Chronic social defeat stress and glucocorticoid regulation in brain regions: resistance or hypersensitivity?
- Authors: Bondar N.P.1, Kisaretova P.E.1, Reshetnikov V.V.1, Shulyupova A.S.1, Ryabushkina Y.A.1, Salman R.1
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Affiliations:
- Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences
- Issue: Vol 18, No 4 (2023)
- Pages: 454-455
- Section: Conference proceedings
- URL: https://genescells.ru/2313-1829/article/view/623235
- DOI: https://doi.org/10.17816/gc623235
- ID: 623235
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Abstract
Chronic social stress causes various psychopathologies and is frequently associated with alterations in the HPA axis function. The heightened glucocorticoid hormone levels in the bloodstream instigate an acute bodily response, which fades over time, even with continued glucocorticoid stimulation. It is known that the resistance to elevated hormone levels can affect the effectiveness of therapy in the treatment of stress-induced psychopathologies. Resistance to elevated hormone levels can impact the effectiveness of therapy for stress-induced psychopathologies. To understand the molecular basis of glucocorticoid resistance, we examined the effect of chronic social defeat stress on the transcriptome of two brain regions — the prefrontal cortex and the dorsal raphe nuclei — using an experimental model of depression.
We assessed gene expression levels in C57BL/6 control mice and mice subjected to 30 days of stress, both under basal conditions and following additional stimulation with dexamethasone. The administration of dexamethasone (2 mg/kg) allowed for simulation of the upregulation of glucocorticoids and activation of the glucocorticoid receptor. The results indicate that chronic stress induces gene resistance to glucocorticoid hormones in only 15% of prefrontal cortex genes and 25% of raphe nuclei genes. In stressed animals, there was no response to dexamethasone stimulation, whereas controls showed a reaction. For 66% of the genes in the prefrontal cortex and 40% of the genes in the dorsal raphe nuclei, the response to dexamethasone exhibited a greater intensity in the stressed group as compared to the control group. This set of genes comprises genes linked to immune responses, monoamine conveyance, and synapse establishment. Under stress conditions, as opposed to controls, anti-inflammatory cytokine genes, as well as genes connected to the growth of B- and T-lymphocytes, are downregulated in response to dexamethasone treatment. Furthermore, chronic stress exposure heightens the sensitivity of serotonergic receptor genes Htr1a and Htr5a to dexamethasone. The Htr1a gene exhibited a region-specific response to dexamethasone in stressed animals. Specifically, the expression of the gene increased in response to dexamethasone in the prefrontal cortex, while it decreased in the dorsal raphe nuclei. Additionally, the sensitivity of genes involved in the differentiation of oligodendrocytes changed in the dorsal raphe nuclei of stressed animals.
Thus, our data demonstrate that chronic social defeat stress induces resistance and heightened sensitivity to to glucocorticoid activation, resulting in the development of depression.
Full Text
Chronic social stress causes various psychopathologies and is frequently associated with alterations in the HPA axis function. The heightened glucocorticoid hormone levels in the bloodstream instigate an acute bodily response, which fades over time, even with continued glucocorticoid stimulation. It is known that the resistance to elevated hormone levels can affect the effectiveness of therapy in the treatment of stress-induced psychopathologies. Resistance to elevated hormone levels can impact the effectiveness of therapy for stress-induced psychopathologies. To understand the molecular basis of glucocorticoid resistance, we examined the effect of chronic social defeat stress on the transcriptome of two brain regions — the prefrontal cortex and the dorsal raphe nuclei — using an experimental model of depression.
We assessed gene expression levels in C57BL/6 control mice and mice subjected to 30 days of stress, both under basal conditions and following additional stimulation with dexamethasone. The administration of dexamethasone (2 mg/kg) allowed for simulation of the upregulation of glucocorticoids and activation of the glucocorticoid receptor. The results indicate that chronic stress induces gene resistance to glucocorticoid hormones in only 15% of prefrontal cortex genes and 25% of raphe nuclei genes. In stressed animals, there was no response to dexamethasone stimulation, whereas controls showed a reaction. For 66% of the genes in the prefrontal cortex and 40% of the genes in the dorsal raphe nuclei, the response to dexamethasone exhibited a greater intensity in the stressed group as compared to the control group. This set of genes comprises genes linked to immune responses, monoamine conveyance, and synapse establishment. Under stress conditions, as opposed to controls, anti-inflammatory cytokine genes, as well as genes connected to the growth of B- and T-lymphocytes, are downregulated in response to dexamethasone treatment. Furthermore, chronic stress exposure heightens the sensitivity of serotonergic receptor genes Htr1a and Htr5a to dexamethasone. The Htr1a gene exhibited a region-specific response to dexamethasone in stressed animals. Specifically, the expression of the gene increased in response to dexamethasone in the prefrontal cortex, while it decreased in the dorsal raphe nuclei. Additionally, the sensitivity of genes involved in the differentiation of oligodendrocytes changed in the dorsal raphe nuclei of stressed animals.
Thus, our data demonstrate that chronic social defeat stress induces resistance and heightened sensitivity to to glucocorticoid activation, resulting in the development of depression.
ADDITIONAL INFORMATION
Funding sources. The work was supported by the Russian Science Foundation (project No. 21-15-00142).
Authors' contribution. All authors made a substantial contribution to the conception of the work, acquisition, analysis, interpretation of data for the work, drafting and revising the work, and final approval of the version to be published and agree to be accountable for all aspects of the work.
Competing interests. The authors declare that they have no competing interests.
About the authors
N. P. Bondar
Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences
Author for correspondence.
Email: nbondar@bionet.nsc.ru
Russian Federation, Novosibirsk
P. E. Kisaretova
Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences
Email: nbondar@bionet.nsc.ru
Russian Federation, Novosibirsk
V. V. Reshetnikov
Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences
Email: nbondar@bionet.nsc.ru
Russian Federation, Novosibirsk
A. S. Shulyupova
Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences
Email: nbondar@bionet.nsc.ru
Russian Federation, Novosibirsk
Yu. A. Ryabushkina
Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences
Email: nbondar@bionet.nsc.ru
Russian Federation, Novosibirsk
R. Salman
Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences
Email: nbondar@bionet.nsc.ru
Russian Federation, Novosibirsk
References
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