Hypothalamic POMC Neurons Gate the Fear‐Feeding Trade‐Off
Cristina Miralpeix, Abel Eraso‐Pichot, Vincent Simon, Victor Jouque, Melissa Sadallah, Samantha Clark, Philippe Zizzari, Urszula Skupio, Ana Covelo, Nathalie Dupuy, Jean Charles Nicolas, Astrid Cannich, Thierry Leste‐Lasserre, Guillaume Laplagne, Carmelo Quarta, Giovanni Marsicano, Daniela CotaABSTRACT
To survive, animals must constantly balance the need to obtain food with the need to avoid danger. Feeding is essential, yet perceived danger shifts priority toward safety and transiently suppresses food intake, even when organisms are hungry. Hypothalamic pro‐opiomelanocortin (POMC) neurons align metabolic outputs with energy demands and control feeding. However, the role of POMC neurons in determining the trade‐off between feeding and threat responses remains unclear. Here, fasted mice are exposed to a fear‐conditioning paradigm to examine how POMC neurons influence the choice between feeding and defensive behaviors. Behavioral analyses combined with chemogenetic, neuroanatomical, and molecular approaches show that activation of POMC neurons suppresses feeding during a learned threat and it is associated with corticotropin releasing hormone (CRH) neuron–dependent activation of the hypothalamic–pituitary–adrenal (HPA) axis. These effects require cannabinoid type 1 receptor (CB1R) signaling in POMC neurons, uncovering a POMC–CB1R pathway that tunes behavioral flexibility under a perceived threat. Collectively, the data identify POMC neurons as key integrators of metabolic and stress signals that bias decision making between feeding and threat‐avoidance behaviors.