Chronic adolescent stress alters GR-FKBP5 interactions in the hippocampus of adult female rats

Chronic stress exposure during development can have lasting behavioral consequences that differ in males and females. More specifically, increased depressive behaviors in females, but not males, are observed in both humans and rodent models of chronic stress. Despite these known stress-induced outcomes, the molecular consequences of chronic adolescent stress in the adult brain are less clear. The stress hormone corticosterone activates the glucocorticoid receptor, and activity of the receptor is regulated through interactions with co-chaperones—such as the immunophilin FK506 binding proteins 5 (FKBP5). Previously, it has been reported that the adult stress response is modified by a history of chronic stress; therefore, the current study assessed the impact of chronic adolescent stress on the interactions of the glucocorticoid receptor (GR) with its regulatory co-chaperone FKBP5 in response to acute stress in adulthood. Although protein presence for FKBP5 did not differ by group, assessment of GR-FKBP5 interactions demonstrated that adult females with a history of chronic adolescent stress had elevated GR-FKBP5 interactions in the hippocampus following an acute stress challenge which could potentially contribute to a reduced translocation pattern given previous literature describing the impact of FKBP5 on GR activity. Interestingly, the altered co-chaperone interactions of the GR in the stressed female hippocampus were not coupled to an observable difference in transcription of GR-regulated genes. Together, these studies show that chronic adolescent stress causes lasting changes to co-chaperone interactions with the glucocorticoid receptor following stress exposure in adulthood and highlight the potential role that FKBP5 plays in these modifications. Understanding the long-term implications of adolescent stress exposure will provide a mechanistic framework to guide the development of interventions for adult disorders related to early life stress exposures.

发育阶段长期应激暴露可引发持久的行为学改变，且该改变存在雌雄差异。具体而言，在慢性应激的人类与啮齿类动物模型中，雌性个体的抑郁样行为显著增加，而雄性个体则无此变化。尽管上述应激诱导的表型已被证实，但青春期慢性应激对成年大脑的分子层面影响仍尚不明确。
应激激素皮质酮（corticosterone）可激活糖皮质激素受体（glucocorticoid receptor, GR），而该受体的活性可通过与共伴侣蛋白（co-chaperones）的相互作用进行调控，例如免疫亲和蛋白FK506结合蛋白5（FK506 binding proteins 5, FKBP5）。既往研究表明，个体的慢性应激史会改变其成年后的应激响应，因此本研究旨在探究青春期慢性应激，如何影响成年个体在遭遇急性应激时，糖皮质激素受体（GR）与其调控性共伴侣蛋白FKBP5之间的相互作用。
尽管各组FKBP5的蛋白表达水平并无显著差异，但对GR-FKBP5相互作用的检测结果显示：有青春期慢性应激史的成年雌性个体，在经历急性应激刺激后，其海马体内的GR-FKBP5相互作用水平显著升高。结合既往关于FKBP5对GR活性影响的研究，该变化或可导致GR转位模式减弱。值得注意的是，应激雌性个体海马体中GR的共伴侣蛋白相互作用发生改变这一现象，并未伴随GR调控基因的转录水平出现可观测的差异。
综上，本研究结果表明，青春期慢性应激可在成年个体遭遇应激暴露后，持续改变糖皮质激素受体与其共伴侣蛋白的相互作用，并凸显了FKBP5在该修饰过程中的潜在作用。阐明青春期应激暴露的长期影响，将为开发针对早期生活应激相关成年期疾病的干预手段提供机制层面的理论框架。