PROJECT SUMMARY The overall goal of this proposal is to understand sex differences in the neural regulation of feeding, specifically how the anorexogenic effects of estradiol are modulated by a new hypothalamic node of the feeding circuit. Previous research identified somatostatin (SST)-producing neurons as part of the neural circuit that controls feeding, but sex differences were not explored. We find that activating SST neurons in the region that spans the tuberal and ventromedial nuclei of the hypothalamus increases feeding in male and female mice. However, ablating these neurons decreases feeding only in females, only during the high-estrogen phase of the estrous cycle, and only when their body mass is relatively low. These findings are consistent with previous studies but go further to reveal a context-dependent role for SST neurons in the regulation of feeding. We hypothesize that SST neurons of the tuberal nucleus are a sex-specific, modulatory node within the brain that can mask the anorexic effects of estradiol when energy reserves are low. The proposal outlines studies in mice to determine how SST neuronal function is modulated by both reproductive and metabolic cues. In Aim 1, we use cell-specific manipulations combined with gonadal hormone manipulations to reveal how SST neuron function is modulated by reproductive state. In Aim 2, we use cell-specific manipulations combined with manipulations of body mass and adiposity to reveal how SST neuron function is modulated by metabolic state. In Aim 3, we use fluorescent labeling and flow cytometry followed by RNA-sequencing (flow-Seq) to assess how SST neurons may be responsive to reproductive and metabolic conditions and whether this differs by sex. Together, these studies will help us understand how neural circuits integrate multiple peripheral signals to fine tune behavior and physiology across dynamic states.