A sex-specific thermogenic neurocircuit induced by stressful olfactory inputs.

Abstract When detecting danger signals, animals exhibit adaptive changes in physiology and behavior aimed at increasing survival. In small prey animals, such as rodents, olfactory information plays a fundamental role in the perception of their environment and predator avoidance. Exposure to predation has been associated with reduced fatness in male rodents, but whether similar responses exist in both sexes is poorly understood. Exactly how the nervous system regulates weight in the context of danger perception remains unknown. Here we identify a sex-specific response leading to increased energy expenditure and elevated corticosterone in female mice exposed to predator smell or global stimulation of mitral and tufted cells of the olfactory bulb (OB). This response is absent in male mice and is not attenuated by gonadectomy in females. A population of neurons in the dorsomedial hypothalamus (DMH), selectively activated by aversive olfactory signals also receives polysynaptic afferents from mitral and tufted cells of the main OB (MOB). Cell sorting of projection neurons in the DMH receiving olfactory inputs and single-nucleus RNA-sequencing identify cholecystokinin (Cck)-expressing neurons as putative recipients of olfactory inputs. Chemogenetic stimulation of DMHCCK neurons recapitulates the effects of aversive olfactory stimulation on female energy expenditure. Taken together, our results suggest the existence of a female heightened stress reaction recruiting DMHCCK neurons to promote high energy utilization.