A limbic circuit selectively linking active escape to food suppression

Abstract Stress and anxiety are precipitating factors for eating disorders, but the neural basis linking stress to alterations in feeding is not well understood. Here we describe a novel population of stress-responsive neurons in the lateral septum (LS) of mice that express neurotensin (LSNTS) in a sexually dimorphic, estrous cycle-dependent manner. We used in vivo imaging to show that LSNTS neurons are activated by stressful experiences when flight is a viable option, but not by a stressful experience associated with freezing or immobility. LSNTS activation leads to a decrease of food intake and body weight in mice, without altering locomotion or other behaviors associated with anxiety. Molecular profiling of LSNTS neurons showed that these neurons co-express Glp1r (glucagon-like peptide 1 receptor), and both pharmacologic and genetic manipulations of Glp1r signaling in the LS recapitulates the behavioral effects of LSNTS activation. Finally, we mapped the outputs of LSNTS neurons and show that activation of LSNTS nerve terminals in the lateral hypothalamus (LH), a well-established feeding center, also decrease food intake. Taken together, these results show that LSNTS neurons link stress and anorexia via effects on hypothalamic pathways regulating food intake.