HYPOTHALAMIC LEPTIN-RECEPTOR NEURONS ENCODE SOCIOSEXUAL BEHAVIORS IN A SEX- AND CYCLE-SPECIFIC MANNER

The lateral hypothalamus is a critical brain region for aligning behavioral output with internal state. The adipose tissue-derived hormone leptin is an important internal signal that reflects the level of energy stores and strongly biases feeding behavior and energy expenditure. In the LH, leptin-receptor (LepR) expressing neurons facilitate feeding and exploration under anxiogenic conditions, while limiting feeding and promoting sex-specific social interactions under non-anxiogenic conditions. The underlying neuronal computations that enable LepR^LH neurons to balance nutritional and social needs are poorly understood. Here, we investigated how LepR^LH neurons encode behavior during natural social interactions and how this encoding is shaped by sex and reproductive state. We used single-cell calcium imaging to measure the response of LepR^LH neurons in freely behaving mice of both sexes and both main cycle stages. Based on a generalized linear model and random forest regression of single cell activity, we show that LepR^LH neurons display sex- and cycle-specific adaptations in their response to key sociosexual behaviors. In male animals, fewer neurons exhibit alignment to behavior in comparison to their female counterparts, as well as stronger behavioral selectivity. In female animals, the landscape of behavior-aligned responses shifts between cycle stages in a fashion that shows adaptation to the reproductive context of the animal. Together, we demonstrate that activity levels of leptin-sensitive hypothalamic populations during free social behavior is dynamically tuned by sex and reproductive state, providing a functional framework for understanding how internal signals shape hypothalamic behavioral control in a highly contextualized manner.