Russian Journal of PhysiologyRussian Journal of PhysiologyРоссийский физиологический журнал им. И.М. Сеченова0869-81392658-655XThe Russian Academy of Sciences65175510.31857/S0869813924090162AIOKOLEXPERIMENTAL ARTICLESЭКСПЕРИМЕНТАЛЬНЫЕ СТАТЬИResearch ArticleThe influence of social isolation and enriched environment on the activity of the hypothalamic-pituitary-adrenocortical (HPA) axis, pain sensitivity, and behavior in rats after exposure to an ulcerogenic stressorВлияние социальной изоляции и обогащенной среды на активность гипоталамо-гипофизарно-адренокортикальной системы, болевую чувствительность и поведение крыс после ульцерогенного стрессораYaruskinaN. I.ЯрушкинаН. И.
Russian Federation
yarushkinani@infran.ruZenkoM. Yu.ЗенькоМ. Ю.
Russian Federation
yarushkinani@infran.ruMorozovaO. Yu.МорозоваО. Ю.
Russian Federation
yarushkinani@infran.ruKomkovaO. P.КомковаО. П.
Russian Federation
yarushkinani@infran.ruBaranovaK. A.БарановаК. А.
Russian Federation
yarushkinani@infran.ruZhuikovaS. E.ЖуйковаС. Е.
Russian Federation
yarushkinani@infran.ruRybnikovaE. A.РыбниковаЕ. А.
Russian Federation
yarushkinani@infran.ruFilaretovaL. P.ФиларетоваЛ. П.
Russian Federation
yarushkinani@infran.ruPavlov Institute of PhysiologyИнститут физиологии им. И.П. Павлова РАН1509202411091510152802022025Copyright ©; 2024, Russian Academy of SciencesCopyright ©; 2024, Российская академия наук2024Russian Academy of SciencesРоссийская академия наукhttps://journals.eco-vector.com/0869-8139/article/view/651755

The results we obtained earlier indicate the potential for corrective effects on the negative consequences of social isolation on the functioning of the body through an enriched environment. The aim of the present study was to investigate the influence of housing conditions for rats – standard conditions, social isolation, and an enriched environment – on the activity of the hypothalamic-pituitary-adrenocortical (HPA) axis, focusing on HPA axis stress reactivity, pain sensitivity, and rat behavior following exposure to an ulcerogenic stressor. The experiments were conducted on male Sprague-Dawley rats. Thirty-day-old rats, after being weaned from their mothers, were placed in different housing conditions for four weeks: standard environment (SE), isolation (SI), or an enriched environment (EE). After four weeks, rats from each group were exposed to an ulcerogenic stressor (US): 3 hours of cold immobilization (10 °C). Starting the day after US exposure, for one week, all groups of rats were sequentially assessed for somatic pain sensitivity (in the “hot plate” test), behavior (in the “open field” and “elevated plus maze” tests), and HPA stress reactivity (based on corticosterone levels in response to mild procedural stress). According to the results, SI conditions in our experimental setup led to a faster increase in body weight with age, higher anxiety levels, depressive-like reactions in half of the animals studied, and increased sensitivity to painful stimuli. At the same time, rats kept in the EE showed higher HPA axis stress reactivity, greater motor and exploratory activity, lower anxiety, and lower sensitivity to painful stimuli. The obtained results provide new evidence supporting our previous conclusion that SI exerts maladaptive effects on the overall functional state of the rats' bodies, while EE, on the contrary, leads to adaptive changes in the body. This study highlights the importance of an integrative approach when studying the effects of SI and EE on the body.

