FKBP51 in the oval bed nucleus of the stria terminalis regulates anxiety-like behaviour.

The co-chaperone FKBP51, encoded by the Fkbp5 gene, has been identified as central risk factor for anxiety-related disorders and stress system dysregulation. In the brain, the oval bed nucleus of the stria terminalis (ovBNST) has been implicated in stress-induced anxiety. However, the role of Fkbp5 in the ovBNST and its impact on anxiety-like behavior have remained unknown. Here we show in mice that Fkbp5 in the ovBNST is reactive to acute stress and co-expressed with the stress-regulated neuropeptides Tac2 and Crh Subsequently, results obtained from viral-mediated manipulation indicate that Fkbp5 overexpression (OE) in the ovBNST results in an anxiolytic-like tendency regarding behavior and endocrinology, whereas a Fkbp5 knockout exposed a clear anxiogenic phenotype, indicating that native ovBNST expression and regulation is necessary for normal anxiety-related behavior. Notably, our data suggests that a stress-induced increase of Fkbp5 in the ovBNST may in fact have a protective role, leading to a transient decrease in anxiety and suppression of a future stress-induced hypothalamic-pituitary-adrenal (HPA) axis activation. Together, our findings provide a first insight into the previously unknown relationship and effects of Fkbp5 and the ovBNST on anxiety-like behavior and HPA axis functioning.Significance StatementThe co-chaperone FKBP51 is a known risk factor for psychiatric disorders and stress system dysregulation. Both FKBP51 and the oval bed nucleus of the stria terminalis (ovBNST) have been implicated in anxiety, yet their combined effects of mediating anxiety-like states have not been explored. Here we provide a characterization of the role of Fkbp5 in the ovBNST on HPA axis function and anxiety-related behavior. Our findings suggest that stress induction of Fkbp5 in the ovBNST may have a protective role, leading to decreased anxiety and suppression of a future stress-induced HPA axis activation. Overall, this study constitutes a basic step towards understanding the underlying mechanisms of Fkbp5 signaling in the ovBNST and their role in stress-induced anxiety disorders.