The co-chaperone Fkbp5 shapes the acute stress response in the paraventricular nucleus of the hypothalamus

Disturbed activation or regulation of the stress response through the hypothalamic-pituitary-adrenal (HPA) axis is a fundamental component of multiple stress-related diseases, including psychiatric, metabolic and immune disorders. The FK506 binding protein 51 (FKBP5) is a negative regulator of the glucocorticoid receptor (GR), a main driver of HPA axis regulation, and polymorphisms have been repeatedly linked to stress-related disorders in humans. However, the specific role of in the paraventricular nucleus of the hypothalamus (PVN) in shaping HPA axis (re)activity remains to be elucidated. Using deletion, overexpression, and rescue of exclusively in the PVN, we establish the fundamental importance of in the HPA axis stress response. Furthermore, we show that manipulation alters GR activation and elucidate the cellular complexity in the PVN, in which operates.