Полученные нами ранее результаты свидетельствуют о возможности корректирующих эффектов негативных последствий социальной изоляции на функционирование организма с помощью обогащенной среды. Задача настоящей работы заключалась в изучении влияния условий содержания крыс – стандартных условий, социальной изоляции и обогащенной среды – на стресс-реактивность гипоталамо-гипофизарно-адренокортикальной системы (ГГАКС), болевую чувствительность и поведение крыс после действия ульцерогенного стрессора. Эксперименты проводили на крысах-самцах линии Спрейг-Доули. Крысят 30-дневного возраста после отъема от матери помещали на 4 недели в разные условия содержания: стандартные условия (СУ), изоляцию (СИ) или обогащенную среду (ОС). Через 4 недели крыс каждой группы подвергали действию ульцерогенного стрессора (УС): 3 ч иммобилизации при холоде (10 °С). Начиная со следующего после действия УС дня, в течение недели у всех групп крыс последовательно оценивали соматическую болевую чувствительность (в тесте «горячей пластины»), поведение (в тестах «открытое поле» и «приподнятый крестообразный лабиринт») и стресс-реактивность ГГАКС (по уровню кортикостерона в крови в ответ на слабый процедурный стрессор). Согласно полученным результатам, содержание крыс в условиях СИ в наших экспериментах приводило к более быстрому увеличению массы их тела с увеличением возраста, повышению уровня тревожности, появлению депрессивноподобных реакций у половины исследованных животных, увеличению чувствительности к болевому воздействию. В то же время крысы, содержавшиеся в ОС, отличались повышенной стресс-реактивностью ГГАКС, большей моторной и исследовательской активностью, меньшей тревожностью и меньшей чувствительностью к болевому воздействию. Полученные результаты представляют новые аргументы в пользу ранее сделанного нами заключения о том, что СИ крыс оказывает дезадаптивное влияние на общее функциональное состояние организма, а ОС, напротив, приводит к адаптивным изменениям. Проведенное исследование акцентирует внимание на важности интегративного подхода при исследовании эффектов СИ и ОС на организм.

social isolationenriched environmentstressglucocorticoid hormonesstress reactivity of the hypothalamic-pituitary-adrenocortical systemgastric erosionsbehaviorpain sensitivityratsсоциальная изоляцияобогащенная средастрессглюкокортикоидные гормоныстресс-реактивность гипоталамо-гипофизарно-адренокортикальной системыэрозии желудкаповедениеболевая чувствительностьМинистерство науки и высшего образования РФMinistry of Science and Higher Education of the Russian Federation075-15-2022-303Holt-Lunstad J (2021) A pandemic of social isolation? World Psychiatry 20: 55–56. https://doi.org/10.1002/WPS.20839Fang B, Yang S, Liu H, Zhang Y, Xu R, Chen G (2019) Association between depression and subsequent peptic ulcer occurrence among older people living alone: A prospective study investigating the role of change in social engagement. J Psychosom Res 122: 94–103. https://doi.org/10.1016/J.JPSYCHORES.2019.04.002Mikocka-Walus A, Skvarc D, de Acosta MB, Evertsz FB, Bernstein CN, Burisch J, Ferreira N, Gearry RB, Graff LA, Jedel S, Mokrowiecka A, Stengel A, Trindade IA, van Tilburg MAL, Knowles SR (2022) Exploring the Relationship Between Self-Isolation and Distress Among People with Gastrointestinal Disorders During the COVID-19 Pandemic. J Clin Psychol Med Settings 29: 654–665. https://doi.org/10.1007/S10880-021-09818-9Xiong Y, Hong H, Liu C, Zhang YQ (2023) Social isolation and the brain: effects and mechanisms. Mol Psychiatry 28: 191–201. https://doi.org/10.1038/S41380-022-01835-WZhang P, Yan J, Wei J, Li Y, Sun C (2024) Disrupted synaptic homeostasis and partial occlusion of associative long-term potentiation in the human cortex during social isolation. J Affect Disord 344: 207–218. https://doi.org/10.1016/J.JAD.2023.10.080Bannon S, Greenberg J, Mace RA, Locascio JJ, Vranceanu AM (2021) The role of social isolation in physical and emotional outcomes among patients with chronic pain. Gen Hosp Psychiatry 69: 50–54. https://doi.org/10.1016/J.GENHOSPPSYCH.2021.01.009Лобов ГИ (2024) Социальная изоляция: связь с заболеваниями сердечно-сосудистой системы. Успехи физиол наук 55(1): 31–46. [Lobov GI (2024) Social isolation relationship with cardiovascular diseases. Uspekhi fiziol nauk 55(1): 31–46. (In Russ)]. https://doi.org/10.31857/S0301179824010045Golaszewski NM, Lacroix AZ, Godino JG, Allison