Lateral septum neurotensin neurons link stress and anorexia

Anorexia Nervosa (AN) is an eating disorder characterized by severe voluntary food restriction 1 . Stress is known to be a precipitating factor in AN 2-5 , but the underlying biology linking stress to feeding is not well understood. Here we describe a novel population of stress-responsive neurons in the lateral septum (LS) that express neurotensin (Nts LS ) and negatively regulate food intake. We used in vivo fiber photometry and chemo/optogenetics to show that Nts LS neurons are activated by stressful experiences, including active escape in a predator-induced stress paradigm, and specifically decrease food intake in mice, without altering anxiety or locomotor behaviors. These neurons co-express Glp1r, and pharmacologic or genetic manipulations of Glp1r signaling in the LS recapitulate the behavioral findings shown using chemo/optogenetics. Finally, we mapped the outputs of Nts LS neurons and show that activation of Nts LS neuronal terminals in the lateral hypothalamus (LH) also decrease food intake. Taken together, these results show that NTS LS neurons serve as a potential link between stress and anorexia and act by modulating hypothalamic pathways regulating feeding.