Project Summary Goal-directed behavior is dependent on a constellation of ‘executive’ cognitive and behavioral processes dependent on the prefrontal cortex (PFC) and extended frontostriatal circuitry. Dysregulation of PFC-dependent cognition and behavior is associated with numerous psychopathologies, including ADHD. Currently there is a dire need for improved treatments for frontostriatal dysregulation. For example, while psychostimulants are highly effective in the treatment of ADHD, they lack full efficacy across the broader patient population and are increasingly subject to abuse. Unfortunately, the development of novel pharmacological treatments for PFC dependent cognitive dysfunction is limited by a scarcity of alternative targets. From this perspective, it is of interest that corticotropin-releasing factor (CRF) and its receptors are prominent in the PFC. In recently completed studies, we demonstrated that CRF receptor blockade within the caudal dorsomedial PFC (dmPFC) improves working memory in male rats, similar to all approved drug treatments for ADHD. Thus, CRF may represent a novel target for the development of new treatments for PFC-dependent cognitive dysfunction. The proposed multidisciplinary studies will provide a better understanding of the broader cognitive actions of CRF neurotransmission in the PFC in males and females and identify the circuit mechanisms responsible for these actions. Aim 1 will determine the broader impact of PFC CRF receptors across PFC-dependent cognitive processes in both males and females using intra-PFC infusions of CRF and CRF antagonists. Aim 2 uses recently developed viral vector-based chemogenetic manipulations of PFC CRF neurons combined with intra-PFC infusions of a CRF antagonist to determine whether local neurons are a primary source of CRF for PFC CRF receptors. Finally, Aim 3 uses ensemble neuronal recordings to determine the extent to which PFC CRF receptors and neurons impair neuronal coding within the dorsomedial frontostriatal circuit. Collectively, these studies will provide novel insight into the neurobiology of frontostriatal-dependent cognition. In doing so, these studies may provide a better understanding of the neural bases of PFC cognitive dysfunction and lead to novel treatment strategies for PFC-dependent cognitive dysfunction.