Russian Journal of PhysiologyRussian Journal of PhysiologyРоссийский физиологический журнал им. И.М. Сеченова0869-81392658-655XThe Russian Academy of Sciences68295510.31857/S0869813925010081UJZZUAEXPERIMENTAL ARTICLESЭКСПЕРИМЕНТАЛЬНЫЕ СТАТЬИResearch ArticleThe influence of the duration of chronic unpredictable mild stress on the effectiveness of modeling depressive-like state in rats of different agesВлияние длительности хронического непредсказуемого стресса на эффективность моделирования депрессивно подобного состояния у крыс разного возрастаNadeiaO. V.НадейО. В.
Russian Federation
olganadej@gmail.comProkopenkoE. S.ПрокопенкоЕ. С.
Russian Federation
olganadej@gmail.comAgalakovaN. I.АгалаковаН. И.
Russian Federation
olganadej@gmail.comSechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of SciencesИнститут эволюционной физиологии и биохимии им. И.М. Сеченова РАНSaint Petersburg State UniversityСанкт-Петербургский государственный университет14012025111112113705062025Copyright ©; 2025, Russian Academy of SciencesCopyright ©; 2025, Российская академия наук2025Russian Academy of SciencesРоссийская академия наукhttps://journals.eco-vector.com/0869-8139/article/view/682955

The aim of the study was to determine the optimal duration of chronic unpredictable mild stress (CUMS) exposure for the induction of depressive-like state (DLS) in rats of different ages. Male Wistar rats aged 6 weeks (young), 10 months (adult), and 20 months (old) were used in the experiment. The rats were divided into control and experimental groups that underwent 4-week and 7-week CUMS exposure, respectively. DLS was induced using the CUMS protocol, for which the animals were subjected to alternating short and long-term stress stimuli for 4 or 7 weeks. The hedonic state of the rats was assessed by their preferences for sucrose, and DLS was evaluated using open field and forced swim tests, as well as by corticosterone levels in blood plasma. In rats from all age groups, the reduction in sucrose intake was observed beginning at 4 weeks following exposure to chronic stress. However, all individuals in the CUMS groups were classified as having anhedonia-like symptoms after 7 weeks of stress exposure only. Long-term exposure to chronic stress resulted in decrease in exploratory activity and an increase in anxiety levels in animals of all ages during the open field test. In the forced swimming test, the indications of behavioral despair, including the decline in latency to the first episode of immobility and an increase in total duration of immobility, were also more pronounced in rats exposed to stress for 7 weeks. Additionally, young rats that underwent CUMS protocol demonstrated more prominent behavioral abnormalities compared to adult and older individuals. 7-weeks of CUMS exposure led to significant increase in corticosterone levels, indicative of DLS, in all rats. Therefore, the findings from all tests suggest that a longer CUMS protocol is required for the development of depression-like behavior in male Wistar rats, and younger individuals are more vulnerable to the effects of chronic stress.

Целью работы было определить оптимальную длительность процедуры хронического непредсказуемого стресса (ХНС) для формирования депрессивно подобного состояния (ДПС) у крыс разного возраста. Самцы крыс Wistar в возрасте 6 недель (условно названные молодыми), 10 месяцев (взрослые) и 20 месяцев (старые) были разделены на контрольные и экспериментальные группы. ДПС индуцировали с помощью процедуры ХНС, для чего животным в течение 4 или 7 недель предъявляли чередующиеся короткие и длительные стрессовые стимулы. Гедонический статус животных оценивали по изменению предпочтения потребления сахарозы, развитие ДПС – с помощью тестов «открытое поле» и вынужденного плавания, а также по содержанию кортикостерона в плазме крови. У крыс из всех возрастных групп, подвергавшихся действию ХНС, снижение предпочтения сахарозы наблюдалось, начиная с 4-й недели, однако все особи были классифицированы как ангедоноподобные после 7 недель стрессирования. Более длительное воздействие хронического стресса привело к снижению исследовательской активности и увеличению тревожности у животных всех возрастов в тесте «открытое поле». В тесте вынужденного плавания признаки поведенческого отчаяния – снижение периода задержки до первого эпизода неподвижности и увеличение общего времени неподвижности – также были более очевидны у крыс, подвергавшихся стрессу в течение 7 недель. Кроме того, молодые крысы, подвергшиеся процедуре ХНС, демонстрировали более значительные нарушения поведения, чем взрослые и старые особи. В плазме крови всех крыс, подвергавшихся ХНС в течение 7 недель, наблюдалось достоверное увеличение концентрации кортикостерона, характерное для ДПС. Таким образом, результаты всех тестов показали, что для развития ДПС у самцов крыс Wistar необходима более длительная процедура ХНС, а молодые особи более восприимчивы к действию хронического стресса.

