Project Summary Individuals with post-traumatic stress disorder (PTSD) consume alcohol as an attempt to alleviate symptoms, which can increase the risk of developing a drinking problem. However, well-adapted coping responses to stress may protect against development of PTSD and mitigate subsequent alcohol use. Further, not only are women twice as likely as men to suffer from PTSD, but certain individuals may be more susceptible or resilient in adapting to stressful events. This suggests specific brain mechanisms that mediate sex differences in response to stress and also individual differences in coping responses may mitigate against lasting consequences of stress such as alcohol consumption. In this proposal, I will investigate how failure to engage in adaptive coping strategies to stress may be driven by hypofunctioning between corticolimbic regions specifically the prelimbic (PrL) cortex and the basolateral amygdala (BLA), and whether increases in endocannabinoid signaling can restore this maladaptive behavior. I utilize an animal model of stress exposure to the predator odor TMT, which produces distinct coping behaviors between male and female rats, as well as individual differences in subsequent increases in alcohol self-administration. Using this model, I will utilize a variety of chemogenetic, electrophysiological and optogenetic techniques to directly manipulate the PrLBLA circuit and examine its functional role in driving adaptive responses to stress and alcohol self-administration in male and female rats. Further, I will investigate the direct role of endocannabinoid signaling in modulating maladaptive versus adaptive coping responses and whether this signaling can act as a protective mechanism against later escalations in alcohol self-administration. The K99 portion of this proposal involves extensive training using chemogenetic and cell-specific molecular approaches and advanced electrophysiological techniques to probe both functional changes and in vivo neuroadaptive responses. This training will provide me with a stronger neuroscience foundation which will be critical to increase my competitiveness on the job market and will be important in my independent career. Uncovering the neural mechanisms that drive maladaptive coping behavior and subsequent alcohol self-administration within the K99 portion will provide future directions for the R00 phase. Studies within the R00 phase will specifically assess whether endocannabinoids can directly restore PrL hypofunctioning that leads to dysregulated neuroadaptations within the BLA and central amygdala (CeA) circuitry that drives behavioral outcomes to stress. Together, completion of these aims will establish corticolimbic circuitry and endocannabinoid mechanisms that drive coping strategies during predator odor stress and alcohol drinking. Additionally, studies in this application will further my long-term research goal which is to elucidate neurobiological mechanisms that underlie sex dif...