Project Summary There is an increased risk for abnormal social behavior in individuals suffering from psychiatric disorders. This is highlighted by the common comorbidity between aggression and addiction to opioids and other drugs. One form of aggression in particular – appetitive aggression – exhibits symptomatology that closely mimics drug addiction, and it is hypothesized that appetitive aggression is due to dysregulation of reward circuits in a manner akin to drug addiction. This is an unproven hypothesis, and in contrast to drug addiction, the circuits underlying motivational components of aggressive behavior in rodent models are largely unknown. Therefore, the aim of this proposal is to obtain the necessary training to identify, interrogate, and manipulate mechanisms underlying relapse to aggression seeking. It will also determine the effect of opioid dependence on relapse to aggression seeking. This proposal will focus first on identifying the intact whole brain functional connectome of relapse to aggression seeking, and then more specifically address the role of the nucleus accumbens (NAc) and its afferent projections. The choice of this brain region is based on converging preliminary data implicating a critical role for NAc in aggression reward, and NAc’s well established role as a critical locus regulating drug addiction. This will be achieved using a novel behavioral model of aggression self-administration and relapse. The functional and structural connectome will be identified using iDisco+, a whole brain clearing method, in conjunction with viral retrograde tracing and Fos (a marker of neuronal activity) immunohistochemistry. Because of the limited temporal resolution of Fos during learned behaviors, awake-behaving single-unit electrophysiological recording will be used to observe how NAc neurons encodes aggression reward. Next, the causal significance of the NAc and its afferent projections will be examined using region, circuit, and cell-type specific chemogenetic manipulations. Lastly, this proposal will study the effect of oxycodone (a commonly abused prescription opioid) dependence on relapse to aggression seeking, towards identification of novel therapeutic interventions for the treatment of aggression comorbid with opioid addiction.