Impact of BDNF on the Development of Social Behavior Circuits

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Project Summary Social behavioral impairments are common and highly disabling symptoms in many psychiatric disorders, including depression and anxiety disorders that emerge in adolescence and young adulthood. The intrinsic complexity of social behavioral outcomes have made understanding their underlying neural correlates difficult. In particular, the molecular mechanisms regulating the development and function of social behavioral circuits remain largely unknown. In this context, one potential candidate molecule is brain-derived neurotrophic factor (BDNF), a key regulator of neuronal synaptic plasticity that has been implicated in depression and anxiety disorders, and is also highly expressed in brain regions implicated in social behaviors. Our central hypothesis is that BDNF is required for the proper development during a peri-adolescent timeframe of a key orbitofrontal cortex (OFC)-to-amygdala circuit that supports social approach behavior. Multiple studies in rodents, non-human primates, and humans indicate that the OFC supports cost-benefit decision making, and encodes and updates representations of the expected value of future outcomes, suggesting that the OFC may play a role in motivating social approach behavior. Our extensive preliminary data in loss-of-function BDNF mouse lines support the premise of the requirement of BDNF in the peri-adolescent development of OFC-amygdala circuits related to social function. We propose to assess the impact of BDNF on the structural and functional development of this OFC-to-amygdala circuit during the peri-adolescent period. We will use a live calcium imaging technique (fiber photometry) to record the activity of this circuit during a repertoire of social behaviors. In addition, we will use chemogenetic tools to bi-directionally modulate the activity of these neurons and to delineate more precisely what aspects of social behavior are mediated by these OFC projections. Finally, we will utilize newly developed viral reagents for circuit-specific and developmentally-timed manipulations of BDNF signaling. Our studies are designed identify a new role for BDNF during peri-adolescence to establish optimal function of cortico-amygdala circuits related to social behaviors.