ratsdepressive-like statechronic unpredictable mild stressanhedoniaopen field testforced swim testcorticosteroneкрысыдепрессивно подобное состояниехронический непредсказуемый стрессангедониятест «открытое поле»тест вынужденного плаваниякортикостеронПравительство РФGovernment of RF075-00264-24-00Moreno-Agostino D, Wu YT, Daskalopoulou C, Hasan MT, Huisman M, Prina M (2021) Global trends in the prevalence and incidence of depression: a systematic review and meta-analysis. J Affect Disord 281: 235–243. https://doi.org/10.1016/j.jad.2020.12.035Ezawa ID, Robinson N, Hollon SD (2024) Prevalence Increases as Treatments Improve: An Evolutionary Perspective on the Treatment-Prevalence Paradox in Depression. Annu Rev Clin Psychol 20(1): 201–228. https://doi.org/10.1146/annurev-clinpsy-080822-04044Xu Y, Li R, Hu C, He Y, Zhang X, Jin L (2024) Global, regional, and national incidence trends of depressive disorder, 1990–2019: An age-period-cohort analysis based on the Global Burden of Disease 2019 study. Gen Hosp Psychiatry 88: 51–60. https://doi.org/10.1016/j.genhosppsych.2024.03.003Bromet E, Andrade LH, Hwang I, Sampson NA, Alonso J, de Girolamo G, de Graaf R, Demyttenaere K, Hu C, Iwata N, Karam AN, Kaur J, Kostyuchenko S, Lépine JP, Levinson D, Matschinger H, Mora ME, Browne MO, Posada-Villa J, Viana MC, Williams DR, Kessler RC (2011) Cross-national epidemiology of DSM-IV major depressive episode. BMC Med 9: 90. https://doi.org/10.1186/1741-7015-9-90Шальнова СА, Евстифеева СЕ, Деев АД, Артамонова ГВ, Гатагонова ТМ, Дупляков ДВ, Ефанов АЮ, Жернакова ЮВ, Конради АО, Либис РА, Минаков ЭВ, Недогода СВ, Ощепкова ЕВ, Романчук СВ, Ротарь ОП, Трубачева ИА, Шляхто ЕВ, Бойцов СА (2014) Распространенность тревоги и депрессии в различных регионах Российской Федерации и ее ассоциации с социально-демографическими факторами (по данным исследования Эссе-РФ). Терапевт Арх 12. [Shal’nova SA, Evstifeeva SE, Deev AD, Artamonova GV, Gatagonova TM, Duplyakov DV, Efanov AYu, Zhernakova YuV, Konradi AO, Libis RA, Minakov EV, Nedogoda SV, Oschepkova EV, Romanchyuk SV, Rotar’ OP, Trubacheva IA, Schlyakhto EV, Boitsov SA (2014) Prevalence of anxiety and depression in various regions of the Russian Federation and its association with socio-demographic factors (Essay-RF study). Terapevt Arkh 12. (In Russ)].Rong J, Cheng P, Li D, Wang X, Zhao D (2024) Global, regional, and national temporal trends in prevalence for depressive disorders in older adults, 1990–2019: An age-period-cohort analysis based on the global burden of disease study 2019. Ageing Res Rev 100: 102443. https://doi.org/10.1016/j.arr.2024.102443Javakhishvili M, Spatz Widom C (2021) Childhood Maltreatment, Sleep Disturbances, and Anxiety and Depression: A Prospective Longitudinal Investigation. J Appl Dev Psychol 77: 101351. https://doi.org/10.1016/j.appdev.2021.101351Rice F, Riglin L, Lomax T, Souter E, Potter R, Smith DJ, Thapar AK, Thapar A (2019) Adolescent and adult differences in major depression symptom profiles. J Affect Disord 243: 175–181. https://doi.org/10.1016/j.jad.2018.09.015Sharma S, Chawla S, Kumar P, Ahmad R, Kumar Verma P (2024) The chronic unpredictable mild stress (CUMS) paradigm: Bridging the gap in depression research from bench to bedside. Brain Res 1843: 149123. https://doi.org/10.1016/j.brainres.2024.149123Antoniuk