I.P. Pavlov Journal of Higher Nervous ActivityI.P. Pavlov Journal of Higher Nervous ActivityЖурнал высшей нервной деятельности им. И.П. Павлова0044-46773034-5316The Russian Academy of Sciences65209910.31857/S0044467724020058ФИЗИОЛОГИЧЕСКИЕ МЕХАНИЗМЫ ПОВЕДЕНИЯ ЖИВОТНЫХ: ВОСПРИЯТИЕ ВНЕШНИХ СТИМУЛОВ, ДВИГАТЕЛЬНАЯ АКТИВНОСТЬ, ОБУЧЕНИЕ И ПАМЯТЬФИЗИОЛОГИЧЕСКИЕ МЕХАНИЗМЫ ПОВЕДЕНИЯ ЖИВОТНЫХ: ВОСПРИЯТИЕ ВНЕШНИХ СТИМУЛОВ, ДВИГАТЕЛЬНАЯ АКТИВНОСТЬ, ОБУЧЕНИЕ И ПАМЯТЬResearch ArticleMechanisms of adaptation of the hypothalamic-pituitary-adrenal axis in male mice under chronic social defeat stressМеханизмы адаптации гипоталамо-гипофизарно-надпочечниковой системы у самцов мышей под влиянием хронического стресса социальных пораженийSapronovaА. А.СапроноваА. А.
Russian Federation
sapronovann@gmail.comRyabushkinaY. A.РябушкинаЮ. А.
Russian Federation
sapronovann@gmail.comKisaretovаP. E.КисаретоваП. Э.
Russian Federation
sapronovann@gmail.comBondarN. P.БондарьН. П.
Russian Federation
sapronovann@gmail.comSiberian Branch, Russian Academy of Sciences, Institute of Cytology and GeneticsИнститут цитологии и генетики СО РАНNovosibirsk State Research UniversityНовосибирский государственный исследовательский университет2108202474219720902022025Copyright ©; 2024, Russian Academy of SciencesCopyright ©; 2024, Российская академия наук2024Russian Academy of SciencesРоссийская академия наукhttps://innoscience.ru/0044-4677/article/view/652099

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.

Гипоталамо-гипофизарно-надпочечниковая система (ГГНС) играет важную роль в механизмах адаптации к хроническому стрессу. Модель хронического социального стресса (ХСС), основанная на опыте поражений в ежедневных агонистических взаимодействиях, вызывает у мышей развитие депрессивно-подобного состояния, которое чаще всего сопровождается повышением уровня кортикостерона в крови. В данной работе мы оценили, какие изменения, которые могут влиять на регуляцию синтеза кортикостерона и его уровень в крови, происходят в центральном (гипоталамус) и периферическом (надпочечники) звеньях ГГНС под влиянием хронического социального стресса. Опыт хронического социального стресса вызывает увеличение относительной массы надпочечников, увеличение уровня экспрессии гена Crh в гипоталамусе и экспрессии генов ферментов синтеза кортикостерона Star, Cyp11a1, Cyp11b1 в надпочечниках. Одновременно с этим в гипоталамусе снижается экспрессия Fkbp5 и Nr3c1 и повышается экспрессия Crhbp, а в надпочечниках снижается экспрессия гена Mc2r и Hsd11b1, что суммарно направлено на уменьшение количества выделяемого надпочечниками кортикостерона и приводит к ограничению глюкокортикоидного ответа. Таким образом, хронический стресс приводит к дисбалансу активирующих и стабилизирующих механизмов регуляции ГГНС и возможному неадекватному ответу на дополнительные стрессорные стимулы.

