Laboratory for Molecular Psychosomatics, Department of Psychosomatic Medicine and Psychotherapy, University of Ulm, 89081 Ulm, Germany.
Laboratory for Molecular Psychosomatics, Department of Psychosomatic Medicine and Psychotherapy, University of Ulm, 89081 Ulm, Germany.
Psychoneuroendocrinology. 2020 Dec;122:104880. doi: 10.1016/j.psyneuen.2020.104880. Epub 2020 Oct 8.
Chronic subordinate colony housing (CSC, 19 days), an established and preclinically-validated mouse model for posttraumatic stress disorder (PTSD), causes evening hypocorticism and a reduced adrenal in vitro ACTH (adrenocorticotropic hormone) sensitivity despite pronounced adrenal hyperplasia. However, until now it remains unclear at what time point during CSC exposure evening hypocorticism and adrenal in vitro ACTH insensitivity develop and whether the repeated change of dominant aggressor mice plays an important role in this context. It is, therefore, the aim of the current study, to explore the detailed time course of these stress-induced adrenal changes.
Adrenal weight, plasma corticosterone (CORT) and ACTH were assessed in the morning of days 8 (right before exposure to the 2nd aggressor), 9 (24 h after exposure to the 2nd aggressor), 15 (right before exposure to the 3rd aggressor), 16 (24 h after exposure to the 3rd aggressor) and 20 or in the evening of days 8 (10 h after exposure to the 2nd aggressor), 9 (34 h after exposure to the 2nd aggressor), 15 (10 h after exposure to the 3rd aggressor), 16 (34 h after exposure to the 3rd aggressor) and 20 of CSC exposure. Moreover, we in vitro cultured adrenal explants of all mice euthanized in the morning of days 8, 9, 15, 16 and 20 either in the presence or absence of ACTH to subsequently assess CORT concentration in the supernatants.
Our results indicate that while adrenal mass was increased at all time points assessed, plasma morning CORT only transiently increased in response to the 2nd (on day 8) but not 3rd (on day 15) dominant aggressor mouse. Moreover, although mild signs of adrenal in vitro ACTH insensitivity developed already after one week of CSC exposure, moderate and severe adrenal in vitro ACTH insensitivity required two and three weeks of chronic subordination, respectively.
Together with unaffected plasma ACTH levels at all time points assessed, our data suggest that stress-induced adrenal in vitro ACTH insensitivity develops gradually during times of chronic subordination while subordination to different aggressor mice aggravates its severity. Moreover, a mild form of adrenal ACTH insensitivity seems to allow prevention of morning hypercorticism on day 8 of CSC, despite functional adrenal mass being increased, while a moderate and severe form of adrenal ACTH insensitivity in CSC mice seems to promote HPA axis adaptation to repeated homotypic stressor exposure (i.e. dominant aggressor mice) and basal evening hypocorticism in CSC mice, respectively. Our results might, therefore, be the basis for future clinical studies assessing CORT supplementation as novel treatment regimen for somatic and affective pathologies linked to chronic and/or traumatic stress.
慢性从属群体饲养（CSC，19 天）是一种已建立且在临床前得到验证的创伤后应激障碍（PTSD）小鼠模型，尽管肾上腺明显增生，但会导致傍晚皮质醇降低和体外 ACTH（促肾上腺皮质激素）敏感性降低。然而，直到现在，仍不清楚在 CSC 暴露期间何时会出现傍晚皮质醇降低和体外 ACTH 敏感性降低，以及反复更换优势攻击鼠是否在这方面起着重要作用。因此，目前的研究旨在探讨这些应激诱导的肾上腺变化的详细时间过程。
在 CSC 暴露的第 8 天（暴露于第二只攻击鼠之前）、第 9 天（暴露于第二只攻击鼠后 24 小时）、第 15 天（暴露于第三只攻击鼠之前）、第 16 天（暴露于第三只攻击鼠后 24 小时）和第 20 天的早晨评估肾上腺重量、血浆皮质酮（CORT）和 ACTH。此外，我们还在第 8 天的早晨（暴露于第二只攻击鼠后 10 小时）、第 9 天（暴露于第二只攻击鼠后 34 小时）、第 15 天（暴露于第三只攻击鼠后 10 小时）、第 16 天（暴露于第三只攻击鼠后 34 小时）和第 20 天的傍晚处死所有 CSC 暴露的小鼠，并在体外培养肾上腺组织培养物，无论是否存在 ACTH，以随后评估上清液中的 CORT 浓度。
我们的结果表明，尽管在所有评估的时间点肾上腺质量都增加，但血浆晨 CORT 仅在对第二只（第 8 天）而不是第三只（第 15 天）优势攻击鼠的反应中短暂增加。此外，尽管在 CSC 暴露一周后已经出现轻度的体外 ACTH 敏感性降低，但中度和重度的体外 ACTH 敏感性需要两周和三周的慢性从属时间。
结合所有评估时间点的血浆 ACTH 水平不受影响，我们的数据表明，应激诱导的体外 ACTH 敏感性在慢性从属期间逐渐发展，而与不同攻击鼠的从属会加剧其严重程度。此外，轻度的肾上腺 ACTH 敏感性似乎可以防止 CSC 第 8 天的早晨皮质醇升高，尽管功能性肾上腺质量增加，而 CSC 小鼠中度和重度的肾上腺 ACTH 敏感性似乎促进了 HPA 轴对重复同种应激源暴露（即优势攻击鼠）的适应和 CSC 小鼠基础傍晚皮质醇降低。因此，我们的结果可能为未来评估 CORT 补充作为与慢性和/或创伤性应激相关的躯体和情感病理学的新型治疗方案的临床研究提供基础。
