Mechanisms of Stress-Enhanced Aversive Conditioning

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 DESCRIPTION (provided by applicant): In some individuals, traumatic stressful experiences leave lasting painful memories. In others, they cause dissociative amnesia-an inability to consciously access memories of the traumatic events. Nevertheless, such inaccessible memories can profoundly disrupt affective and social functioning. At a fundamental level, dissociative amnesia is thought to be rooted in state-dependent learning, wherein memories encoded in a certain affective or drug-induced state can best be retrieved when the brain is in the same state. Research into the neurobiology of state-dependent learning will give us a better understanding of the development of dissociative amnesia and stress-related psychopathologies. Using mouse models, we propose to identify the molecular mechanisms of state-dependent fear conditioning and the circuit mechanisms by which they affect social behavior. We will use contextual fear conditioning as a model of episodic memory processed by the hippocampal formation. Based on our recent findings, we hypothesize that (1) hippocampal extrasynaptic GABAA receptors (GABAAR) and their sex-specific interactions with oxytocin receptors (Oxtr) contribute to state-dependent fear conditioning, and (2) these mechanisms disrupt distinct social behavioral phenotypes by interfering with hippocampal-lateral septal circuits. Our specific aims are designed to establish which extrasynaptic GABAAR complexes contribute to state-dependent fear conditioning (Aim 1), how they are regulated by Oxtr (Aim 2), and whether they affect social behavior through dorsohippocampal- and ventrohippocampal-lateral septal circuits (Aim 3). We expect to demonstrate important hippocampal subdivision- and sex-dependent contributions of Oxtr to the main GABAergic effects. These mechanisms could constitute new targets for the treatment of dissociative symptoms and social deficits accompanying stress-related disorders.