chronic social defeat stresshypothalamusadrenal glandsHPAC57BL/6J miceхронический социальный стрессгипоталамуснадпочечникиГГНСмыши линии C57BL/6JРоссийский Научный ФондRussian Science Foundation21-15-00142Августинович Д.Ф., Бондарь Н.П. Особенности социального поведения мышей после длительного действия психоэмоционального и инфекционного факторов. Рос. Физиол. Журн. 2021. 107 (1): 28–42 https://doi.org/10.31857/S0869813921010039Aguilera G., Kiss A., Lu A., Camacho C. Regulation of adrenal steroidogenesis during chronic stress. Endocr. Res. 1996. 22 (4): 433–443. Informa Healthcare. https://doi.org/10.1080/07435809609043729Algamal M., Pearson A.J., Hahn-Townsend C., Burca I., Mullan M., Crawford F., Ojo J.O. Repeated unpredictable stress and social isolation induce chronic HPA axis dysfunction and persistent abnormal fear memory. Prog. Neuro-Psychopharmacology Biol. Psychiatry 2021. 104 Elsevier Inc. https://doi.org/10.1016/j.pnpbp.2020.110035Avgustinovich D.F., Kovalenko I.L., Kudryavtseva N.N. A model of anxious depression: persistence of behavioral pathology. Neurosci. Behav. Physiol. 2005. 35 (9): 917– 924. https://doi.org/10.1007/S11055-005-0146-6Avgustinovich D.F., Tenditnik M.V., Bondar N.P., Marenina M.K., Zhanaeva S.Y., Lvova M.N. et al. Behavioral effects and inflammatory markers in the brain and periphery after repeated social defeat stress burdened by Opisthorchis felineus infection in mice. Physiol. Behav. 2022. 252. https://doi.org/10.1016/j.physbeh.2022.113846Ayriyants K.A., Ryabushkina Y.A., Sapronova A.A., Ivanchikhina A.V., Kolesnikova M.M., Bondar N.P., Reshetnikov V.V. A comparison of stress reactivity between BTBR and C57BL/6J mice: an impact of early-life stress. Exp. Brain Res. 2023. 241 (3): 687–698. https://doi.org/10.1007/S00221-022-06541-1Bartolomucci A. Social stress, immune functions and disease in rodents. Front. Neuroendocrinol. 2007. 28 (1): 28–49. https://doi.org/10.1016/j.yfrne.2007.02.001Bartolomucci A., Leopardi R. Stress and Depression: Preclinical Research and Clinical Implications. PLoS One 2009. 4 (1): e4265. https://doi.org/10.1371/JOURNAL.PONE.0004265Berger I., Werdermann M., Bornstein S. R., Steenblock C. The adrenal gland in stress – Adaptation on a cellular level. J. Steroid Biochem. Mol. Biol. 2019. 190: 198–206. https://doi.org/10.1016/j.jsbmb.2019.04.006Berton O., McClung C.A., DiLeone R.J., Krishnan V., Renthal W., Russo S.J. et al. Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science. 2006. 311 (5762): 864–868. https://doi.org/10.1126/SCIENCE.1120972Bondar N., Bryzgalov L., Ershov N., Gusev F., Reshetnikov V., Avgustinovich D. et al. Molecular adaptations to social defeat stress and induced depression in mice. Mol. Neurobiol. 2018. 55 (4): 3394–3407. https://doi.org/10.1007/S12035-017-0586-3Bondar N.P., Kovalenko I.L., Avgustinovich D.F., Smagin D.A., Kudryavtseva N.N. Anhedonia in the shadow of chronic social defeat stress, or when the experimental context matters. Open Behav. Sci. J. 2009. 3 (1): 17–27. https://doi.org/10.2174/1874230000903010017Carnevali L., Montano N., Tobaldini E., Thayer J.F., Sgoifo A. The contagion of social defeat stress: Insights from rodent studies. Neurosci. Biobehav. Rev. 2020. 111: 12–18. https://doi.org/10.1016/j.neubiorev.2020.01.011Castagné V., Porsolt R.D., Moser P. Use of latency to immobility improves detection of antidepressant – like activity in the behavioral despair test in the mouse. Eur. J. Pharmacol. 2009. 616 (1–3): 128–133. https://doi.org/10.1016/j.ejphar.2009.06.018Dias C., Feng J., Sun H., Shao N.Y., Mazei-Robison M.S., Damez-Werno D. et al. β-catenin mediates stress resilience through Dicer1/microRNA regulation. Nat. 2014. 