Veterans with schizophrenia are among the most ill of those treated at VA facilities, which presents a great burden on care and VA resources. The inadequacy of treatment response and myriad side effects of current medications makes long-term care and medication adherence difficult. Hence, better treatment of Veterans with psychotic disorders will greatly improve their overall quality of life and long-term care. Recent evidence suggests that social isolation or withdrawal may contribute to the emergence of psychiatric illness, or be a precipitating factor. For example, social withdrawal in schizophrenia occurs prior to symptoms of psychosis and continued social decline predicts conversion to psychosis. Individuals with schizophrenia show disruptions in frontal cortex and hippocampal circuitry, which contribute to negative symptoms and cognitive deficits. Cognitive deficits are particularly debilitating and remain undertreated with current antipsychotic medications. Based on the course of illness it is likely that the severity of social withdrawal/isolation contributes to the neuropathology in schizophrenia; however, the mechanism through which this progression occurs is not known. Because of ongoing deterioration in symptoms and better prognosis with early therapeutic interventions, there is a need to identifying potential risk factors, prodromal symptoms, and biomarkers to help screen military personnel at risk for serious mental illness and provide opportunities for early intervention. The goals of the proposed studies are (1) to determine the impact of social isolation (SI) in rodents on frontal cortex and hippocampal circuitry and behaviors relevant to schizophrenia (e.g. deficits in cognitive flexibility and sensorimotor gating) and (2) identifying biomarkers predictive of susceptibility, and (3) develop more efficacious early interventions for neuropsychiatric disorders, particularly schizophrenia. Aim 1 studies assess the contribution of glutamate and GABA function in cortex and hippocampus to the development of cognitive deficits in socially isolated rats. Studies examine the progression of both cognitive deficits and alterations in markers of excitatory and inhibitory neurons via immunohistochemistry and glutamatergic neuronal activity via in vivo fiber photometry. Aim 2 studies use optogenetics to determine whether neuromodulation of orbitofrontal cortex (OFC) to dorsomedial striatum (DMS) glutamate projections can remediate cognitive deficits in socially isolated rats. Aim 3 studies examine whether early interventions with a metabotropic glutamate receptor agonist, LY379268, to decrease glutamate signaling can prevent the development of cognitive dysfunction associated with social isolation. These preclinical studies will provide a better understanding of the impact of social isolation on neural circuitry and cognitive behavior and identify potential therapeutic targets for future studies in Veterans.