Cellular and circuit investigation of age-dependent social behaviors

PROJECT SUMMARY Understanding the neural basis of social behavior across development is critical, especially given its implications for a plethora of mental health conditions that result from severe disruptions in social relationships from infancy. Our preliminary studies suggest POMC neurons in the hypothalamus—the brain's source of the potent endogenous opioid, beta-endorphin—might be key players in social behavior during development. For instance, social interactions rapidly activate these neurons in juvenile mice (P24-30) and optogenetic activation of POMC neurons causes strong place preference, suggesting these neurons at this age have rewarding properties. These results—combined with the known molecular heterogeneity and developmental changes in POMC neurons— leads us to hypothesize that POMC neurons are differentially attuned to social behaviors during development to increase social reward; when social behaviors are heightened, as for example during the juvenile period, POMC neurons are recruited, modulating the response to social interactions. On this R21, our overarching goal is to elucidate how POMC neurons respond to social stimuli and regulate social behaviors during development with cellular and circuit resolution. In Aim 1, we will map the in vivo responses of POMC neurons to social cues with unparalleled single cell precision, leveraging novel procedures that our group has developed to perform in vivo two-photon microendoscopy in awake infant (P16-18), juvenile (P24-30) and adult (P65-80) mice. In Aim 2, first, we will record the activity of the POMC neuron projections in the nucleus accumbens to determine the dynamics of circuit-specific POMC neuron activity in relation to social interactions in infant, juvenile, and adult mice. Second, we will explore the effects of inhibiting the same projections on social learning. Overall, by elucidating how POMC neurons respond to social interactions and and influence social behaviors during a formative period of brain development, this research will provide foundational knowledge on how the developing brain regulates age-specific social behaviors. The findings from this research could pave the way for novel approaches to mitigate mental health conditions that stem from disruptions in social behaviors in early life. Moreover, the methodologies developed through this work promise to offer valuable tools for the broader neuroscientific community, enabling investigations into neurodevelopmental processes that play a role in physiological and behavioral processes with cellular and circuit resolution.