An Inhibitory Septum to Lateral Hypothalamus Circuit That Suppresses Feeding.

Feeding behavior is orchestrated by neural circuits primarily residing in the hypothalamus and hindbrain. However, the relative influence of cognitive and emotional brain circuits to the feeding circuitry in the hypothalamus and hindbrain remains unclear. Here, using the cell-type selectivity of genetic methods, circuit mapping, and behavior assays, we sought to decipher neural circuits emanating from the septal nucleus to the lateral hypothalamus (LH) that contribute to neural regulation of food intake in mice. We found that chemogenetic and optogenetic activation of septal vesicular GABA transporter (vGAT)-containing neurons or their projections in the LH reduced food intake in mice. Consistently, chemogenetic inhibition of septal vGAT neurons increased food intake. Furthermore, we investigated a previously unknown neural circuit originating from septal vGAT neurons to a subset of vGAT neurons in the LH, an area involved in homeostatic and hedonic control of energy states. Collectively, our data reveal an inhibitory septohypothalamic feeding circuit that might serve as a therapeutic target for the treatment of eating disorders such as anorexia nervosa. SIGNIFICANCE STATEMENT: Our results demonstrate that top-down projections from the septum to the hypothalamus control food intake negatively. Given the known role for both of these brain regions in the control of feeding and emotion-related behaviors, these findings reveal previously unknown neural circuitry that is likely implicated in emotional aspects of food intake and provide new insights into the development of therapeutic targets for the treatment of eating disorders.