The co-chaperone Fkbp5 shapes the acute stress response in the paraventricular nucleus of the hypothalamus of male mice.
The co-chaperone Fkbp5 shapes the acute stress response in the paraventricular nucleus of the hypothalamus of male mice.
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伴侣FKBP5塑造了雄性小鼠下丘脑室室核中急性应激反应。
DOI：
10.1038/s41380-021-01044-x
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发表时间：
2021-07
影响因子：
11
通讯作者：
Schmidt MV
中科院分区：
文献类型：
--
作者：
Häusl AS;Brix LM;Hartmann J;Pöhlmann ML;Lopez JP;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
通过下丘脑-垂体-肾上腺（HPA）轴的应激反应的激活或调节紊乱是多种应激相关疾病的基本组成部分，包括精神病，代谢和免疫疾病。FK 506结合蛋白51（FKBP 5）是糖皮质激素受体（GR）的负调节因子，糖皮质激素受体是HPA轴调节的主要驱动因素，FKBP 5多态性已被反复与人类应激相关疾病联系起来。然而，下丘脑室旁核（PVN）中Fkbp 5在塑造HPA轴（再）活动中的具体作用仍有待阐明。我们在这里证明，在Sim 1+神经元中Fkbp 5的缺失抑制急性应激反应，并增加GR的敏感性。相反，PVN中Fkbp 5过表达导致慢性HPA轴过度激活，并且在完全Fkbp 5 KO小鼠中PVN特异性拯救Fkbp 5表达使HPA轴表型正常化。单细胞RNA测序揭示了Fkbp 5在PVN中的细胞类型特异性表达模式，并表明Fkbp 5表达在应激后Crh+神经元中特异性上调。最后，Crh特异性Fkbp 5过表达改变Crh神经元活性，但仅部分重现PVN特异性Fkbp 5过表达表型。总之，这些数据确立了PVN中Fkbp 5在塑造HPA轴调节和急性应激反应中的中心和细胞类型特异性重要性。
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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