Abstract
Proper circadian alignment of feeding behavior is necessary to prevent metabolic disease, and thus it is imperative to identify the neural circuits and molecular players that coordinate energy homeostasis. Neurotrophin signaling has been implicated in both metabolic and circadian processes, thereby representing a good candidate for regulating neural circuits driving time-of-day dependent feeding and foraging behavior. Here, we demonstrate that mice lacking the p75 neurotrophin receptor, p75NTR, have a behavioral defect in their ability to adequately respond to energy deficit. In response to fasting, p75KO mice (1) decrease their refeeding food intake compared to controls. Furthermore, following several days of restricted feeding, they (2) are unable to develop food anticipatory behavior (FAA), a phenomenon believed to be the output of a food-entrained circadian oscillator that has yet to be anatomically defined. Strikingly, these two phenotypes are observed only during the daytime, and not at night. These defects lead to increased weight loss, but do not appear to be mediated by changes in peripheral hormones. Notably, these effects are also independent of a role of p75NTR in development, as a global, adult-inducible p75NTR knockout recapitulates the feeding behavior of germline knockout mice. Rather, we demonstrate that p75NTR is discretely expressed in two hypothalamic regions known to be important for feeding behavior, the arcuate (ARC) and dorsomedial (DMH) hypothalamus. We find that p75KO mice have reduced fasting-induced activation of ARC, but not DMH, neurons. In addition, we show that ARC AgRP neuron p75NTR is necessary for fasting-induced refeeding and daytime FAA. We further suggest that AgRP-p75NTR is necessary to mediate AgRP neuron phospho-CREB signaling in response to energy deficit. Finally, given previous reports of involvement of the DMH in food anticipation, we asked whether DMH-p75NTR is necessary for feeding behavior and food anticipation. Strikingly, we find that p75NTR in the DMH is also necessary for FAA, but not for the control of homeostatic feeding. These data establish p75NTR as a novel regulator of energy homeostasis that acts to gate behavioral responses to food scarcity. It further posits that p75NTR may functionally link two independent hypothalamic regions to a time-of-day dependence of circadian food anticipation.
Chemogenetic Synaptic Silencing of Neural Circuits Localizes a Hypothalamus→Midbrain Pathway for Feeding Behavior
