Mechanisms of adaptation of the hypothalamic-pituitary-adrenal axis in male mice under chronic social defeat stress

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Abstract

The hypothalamic-pituitary-adrenal axis (HPA) plays an important role in the mechanisms of adaptation to chronic stress. A model of chronic social defeat stress (CSDS), based on the experience of defeat in daily agonistic interactions, causes the development of a depressive-like state in mice, which is often accompanied by an increase in blood corticosterone levels. In this work, we assessed what changes occur in the central (hypothalamus) and peripheral (adrenal glands) parts of the HPA axis under the influence of chronic social stress, which can affect the regulation of corticosterone synthesis and its level in the blood. The experience of chronic social stress causes an increase in the relative weight of the adrenal glands, an increase in the expression level of Crh gene in the hypothalamus and the expression of the genes for the corticosterone synthesis enzymes Star, Cyp11a1, Cyp11b1 in the adrenal glands. At the same time, in the hypothalamus the expression of Fkbp5 and Nr3c1 decreases and the expression of Crhbp increases, and in the adrenal glands the expression of the Mc2r and Hsd11b1 genes decreases, which is ultimately aimed at reducing the amount of corticosterone secreted by the adrenal glands, and thus limiting the glucocorticoid response. Thus, chronic stress leads to an imbalance of the activating and stabilizing mechanisms of HPA axis regulation and a possible inadequate response to additional stress stimuli.

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About the authors

А. А. Sapronova

Siberian Branch, Russian Academy of Sciences, Institute of Cytology and Genetics

Author for correspondence.
Email: sapronovann@gmail.com
Russian Federation, Novosibirsk

Y. A. Ryabushkina

Siberian Branch, Russian Academy of Sciences, Institute of Cytology and Genetics

Email: sapronovann@gmail.com
Russian Federation, Novosibirsk

P. E. Kisaretovа

Siberian Branch, Russian Academy of Sciences, Institute of Cytology and Genetics; Novosibirsk State Research University

Email: sapronovann@gmail.com
Russian Federation, Novosibirsk; Novosibirsk

N. P. Bondar

Siberian Branch, Russian Academy of Sciences, Institute of Cytology and Genetics; Novosibirsk State Research University

Email: sapronovann@gmail.com
Russian Federation, Novosibirsk; Novosibirsk

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2. Fig. 1. (a) – Relative mass of the adrenal glands (organ mass in milligrams divided by body mass in grams). Data are presented as mean ± error of mean. Statistical analysis with significance assessment by Student’s t-test, * – p < 0.05. K – control group, ХСС – mice with chronic social defeat stress. (б) – Behavioral parameters in the forced swimming test. Data are presented as mean ± error of mean. Statistical analysis with significance assessment by Student’s t-test, * – p < 0.05. K – control group, ХСС – mice with chronic social defeat stress.

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3. Fig. 2. Relative gene expression levels in the hypothalamus. The expression level of each gene was normalized to the expression level of reference genes. Data are presented as mean ± error of mean. The points reflect the value for the individual animal. Data are presented as mean ± error of mean. Statistical analysis with significance assessment by Student’s t-test, * – p < 0.05. K – control group, ХСС – mice with chronic social defeat stress.

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4. Fig. 3. Relative gene expression levels in adrenal glands. The expression level of each gene was normalized to the expression level of reference genes. Data are presented as mean ± error of mean. The points reflect the value for the individual animal. Data are presented as mean ± error of mean. Statistical analysis with significance assessment by Student’s t-test, * – p < 0.05. K – control group, ХСС – mice with chronic social defeat stress.

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