516 (7529): 51–55. Nature Publishing Group. https://doi.org/10.1038/nature13976Friard O., Gamba M. BORIS: a free, versatile open-source event-logging software for video/audio coding and live observations. Methods Ecol. Evol. 2016. 7 (11): 1325–1330. https://doi.org/10.1111/2041-210X.12584Füchsl A.M., Langgartner D., Reber S.O. Mechanisms underlying the increased plasma ACTH levels in chronic psychosocially stressed male mice. PLoS One 2013. 8 (12): e84161. https://doi.org/10.1371/JOUR NAL.PONE.0084161Greenberg P.E., Fournier A.A., Sisitsky T., Simes M., Berman R., Koenigsberg S.H., Kessler R.C. The economic burden of adults with major depressive disorder in the United States (2010 and 2018). Pharmacoeconomics 2021. 39 (6): 653–665. https://doi.org/10.1007/S40273-021-01019-4Guo Q., Wang L., Yuan W., Li L., Zhang J., Hou W. et al. Different effects of chronic social defeat on social behavior and the brain CRF system in adult male C57 mice with different susceptibilities. Behav. Brain Res. 2020. 384: 112553. https://doi.org/10.1016/J.BBR.2020.112553Han M.H., Nestler E.J. Neural substrates of depression and resilience. Neurotherapeutics 2017. 14 (3): 677–686. https://doi.org/10.1007/S13311-017-0527-XHäusl A.S., Brix L.M., Hartmann J., Pöhlmann M.L., Lopez J.P., Menegaz D. et al. The co-chaperone Fkbp5 shapes the acute stress response in the paraventricular nucleus of the hypothalamus of male mice. Mol. Psychiatry. 2021. 26 (7): 3060–3076. https://doi.org/10.1038/s41380-021-01044-xJiang Z., Rajamanickam S., Justice N.J. CRF signaling between neurons in the paraventricular nucleus of the hypothalamus (PVN) coordinates stress responses. Neurobiol. Stress 2019. 11: 100192. Neurobiol Stress. https://doi.org/10.1016/J.YNSTR.2019.100192Juszczak G.R., Stankiewicz A.M. Glucocorticoids, genes and brain function. Prog. Neuropsychopharmacol. Biol. Psychiatry 2018. 82: 136–168. https://doi.org/10.1016/J.PNPBP.2017.11.020Kamimura Y., Kuwagaki E., Hamano S., Kobayashi M., Yamada Y., Takahata Y. et al. Reproducible induction of depressive-like behavior in C57BL/6J mice exposed to chronic social defeat stress with a modified sensory contact protocol. Life Sci. 2021. 282: 119821. https://doi.org/10.1016/j.lfs.2021.119821Ketchesin K.D., Stinnett G.S., Seasholtz A.F. Corticotropin-releasing hormone-binding protein and stress: from invertebrates to humans. Stress. 2017. 20 (5): 449–464. https://doi.org/10.1080/10253890.2017.1322575Krishnan V., Han M.H., Graham D.L., Berton O., Renthal W., Russo S.J. et al. Molecular adaptations underlying Susceptibility and resistance to social defeat in brain reward regions. Cell 2007. 131 (2): 391–404. https://doi.org/10.1016/j.cell.2007.09.018Kudryavtseva N.N., Bakshtanovskaya I.V., Koryakina L.A. Social model of depression in mice of C57BL/6J strain. Pharmacol. Biochem. Behav. 1991. 38 (2): 315–320. https://doi.org/10.1016/0091-3057(91)90284-9Kudryavtseva N.N., Kovalenko I.L., Smagin D A., Galyamina A.G., Babenko V.N. Abnormal social behaviors and dysfunction of autism-related genes associated with daily agonistic interactions in mice. bioRxiv. 2017. 125674. https://doi.org/10.1101/125674Langgartner D., Marks J., Nguyen T.C., Reber S.O. Changes in adrenal functioning induced by chronic psychosocial stress in male mice: A time course study. Psychoneuroendocrinology 2020. 122: 104880. https://doi.org/10.1016/j.psyneuen.2020.104880Lopez J.P., Brivio E., Santambrogio A., Donno C. De, Kos A., Peters M. et al. Single-cell molecular profiling of all three components of the HPA axis reveals adrenal ABCB1 as a regulator of stress adaptation. Sci. Adv. 2021. 