose the following specific aims: 1) Define the thermoregulatory role of ER+ neurons and ER signaling in the MPO, 2) Dissect the neural circuitry that mediates estrogen-induced changes in heat dissipation and generation, and 3) determine the transcriptional effects of estrogen signaling in thermoregulatory ER+ neurons. Together these studies will dissect the effects of estrogens on temperature regulation at the level of circuits, neurons, and gene expression. This mechanistic approach is essential for understanding how estrogens alter body temperature and is a necessary first step toward identifying new non-hormonal therapies for hot flashes and other vasomotor symptoms.