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

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

doi:10.1038/s41380-021-01044-x

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

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

Mathias V Schmidt

Research output: Contribution to journal › Article (Academic Journal) › peer-review

90 Citations (Scopus)

259 Downloads (Pure)

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.

Original language	English
Pages (from-to)	3060-3076
Number of pages	17
Journal	Molecular Psychiatry
Volume	26
Issue number	7
Early online date	1 Mar 2021
DOIs	https://doi.org/10.1038/s41380-021-01044-x
Publication status	Published - Jul 2021

Bibliographical note

Funding Information:
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).

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© 2021, The Author(s).

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Häusl, A. S., Brix, L. M., Hartmann, J., Pöhlmann, M. L., Lopez, J.-P., Menegaz, D., Brivio, E., Engelhardt, C., Roeh, S., Bajaj, T., Rudolph, L., Stoffel, R., Hafner, K., Goss, H. M., Reul, J. M. H. M., Deussing, J. M., Eder, M., Ressler, K. J., Gassen, N. C., ... Schmidt, M. V. (2021). The co-chaperone Fkbp5 shapes the acute stress response in the paraventricular nucleus of the hypothalamus of male mice. Molecular Psychiatry, 26(7), 3060-3076. https://doi.org/10.1038/s41380-021-01044-x

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

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.",

author = "H{\"a}usl, \{Alexander S\} and Brix, \{Lea M\} and Jakob Hartmann and P{\"o}hlmann, \{Max L\} and Juan-Pablo Lopez and Danusa Menegaz and Elena Brivio and Clara Engelhardt and Simone Roeh and Thomas Bajaj and Lisa Rudolph and Rainer Stoffel and Kathrin Hafner and Goss, \{Hannah M\} and Reul, \{Johannes M H M\} and Deussing, \{Jan M\} and Matthias Eder and Ressler, \{Kerry J\} and Gassen, \{Nils C\} and Alon Chen and Schmidt, \{Mathias V\}",

note = "Funding Information: Acknowledgements The authors thank Claudia K{\"u}hne, 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). Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = jul,

doi = "10.1038/s41380-021-01044-x",

language = "English",

volume = "26",

pages = "3060--3076",

journal = "Molecular Psychiatry",

issn = "1359-4184",

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number = "7",

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Häusl, AS, Brix, LM, Hartmann, J, Pöhlmann, ML, Lopez, J-P, Menegaz, D, Brivio, E, Engelhardt, C, Roeh, S, Bajaj, T, Rudolph, L, Stoffel, R, Hafner, K, Goss, HM, Reul, JMHM, Deussing, JM, Eder, M, Ressler, KJ, Gassen, NC, Chen, A & Schmidt, MV 2021, 'The co-chaperone Fkbp5 shapes the acute stress response in the paraventricular nucleus of the hypothalamus of male mice', Molecular Psychiatry, vol. 26, no. 7, pp. 3060-3076. https://doi.org/10.1038/s41380-021-01044-x

TY - JOUR

T1 - The co-chaperone Fkbp5 shapes the acute stress response in the paraventricular nucleus of the hypothalamus of male mice

AU - Häusl, Alexander S

AU - Brix, Lea M

AU - Hartmann, Jakob

AU - Pöhlmann, Max L

AU - Lopez, Juan-Pablo

AU - Menegaz, Danusa

AU - Brivio, Elena

AU - Engelhardt, Clara

AU - Roeh, Simone

AU - Bajaj, Thomas

AU - Rudolph, Lisa

AU - Stoffel, Rainer

AU - Hafner, Kathrin

AU - Goss, Hannah M

AU - Reul, Johannes M H M

AU - Deussing, Jan M

AU - Eder, Matthias

AU - Ressler, Kerry J

AU - Gassen, Nils C

AU - Chen, Alon

AU - Schmidt, Mathias V

N1 - Funding Information: 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). Publisher Copyright: © 2021, The Author(s).

PY - 2021/7

Y1 - 2021/7

N2 - 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.

AB - 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.

U2 - 10.1038/s41380-021-01044-x

DO - 10.1038/s41380-021-01044-x

M3 - Article (Academic Journal)

C2 - 33649453

SN - 1359-4184

VL - 26

SP - 3060

EP - 3076

JO - Molecular Psychiatry

JF - Molecular Psychiatry

IS - 7

ER -

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

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