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

Hausl, Alexander S.; Brix, Lea; Hartmann, Jakob; Poehlmann, Max L.; Lopez, Juan Pablo; Menegaz, Danusa; Brivio, Elena; Engelhardt, Clara; Roeh, Simone; Bajaj, Thomas; Rudolph, Lisa; Stoffel, Rainer; Hafner, Kathrin; Goss, Hannah M.; Reul, Johannes M. H. M.; Deussing, Jan M.; Eder, Matthias; Ressler, Kerry J.; Gassen, Nils C.; Chen, Alon; Schmidt, Mathias V.

doi:10.1038/s41380-021-01044-x

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

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Hausl, Alexander S.
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons261977

Brix, Lea
RG Stress Resilience, Max Planck Institute of Psychiatry, Max Planck Society;
IMPRS Translational Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons135519

Poehlmann, Max L.
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons222540

Lopez, Juan Pablo
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons262522

Menegaz, Danusa
Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons262050

Brivio, Elena
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;
IMPRS Translational Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons207257

Engelhardt, Clara
RG Stress Resilience, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons128467

Roeh, Simone
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80553

Rudolph, Lisa
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons200349

Stoffel, Rainer
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80351

Hafner, Kathrin
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80301

Deussing, Jan M.
RG Molecular Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80315

Eder, Matthias
Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80333

Gassen, Nils C.
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons129892

Chen, Alon
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80514

Schmidt, Mathias V.
RG Stress Resilience, Max Planck Institute of Psychiatry, Max Planck Society;

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Citation

Hausl, A. S., Brix, L., Hartmann, J., Poehlmann, M. L., Lopez, J. P., Menegaz, D., et al. (2021). The co-chaperone Fkbp5 shapes the acute stress response in the paraventricular nucleus of the hypothalamus of male mice. MOLECULAR PSYCHIATRY. doi:10.1038/s41380-021-01044-x.

Cite as: https://hdl.handle.net/21.11116/0000-0008-E01E-A

Abstract

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.