Project Summary/Abstract Prolonged social and environmental stress exposure tax the adaptive capacity (flexibility) of an individual and is widely recognized as a major determinant of risk and severity of neuropsychiatric disease. Disorders such as major depression disorder (MDD), obsessive-compulsive disorder (OCD), and schizophrenia exhibit a number of overlapping behavioral symptomologies, including impaired cognition, that are also observed with chronic psychosocial stress1-3 . The range of cognitive problems is diverse, however the most consistently documented deficits include impaired cognitive flexibility, inhibitory control, and working memory2,3. Impairments in flexibility increase susceptibility to negative life events, reduce emotional control, and promote development of maladaptive behaviors that disrupt abilities to engage effectively2,3. Despite the widespread repercussions of intact flexibility, the neural substrates responsible for coincident processing involved in this behavior remain unclear. The prelimbic cortical region (PrLC) of the medial PFC encodes high order functions, including cognitive flexibility using a complex framework of downstream glutamate projections to the nucleus accumbens (NAc) and thalamic structures such as the mediodorsal thalamus (MDT) to guide behavior and detect and resolve conflicts when rules change. Numerous studies have shown that stress-related psychopathology, including reduced cognitive control is associated with synaptic and structural modifications in PrLC circuits. However, the specific cortical output pathways that exhibit these adaptations and how they impact the function of these networks to promote behavioral consequences of chronic stress are not well-defined. Our recently published findings indicate that in the PrLC, CUS promotes opposing changes in intrinsic excitability, neuronal firing, and balance of excitatatory:inhibitory synaptic regulation in pyramidal neurons (PN) expressing dopamine D1 vs. D2-type receptors. Pilot data show that these opposing effects occur within D1-PN projecting to the NAc and D2-PN projecting to the MDT. This exploratory proposal will build upon these findings by gaining insight into the neuropathology that underlies these adaptations in terms of the source and anatomical selectivity of inhibitory synaptic changes (Aim1) and identifying contributions of these sub-circuits to information processing related to cognitive flexibility (Aim 2). We will use an operant-based model of attentional set-shifting (akin to the Wisconsin Card Sorting Task) in transgenic Cre-mice combined with ex vivo optogenetic whole-cell recordings to assess cell-type/pathway-specific plasticity and in vivo circuit-specific chemogenetics to identify how increasing or decreasing activity of these circuits uniquely alters flexible decision-making.