S, Bijata M, Ponimaskin E, Wlodarczyk J (2019) Chronic unpredictable mild stress for modeling depression in rodents: Meta-analysis of model reliability. Neurosci Biobehav Rev 99: 101–116. https://doi.org/10.1016/j.neubiorev.2018.12.002Markov DD, Novosadova EV (2022) Chronic Unpredictable Mild Stress Model of Depression: Possible Sources of Poor Reproducibility and Latent Variables. Biology (Basel) 11(11): 1621. https://doi.org/10.3390/biology11111621Cotella EM, Gómez AS, Lemen P, Chen C, Fernández G, Hansen C, Herman JP, Paglini MG (2019) Long-term impact of chronic variable stress in adolescence versus adulthood. Prog Neuropsychopharmacol Biol Psychiatry 88: 303–310. https://doi.org/10.1016/j.pnpbp.2018.08.003Menard C, Hodes GE, Russo SJ (2016) Pathogenesis of depression: Insights from human and rodent studies. Neuroscience 321: 138–162. https://doi.org/10.1016/j.neuroscience.2015.05.053Filatova EV, Shadrina MI, Slominsky PA (2021) Major Depression: One Brain, One Disease, One Set of Intertwined Processes. Cells 10(6): 1283. https://doi.org/10.3390/cells10061283Patel D, Kas MJ, Chattarji S, Buwalda B (2019) Rodent models of social stress and neuronal plasticity: Relevance to depressive-like disorders. Behav Brain Res 369: 111900. https://doi.org/10.1016/j.bbr.2019.111900Gencturk S, Unal G (2024) Rodent tests of depression and anxiety: Construct validity and translational relevance. Cogn Affect Behav Neurosci 24(2): 191–224. https://doi.org/10.3758/s13415-024-01171-2Strekalova T, Liu Y, Kiselev D, Khairuddin S, Chiu JLY, Lam J, Chan YS, Pavlov D, Proshin A, Lesch KP, Anthony DC, Lim LW (2022) Chronic mild stress paradigm as a rat model of depression: facts, artifacts, and future perspectives. Psychopharmacology (Berl) 239(3): 663–693. https://doi.org/10.1007/s00213-021-05982-wSalari M, Eftekhar-Vaghefi SH, Asadi-Shekaari M, Esmaeilpour K, Solhjou S, Amiri M, Ahmadi-Zeidabadi M (2023) Impact of ketamine administration on chronic unpredictable stress-induced rat model of depression during extremely low-frequency electromagnetic field exposure: Behavioral, histological and molecular study. Brain Behav 13(5): e2986. https://doi.org/10.1002/brb3.2986Deng Q, Parker E, Wu C, Zhu L, Liu TC, Duan R, Yang L (2024) Repurposing Ketamine in the Therapy of Depression and Depression-Related Disorders: Recent Advances and Future Potential. Aging Dis. https://doi.org/10.14336/AD.2024.0239Ricon T, Toth E, Leshem M, Braun K, Richter-Levin G (2012) Unpredictable chronic stress in juvenile or adult rats has opposite effects, respectively, promoting and impairing resilience. Stress 15(1): 11–20. https://doi.org/10.3109/10253890.2011.572207Kroemer NB, Opel N, Teckentrup V, Li M, Grotegerd D, Meinert S, Walter M (2022) Functional connectivity of the nucleus accumbens and changes in appetite in patients with depression. JAMA Psychiatry 79(10): 993–1003. https://doi.org/10.1001/jamapsychiatry.2022.2414Shin HS, Lee SH, Moon HJ, So YH, Jang HJ, Lee KH, Jung EM (2024) Prolonged stress response induced by chronic stress and corticosterone exposure causes adult neurogenesis inhibition and astrocyte loss in mouse hippocampus. Brain Res Bull 208: 110903. https://doi.org/10.1016/j.brainresbull.2024.02.007Sahagun E, Ward LM, Kinzig KP (2019) Attenuation of stress-induced weight loss with a ketogenic diet. Physiol Behav 212: 112654. https://doi.org/10.1016/j.physbeh.2019.112654Milaneschi Y, Simmons WK, van Rossum EFC, Penninx BW (2019) Depression and obesity: evidence of shared biological mechanisms. Mol Psychiatry 24(1): 18–33. https://doi.org/10.1038/s41380-018-0017-5He R, Zheng R, Zheng J (2023) Causal Association Between Obesity, Circulating Glutamine Levels, and Depression: A Mendelian Randomization Study. J Clin Endocrinol Metab 108(6): 1432–1441. https://doi.org/10.1210/clinem/dgac707Simmons WK, Burrows K, Avery JA (2020) Appetite changes reveal depression subgroups with distinct endocrine, metabolic, and immune states. Mol Psychiatry 25(7): 1457–1468. https://doi.org/10.1038/s41380-018-0093-6Murack M, Chandrasegaram R, Smith KB (2021) Chronic sleep disruption induces depression-like behavior in adolescent male and female mice and sensitization of the hypothalamic-pituitary-adrenal axis in adolescent female mice. Behav Brain Res 399: 113001. https://doi.org/10.1016/j.bbr.2020.113001Gottlieb JF, Goel N, Chen S, Young MA (2021) Meta-analysis of sleep deprivation in the acute treatment of bipolar depression. Acta Psychiatr Scand 143(4): 319–327. https://doi.org/10.1111/acps.13255Mikulska J, Juszczyk G, Gawrońska-Grzywacz M, Herbet M (2021) HPA Axis in the Pathomechanism of Depression and Schizophrenia: New Therapeutic Strategies Based on Its Participation. Brain Sci 11(10): 1298. https://doi.org/10.3390/brainsci11101298Ulrich-Lai YM, Figueiredo HF, Ostrander MM, Choi DC, Engeland WC, Herman JP (2006) Chronic stress induces adrenal hyperplasia and hypertrophy in a subregion-specific manner. Am J Physiol Endocrinol Metab 291(5): E965–E973. https://doi.org/10.1152/ajpendo.00070.2006Rubin RT, Phillips JJ, Sadow TF, McCracken JT (1995) Adrenal gland volume in major depression. Increase during the depressive episode and decrease with successful treatment. Arch Gen Psychiatry 52(3): 213–218. https://doi.org/10.1001/archpsyc.1995.03950150045009Harris BN, Saltzman W (2013) Effects of aging on hypothalamic-pituitary-adrenal (HPA) axis activity and reactivity in virgin male and female California mice (Peromyscus californicus). Gen Comp Endocrinol 186: 41–49. https://doi.org/10.1016/j.ygcen.2013.02.010Tezuka Y, Atsumi N, Blinder AR, Rege J, Giordano TJ, Rainey WE, Turcu AF (2021) The age-dependent changes of the human adrenal cortical zones are not congruent. J Clin Endocrinol Metab 106(5): 1389–1397. https://doi.org/10.1210/clinem/dgab007Nikkheslat N, McLaughlin AP, Hastings C, Zajkowska Z, Nettis MA, Mariani N, Enache D, Lombardo G, Pointon L, Cowen PJ, Cavanagh J, Harrison NA, Bullmore ET, NIMA Consortium, Pariante CM, Mondelli V (2020) Childhood trauma, HPA axis activity and antidepressant response in patients with depression. Brain Behav Immun 87: 229–237. https://doi.org/10.1016/j.bbi.2019.11.024Perry RE, Rincón-Cortés M, Braren SH, Brandes-Aitken AN, Opendak M, Pollonini G, Chopra D, Raver CC, Alberini CM, Blair C, Sullivan RM (2019) Corticosterone administration targeting a hypo-reactive HPA axis rescues a socially-avoidant phenotype in scarcity-adversity reared rats. Dev Cogn Neurosci 40: 100716. https://doi.org/10.1016/j.dcn.2019.100716Hirtz R, Libuda L, Hinney A, Föcker