Short-term social isolation acts on hypothalamic neurons to promote social behavior in a sex- and context-dependent manner

Social animals, including both humans and mice, are highly motivated to engage in social interactions. Short-term social isolation increases social motivation and promotes social behavior, but the neural circuits through which it does so remain incompletely understood. Here, we sought to identify neurons that promote social behavior in single-housed female mice, which exhibit increased rates of social investigation, social ultrasonic vocalizations (USVs), and mounting during same-sex interactions that follow a period of short-term (3-day) isolation. We first used immunostaining for the immediate early gene Fos to identify a population of neurons in the preoptic hypothalamus (POA) that increase their activity in single-housed females following same-sex interactions (POAiso neurons). TRAP2-mediated chemogenetic silencing of POAiso neurons in single-housed females significantly attenuates the effects of short-term isolation on social investigation and USV production and also tends to reduce mounting. In contrast, caspase-mediated ablation of POAiso neurons in single-housed females robustly attenuates mounting but has no effect on social investigation or USV production. Optogenetic activation of POAiso neurons in group-housed females promotes USV production but does not recapitulate the effects of short-term isolation on social investigation and mounting. To understand whether a similar population of POAiso neurons promotes social behavior in single-housed males, we performed Fos immunostaining in single-housed males following either same-sex or opposite-sex social interactions. These experiments revealed a population of POA neurons that increase Fos expression in single-housed males following opposite-sex, but not same-sex, interactions.Chemogenetic silencing of POAiso neurons in single-housed males during interactions with females tends to reduce mounting but does not decrease social investigation or USV production. These experiments identify a population of hypothalamic neurons that promote social behavior following short-term isolation in a sex- and social context-dependent manner. ### Competing Interest Statement The authors have declared no competing interest.