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), the main driver of HPA axis regulation, and FKBP5 polymorphisms have been repeatedly linked to stress-related disorders in humans. However, the specific role of Fkbp5 in the paraventricular nucleus of the hypothalamus (PVN) in shaping HPA axis (re)activity remains to be elucidated. We here demonstrate that the deletion of Fkbp5 in Sim1+ neurons dampens the acute stress response and increases GR sensitivity. In contrast, Fkbp5 overexpression in the PVN results in a chronic HPA axis over-activation, and a PVN-specific rescue of Fkbp5 expression in full Fkbp5 KO mice normalizes the HPA axis phenotype. Single-cell RNA sequencing revealed the cell-type-specific expression pattern of Fkbp5 in the PVN and showed that Fkbp5 expression is specifically upregulated in Crh+ neurons after stress. Finally, Crh-specific Fkbp5 overexpression alters Crh neuron activity, but only partially recapitulates the PVN-specific Fkbp5 overexpression phenotype. Together, the data establish the central and cell-type-specific importance of Fkbp5 in the PVN in shaping HPA axis regulation and the acute stress response.
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Acknowledgements The authors thank Claudia Kühne, Mira Jakov-cevski, Daniela Harbich, and Bianca Schmid (Max Planck Institute of Psychiatry, Munich, Germany) for their excellent technical assistant and support. We thank Stefanie Unkmeir, Sabrina Bauer, and the scientific core unit Genetically Engineered Mouse Models for genotyping support. Further, we want to thank Alina Tontsch and the core unit BioPRep (Biomaterial Processing and Repository) for ELISA analysis of ACTH samples. This work was supported by the “OptiMD” grant of the Federal Ministry of Education and Research (01EE1401D; MVS), the BioM M4 award “PROCERA” of the Bavarian State Ministry (MVS), the “Kids2Health” grant of the Federal Ministry of Education and Research (01GL1743C; MVS) and by a NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation (JH).
© 2021, The Author(s).