Modulation of the BNST activity by oxytocin - role in stress, fear and anxiety

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SUMMARY: Stress can precipitate the onset of psychiatric disorders, including generalized anxiety disorder (GAD) and posttraumatic stress disorder. Currently available pharmacotherapies have limited efficacy in anxiety disorders - hence there is an urgent need to identify new approaches that can ameliorate anxiety. Stress-induced abnormalities in neuronal activity lead to long-lasting changes in anxiety, hence targeting the mechanisms underlying these effects in stress-sensitive brain regions may provide new insight for treatment. In rodent and human studies, the bed nucleus of the stria terminalis (BNST) has emerged as a key brain region translating stress into sustained changes in anxiety. Repeated stress increases the activity of BNST output neurons, which produce the stress hormone corticotropin-releasing factor (CRF). This parallels a state of anxiety, fear and hypervigilance, hallmarks of stress-induced mental disorders. Accordingly, activity of the BNST is elevated in patients suffering from GAD. Therefore, the factors that regulate BNST output have untapped potential as novel therapeutic targets. We propose that one such target may be engaging local inhibitory interneurons to strengthen inhibition of BNST output neurons. Oxytocin (OT) has been shown to inhibit the stress response and reduce anxiety, but the sites or cellular targets of these OT actions remain unclear. BNST neurons express OT receptors and receive OT input from the paraventricular nucleus of the hypothalamus (PVN). Our preliminary data indicate that OT activates a subset of inhibitory interneurons in the BNST. Based on this premise, the main objective of this proposal is to establish whether by activating the inhibitory interneurons, OT inhibits BNST output and thus reduces anxiety. The central hypothesis of this proposal is that OT ameliorates stress-induced anxiety-like behavior by engaging interneurons that provide inhibitory control over BNST output (CRF) neurons. This innovative concept will be investigated using cutting- edge experimental approaches, including OT promoter-driven expression of inhibitory DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) to selectively suppress the release of OT in the projection from the PVN to the BNST (OT PVNèBNST pathway). Rigorously designed experiments combining behavioral and electrophysiological measures will test the central hypothesis with the following specific aims: 1) Determine the role of OT in the BNST in the regulation of anxiety and fear in male and female rats and 2) Determine the role of OT in regulating the activity of BNST neurons in male and female rats. Accomplishing these Aims will fill a significant knowledge gap by establishing the role of OT in the BNST in ameliorating the effects of stress. We expect that by refining our understanding of central OT effects this proposal will have a positive impact on uncovering the mechanisms underlying the neurobiology of stress-induced psychiatric disorders.