A Neural Circuit for Hunger Induced Suppression of Socio-affective Behavior

University Of California, San Diego, La Jolla CA

Investigators

Abstract

PROJECT SUMMARY To survive, individuals must appropriately adopt behaviors that fulfill their most pressing needs. This need prioritization requires the brain to flexibly switch between promoting certain behaviors while suppressing others based on different contexts. Feeding and socializing are motivated behaviors that are both critical for survival. During hunger, feeding must be prioritized over social behaviors, and an inability to do so could be detrimental. Though individuals must continuously integrate internal and external cues to select appropriate behaviors, feeding and social behaviors are often studied in isolation, leaving a critical gap in understanding the neural circuits connecting them. This knowledge gap hinders the development of treatments for neuropsychiatric conditions where social dysfunction and disordered eating frequently co-occur, including anxiety, depression, and autism spectrum disorder. To study social and affective behaviors in mice, the Smith lab developed the ‘social transfer of pain’ model, where ‘bystander’ mice display prosocial behaviors and acquire the pain state of an injured partner following a brief social interaction. Interestingly, food deprivation of bystanders suppresses these socio-affective behaviors. Furthermore, the nucleus accumbens (NAc) and paraventricular nucleus of the hypothalamus (PVH) are important for these social behaviors and receive inhibitory input from hunger-activated agouti-related peptide (AgRP) expressing neurons originating in the arcuate nucleus of the hypothalamus (ARC). Activation of ARCAgRP+ neurons drives feeding and suppresses social interactions, though the specific downstream regions inhibited by these neurons to mediate the effects of hunger on social behaviors have not been identified. To identify this circuit-level mechanism, this proposal will test the central hypothesis that activation of ARCAgRP+ projections to NAc and PVH suppresses socio-affective behaviors during hunger. This study will determine (1) how food deprivation alters neural activity during the social transfer of pain and (2) if ARCAgRP+ projections to the NAc and PVH are necessary for the hunger-induced suppression of socio-affective behaviors. The first aim will be tested using immunohistochemistry to determine if food deprivation increases activation in hunger-signaling ARCAgRP+ neurons and decreases activation in the NAc and PVH. Then, to test this in vivo, fiber photometry will be used to record activity of ARCAgRP+ à NAc and ARCAgRP+ à PVH projections in food-deprived bystanders during the social transfer of pain. The second aim will use optogenetic inhibition to test the necessity of these projections, whereby inhibiting activity in these projections is expected to prevent the hunger-induced suppression of socio-affective behaviors. This research will reveal the neural mechanism by which hunger modulates social and affective behaviors, providing critical insights on how motivated behaviors are prioritized in the brain. This is an essential step in developing novel therapeutics for social deficits and disordered eating in neuropsychiatric conditions.