M, Bühlmeier J, Holterhus PM, Kulle A, Kiewert C, Hauffa BP, Hebebrand J, Grasemann C (2022) The adrenal steroid profile in adolescent depression: a valuable bio-readout?. Transl Psychiatry 12(1): 255. https://doi.org/10.1038/s41398-022-01966-2Zhang K, Wang F, Zhai M (2023) Hyperactive neuronal autophagy depletes BDNF and impairs adult hippocampal neurogenesis in a corticosterone-induced mouse model of depression. Theranostics 13(3): 1059–1075. https://doi.org/10.7150/thno.81067Primo MJ, Fonseca-Rodrigues D, Almeida A, Teixeira PM, Pinto-Ribeiro F (2023) Sucrose preference test: A systematic review of protocols for the assessment of anhedonia in rodents. Eur Neuropsychopharmacol 77: 80–92. https://doi.org/10.1016/j.euroneuro.2023.08.496Bonanni L, Gualtieri F, Lester D, Falcone G, Nardella A, Fiorillo A, Pompili M (2019) Can anhedonia be considered a suicide risk factor? Review Literat Medicina (Kaunas) 55(8): 458. https://doi.org/10.3390/medicina55080458Markov DD (2022) Sucrose Preference Test as a Measure of Anhedonic Behavior in a Chronic Unpredictable Mild Stress Model of Depression: Outstanding Issues. Brain Sci 12(10): 1287. https://doi.org/10.3390/brainsci12101287Rosso M, Wirz R, Loretan AV (2022) Reliability of common mouse behavioural tests of anxiety: A systematic review and meta-analysis on the effects of anxiolytics. Neurosci Biobehav Rev 143: 104928. https://doi.org/10.1016/j.neubiorev.2022.104928Zhang M, Wu W, Huang C, Cai T, Zhao N, Liu S, Yang S (2022) Shuxie-1 decoction alleviated CUMS-induced liver injury via IL-6/JAK2/STAT3 signaling. Front Pharm 13: 848355. https://doi.org/10.3389/fphar.2022.848355Gupta GL, Sharma L, Sharma M (2023) 18β-Glycyrrhetinic acid ameliorates neuroinflammation linked depressive behavior instigated by chronic unpredictable mild stress via triggering BDNF/TrkB signaling pathway in rats. Neurochem Res 48(2): 551–569. https://doi.org/10.1007/s11064-022-03779-7Li HZ, Liu KG, Zeng NX, Wu XF, Lu WJ, Xu HF, Yan C, Wu LL (2022) Luteolin enhances choroid plexus 5-MTHF brain transport to promote hippocampal neurogenesis in LOD rats. Front Pharm 13: 826568. https://doi.org/10.3389/fphar.2022.826568Brandwein C, Leenaars CHC, Becker L, Pfeiffer N, Iorgu AM, Hahn M, Vairani GA, Lewejohann L, Bleich A, Mallien AS, Gass P (2023) A systematic mapping review of the evolution of the rat Forced Swim Test: Protocols and outcome parameters. Pharmacol Res 196: 106917. https://doi.org/10.1016/j.phrs.2023.106917Al-Ramadhan FR, Abulmeaty MMA, Alquraishi M, Razak S, Alhussain MH (2023) Effect of vitamin D3 on depressive behaviors of rats exposed to chronic unpredictable mild stress. Biomedicines 11(8): 2112. https://doi.org/10.3390/biomedicines11082112Du X, Yin M, Yuan L, Zhang G, Fan Y, Li Z, Yuan N, Lv X, Zhao X, Zou S, Deng W, Kosten TR, Zhang XY (2020) Reduction of depression-like behavior in rat model induced by ShRNA targeting norepinephrine transporter in locus coeruleus. Transl Psychiatry 10(1): 130. https://doi.org/10.1038/s41398-020-0808-8Li H, Wang P, Zhou Y, Zhao F, Gao X, Wu C, Wu T, Jiang L, Zhang D (2022) Correlation between intestinal microbiotal imbalance and 5-HT metabolism, immune inflammation in chronic unpredictable mild stress male rats. Genes Brain Behav 21(6): e12806. https://doi.org/10.1111/gbb.12806