7 (5): eabe4497. https://doi.org/10.1126/SCIADV.ABE4497Lu J., Gong X., Yao X., Guang Y., Yang H., Ji R. et al. Prolonged chronic social defeat stress promotes less resilience and higher uniformity in depression-like behaviors in adult male mice. Biochem. Biophys. Res. Commun. 2021. 553: 107–113. https://doi.org/10.1016/j.bbrc.2021.03.058Merk V.M., Renzulli P., Vrugt B., Fleischmann A., Brunner T. Glucocorticoids are differentially synthesized along the murine and human respiratory tree. Allergy Eur. J. Allergy Clin. Immunol. 2023. 78 (9): 2428–2440. https://doi.org/10.1111/ALL.15765Merkulov V.M., Merkulova T.I., Bondar N.P. Mechanisms of brain glucocorticoid resistance in stress-induced psychopathologies. Biochemistry. (Mosc). 2017. 82 (3): 351–365. https://doi.org/10.1134/S0006297917030142Mourtzi N., Sertedaki A., Charmandari E. Glucocorticoid signaling and epigenetic alterations in stress-related disorders. Int. J. Mol. Sci. 2021. 22 (11): 5964. https://doi.org/10.3390/IJMS22115964Murra D., Hilde K.L., Fitzpatrick A., Maras P.M., Watson S.J., Akil H. Characterizing the behavioral and neuroendocrine features of susceptibility and resilience to social stress. Neurobiol. Stress 2022. 17: 100437. https://doi.org/10.1016/J.YNSTR.2022.100437Nakatake Y., Furuie H., Yamada M., Kuniishi H., Ukezono M., Yoshizawa K., Yamada M. The effects of emotional stress are not identical to those of physical stress in mouse model of social defeat stress. Neurosci. Res. 2020. 158: 56–63. https://doi.org/10.1016/J.NEURES.2019.10.008Reber S.O., Birkeneder L., Veenema A.H., Obermeier F., Falk W., Straub R.H., Neumann I.D. Adrenal insufficiency and colonic inflammation after a novel chronic psycho-social stress paradigm in mice: implications and mechanisms. Endocrinology 2007. 148 (2): 670–682. https://doi.org/10.1210/EN.2006-0983Ulrich-Lai Y.M., Figueiredo H.F., Ostrander M.M., Choi D.C., Engeland W.C., Herman J.P. Chronic stress induces adrenal hyperplasia and hypertrophy in a subregion-specific manner. Am. J. Physiol. Endocrinol. Metab. 2006. 291 (5): E965-73. https://doi.org/10.1152/AJPENDO.00070.2006Uschold-Schmidt N., Nyuyki K.D., Füchsl A.M., Neumann I.D., Reber S.O. Chronic psychosocial stress results in sensitization of the HPA axis to acute heterotypic stressors despite a reduction of adrenal in vitro ACTH responsiveness. Psychoneuroendocrinology 2012. 37 (10): 1676– 1687. https://doi.org/10.1016/j.psyneuen.2012.02.015Uschold-Schmidt N., Peterlik D., Füchsl A.M., Reber S.O. HPA axis changes during the initial phase of psychosocial stressor exposure in male mice. J. Endocrinol. 2013. 218 (2): 193–203. https://doi.org/10.1530/JOE-13-0027Vagnerová K., Jágr M., Mekadim C., Ergang P., Sechovcová H., Vodička M. et al. Profiling of adrenal corticosteroids in blood and local tissues of mice during chronic stress. Sci. Rep. 2023. 13 (1): 7278. https://doi.org/10.1038/S41598-023-34395-2Vagnerová K., Vodička M., Hermanová P., Ergang P., Šrůtková D., Klusoňová P. et al. Interactions between gut microbiota and acute restraint stress in peripheral structures of the hypothalamic–pituitary–adrenal axis and the intestine of male mice. Front. Immunol. 2019. 10: 2655. https://doi.org/10.3389/FIMMU.2019.02655Venzala E., García-García A.L., Elizalde N., Delagrange P., Tordera R.M. Chronic social defeat stress model: behavioral features, antidepressant action, and interaction with biological risk factors. Psychopharmacology (Berl). 2012. 224 (2): 313–325. https://doi.org/10.1007/S00213-012-2754-5Warren B.L., Vialou V.F., Iñiguez S.D., Alcantara L.F., Wright K.N., Feng J. et al. Neurobiological sequelae of witnessing stressful events in adult mice. Biol. Psychiatry 2013. 73 (1): 7–14. Biol. Psychiatry. https://doi.org/10.1016/J.BIOPSYCH.2012.06.006