Mechanisms of Stress-Enhanced Aversive Conditioning

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.