Project Abstract The ability to efficiently defend one’s home territory from intruders is an essential behavioral adaptation. However, the neurobiology of this experience-dependent plasticity is unknown. Furthermore, the neural mechanisms in females and sex differences are also unknown; these are critical barriers of therapeutic interventions aimed at improving mental health. My graduate research suggests that females are more sensitive to the rewarding effects of aggressive experience and that oxytocin (OT) transmission may underlie these sex differences. My recent post-doctoral studies support synaptic plasticity in the prefrontal cortex (PFC) and nucleus accumbens (NAc) underlies the adaptive consequences of aggressive experience. Thus, the goal of this proposal is to synthesize my research by 1) acquiring training in state-of-the-art electrophysiological techniques and investigate aggression-induced synaptic plasticity of PFC input to medium spiny neurons (MSNs) in the NAc, and 2) then apply these new skills to assess the contribution of OT to synaptic plasticity of NAc MSNs. Both phases will advance our understanding of the causal role of two distinct circuits in driving aggression reward in both sexes, and provide the training and resources to establish my independent career. Under the collective mentorship of Drs. Patrick Rothwell (primary mentor), Robert Meisel (co-mentor), state-of-the-art research facilities, and expert research consultants, I will have access to a unique and custom set of resources. Dr. Rothwell will lead my training in slice electrophysiology, optogenetics and calcium imaging with fiber photometry. To elucidate specific components of neuronal physiology, I will learn how to measure the effects of aggressive experience on basal synaptic strength of NAc MSNs in male and female Syrian hamsters. I will then assess the effects of aggressive experience on calcium signaling of NAc MSNs in male and females. In combination, I will also utilize optogenetics to assess the involvement of PFC glutamate projections in driving physiological changes and aggression reward in males and females. I predict enhanced PFC synaptic transmission onto NAc MSN drives aggressive experience-dependent behavioral plasticity, e.g. aggression reward and motivation. For the R00 phase I will establish an independent research lab and then implement the skills acquired during the K99 to investigate the role of OT in NAc synaptic plasticity, as well as driving aggression reward and motivation in males and females. OT has been historically considered a monotonic love hormone. However, this proposal seeks to further revolutionize our understanding of the non-canonical and non-monotonic nature of OT and improve sex-specific therapeutic strategies to combat psychiatric disease. I predict OT is a mediator of the NAc MSN synaptic plasticity that drives the enhanced aggression reward and motivation in females compared to males. Collectively, this proposal wil...