Summary Traumatic stress exposure elicits behavioral and physiological responses that can compromise health and well-being, generating brain and bodily changes that can intrude on appropriate emotional regulation. Numerous disease states, most notably post-traumatic stress disorder, share behavioral and physiological dysfunctions typical of traumatic stress exposure, indicative of a link between stress and disease. The long- term objective of this research line is to understand brain mechanisms that control behavioral stress responses, knowledge that will be essential for designing strategies for management of maladaptive behaviors in stress-linked disorders. This proposal queries the neurocircuitry underlying lasting behavioral pathologies linked to severe stress, focusing on the role of intralimbic cortex (IL) connections in driving pathology. Prior research and our preliminary data present strong evidence for reduced IL excitability following severe stress exposure, and functional hypoactivity of the human IL homolog is associated with PTSD. This proposal is designed to understand the mechanisms underlying stress-induced IL hypofunction, concentrating on changes in intrinsic processes and afferent connectivity. Aim 1 is designed to test the necessity and sufficiency of IL afferent input in causing long-lasting severe stress-induced impairments in fear adaptation (extinction) and reinstatement of fear following stress reminders, using a rat model of trauma exposure (single prolonged stress). The role of IL afferent connections from the prelimbic cortex (PL) and ventral hippocampus (vHPA) in SPS-induced fear pathology will be tested using viral vector mediated expression of excitatory and inhibitory DREADDs, and circuit mapping employed to test engagement PL-IL and vHPC-IL circuitry . Aim 2 will use electrophysiological approaches to explore cellular and connectional mechanisms driving IL hypoactivity following SPS, focusing on intrinsic neuronal excitabilty and synaptic drive by PL and vHPC projections to the IL. Aim 3 will use a multi-dimensional approach to identify molecular processes underlying IL hypoexcitability, using an analysis platform integrating genomic, proteome and kinome data. Studies will use bioinformatic approaches to determine possible drug targets for intervention in males and females. Results of these studies will inform development of new pharmacological and/or circuit-targeting intervention strategies to promote stress resilience in individuals exposed to traumatic or severe stress.