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

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

doi:10.1038/s41380-021-01044-x

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.

Highlights

As paraventricular nucleus of the hypothalamus (PVN) Fkbp5 mRNA levels are highly responsive to an acute stressor [10], we hypothesized that Fkbp5PVN−/− mice have an altered stress response following an acute challenge
Already after 15 min of restraint stress adult and young Fkbp5PVN−/− mice displayed significantly reduced plasma corticosterone levels compared to the control group (Fig. 1D)
The subsequent corticotropin-releasing hormone (CRH) injection resulted in a higher corticosterone release in Fkbp5PVN OE mice compared to controls (Fig. 2F). These results suggest that excess levels of Fkbp5 in the PVN lead to a decreased glucocorticoid receptor (GR) sensitivity and thereby to an altered HPA axis response

Summary

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Most of the animal data were obtained from wild-type (WT) or conventional Fkbp knockout mice, thereby lacking cell-type-specific insights of Fkbp function [8, 18]. To tackle this paucity of information, we here investigate the specific role of Fkbp in the paraventricular nucleus of the hypothalamus (PVN) the key brain region orchestrating the stress response [19]. Using site-specific manipulations of Fkbp, single-cell RNA expression profiling, and functional downstream pathway analyzes, our data unravel a key role of PVN Fkbp in shaping the body’s stress system (re) activity, with important implications for its contribution to stress-related disorders

Material and methods

Sampling procedure

Results

Discussion

Compliance with ethical standards