Cristina Miralpeix
University of Bordeaux, INSERM, Neurocentre Magendie, U1215, F-3300 Bordeaux, France
Cristina Miralpeix1,*, Abel Eraso-Pichot1,*, Melissa Sadallah1, Victor Jouque<, Urszula
Skupio1, Vincent Simon1, Philippe Zizzari1, Samantha James1, Carmelo Quarta1, Giovanni
Marsicano1, Daniela Cota1.
1 University of Bordeaux, INSERM, Neurocentre Magendie, U1215, F-3300 Bordeaux, France.
*These authors contributed equally.
Title
Hypothalamic POMC neurons control competing behaviours
Abstract
Survival in natural habitats forces animals to constantly adapt their behavior according to their intrinsic needs and environmental conditions. This situation can put basic physiological responses in competition, forcing the animal to make a choice. For instance, a hungry animal in a threatening situation will favor fear responses over their motivation to eat to ensure survival. However, in this context, how the brain senses the inner state and a threatening situation to orchestrate an optimal survival response has been poorly studied. Within the hypothalamus, pro-opiomelanocortin (POMC)-expressing neurons classically promote satiety during energy surfeit and have a role in the physiological adaptations that occur during stressful and fearful events. Recent findings from our lab have demonstrated that POMC neurons activity is regulated by cannabinoid type 1 (CB1) receptors, key physiological determinants of synaptic and behavioral functions. Here, we hypothesized that CB1 receptor-dependent signaling in POMC neurons is at the intersection of fear and feeding responses. Mice lacking CB1 in POMC neurons POMC-CB1-KO, did not show any relevant change in food intake in basal condition compared to their control littermates. However, when POMC-CB1-KO mice were fasted and in a fearful situation (using fear-conditioning protocol), they displayed higher motivation for eating and decreased fear response than their control littermates. Immunofluorescence and chemogenetic studies showed that POMC activation is necessary for suppressing the motivation to eat in a threatening situation. However, POMC neurons without CB1 are in a hyperactive state, possibly impairing proper decision making. In addition, POMC neurons are a heterogeneous population that can express both inhibitory and excitatory neurotransmitters. We have observed that mice with impaired release of GABA in POMC neurons, also favor eating behavior over fear responses. Thus, these results suggest that CB1 receptors and GABA release in POMC neurons are key to balancing fear and feeding behaviours. Finally, since a threatening situation can activate the stress response and POMC neurons modulate stress hormones release through CRH neurons, we evaluated corticosterone plasma levels observing that corticosterone levels of POMC-CB1-WT and KO correlate with their eating behaviour and fear response. Therefore, we are now deciphering a POMC-to-CRH neurons circuit as possible key to control competing behaviors.