MA, Manson JE, King JJ, Weitlauf JC, Bea JW, Garcia L, Kroenke CH, Saquib N, Cannell B, Nguyen S, Bellettiere J (2022) Evaluation of Social Isolation, Loneliness, and Cardiovascular Disease Among Older Women in the US. JAMA Netw open 5: e2146461. https://doi.org/10.1001/JAMANETWORKOPEN.2021.46461Bu F, Steptoe A, Fancourt D (2020) Who is lonely in lockdown? Cross-cohort analyses of predictors of loneliness before and during the COVID-19 pandemic. Public Health 186: 31–34. https://doi.org/10.1016/J.PUHE.2020.06.036Guven EB, Pranic NM, Unal G (2022) The differential effects of brief environmental enrichment following social isolation in rats. Cogn Affect Behav Neurosci 22: 818–832. https://doi.org/10.3758/S13415-022-00989-YLeemhuis E, Esposito RM, De Gennaro L, Pazzaglia M (2021) Go Virtual to Get Real: Virtual Reality as a Resource for Spinal Cord Treatment. Int J Environ Res Public Health 18: 1–10. https://doi.org/10.3390/IJERPH18041819Sihvonen AJ, Pitkäniemi A, Särkämö T, Soinila S (2022) Isn’t There Room for Music in Chronic Pain Management? J Pain 23: 1143–1150. https://doi.org/10.1016/J.JPAIN.2022.01.003Crofton EJ, Zhang Y, Green TA (2015) Inoculation stress hypothesis of environmental enrichment. Neurosci Biobehav Rev 49: 19–31. https://doi.org/10.1016/J.NEUBIOREV.2014.11.017Brown RE (2020) Donald O. Hebb and the organization of behavior: 17 years in the writing. Mol Brain 13. https://doi.org/10.1186/S13041-020-00567-8Diamond MC, Krech D, Rosenzweig MR (1964) The effects of an enriched environment of histology of rat cerebral cortex. J Comp Neurol 123: 111–119. https://doi.org/10.1002/CNE.901230110Wang H, Xu X, Xu X, Gao J, Zhang T (2020) Enriched Environment and Social Isolation Affect Cognition Ability via Altering Excitatory and Inhibitory Synaptic Density in Mice Hippocampus. Neurochem Res 45: 2417–2432. https://doi.org/10.1007/S11064-020-03102-2Braun MD, Kisko TM, Witt SH, Rietschel M, Schwarting RKW, Wöhr M (2019) Long-term environmental impact on object recognition, spatial memory and reversal learning capabilities in Cacna1c-haploinsufficient rats. Hum Mol Genet 28: 4113–4131. https://doi.org/10.1093/HMG/DDZ235Popa N, Boyer F, Jaouen F, Belzeaux R, Gascon E (2020) Social Isolation and Enrichment Induce Unique miRNA Signatures in the Prefrontal Cortex and Behavioral Changes in Mice. Science 23(12): 101790. https://doi.org/10.1016/J.ISCI.2020.101790Lopez MF, Laber K (2015) Impact of social isolation and enriched environment during adolescence on voluntary ethanol intake and anxiety in C57BL/6J mice. Physiol Behav 148: 151–156. https://doi.org/10.1016/J.PHYSBEH.2014.11.012Vannan A, Powell GL, Scott SN, Pagni BA, Neisewander JL (2018) Animal Models of the Impact of Social Stress on Cocaine Use Disorders. Int Rev Neurobiol 140: 131–169. https://doi.org/10.1016/BS.IRN.2018.07.005Zhao X, Mohammed R, Tran H, Erickson M, Kentner AC (2021) Poly (I: C)-induced maternal immune activation modifies ventral hippocampal regulation of stress reactivity: prevention by environmental enrichment. Brain Behav Immun 95: 203–215. https://doi.org/10.1016/J.BBI.2021.03.018Guarnieri LO, Pereira-Caixeta AR, Medeiros DC, Aquino NSS, Szawka RE, Mendes E M A M, Moraes MFD, Pereira GS (2020) Pro-neurogenic effect of fluoxetine in the olfactory bulb is concomitant to improvements in social memory and depressive-like behavior of socially isolated mice. Transl Psychiatry 10(1): 33. https://doi.org/10.1038/S41398-020-0701-5Крупина НА, Ширенова СД (2023) Нарушения когнитивных функций при длительной социальной изоляции: результаты исследований на людях и экспериментов на животных. Успехи физиол наук 54(3): 18–35. [Krupina NA, Shirenova SD (2023) Cognitive impairment under prolonged social isolation: insights from human studies and animal experiments. Uspekhi fiziol nauk 54(3): 18–35. (In Russ)]. https://doi.org/10.31857/S0301179823040045Filaretova LP, Komkova OP, Morozova OY, Punina PV, Yarushkina NI (2024) Environmental enrichment reverses proulcerogenic action of social isolation on the gastric mucosa and positively influences pain sensitivity and work capacity. Inflammopharmacology 32: 909–915. https://doi.org/10.1007/S10787-024-01451-WСолнушкин СД, Чихман ВН (2018) Компьютерная обработка биологических изображений. Биомед радиоэлектрон 2: 35–40. [Solnushkin SD, Chikhman VN (2018) Experience of biological image processing. Biomed Radioelectron 2: 35–40.(In Russ)].Jahng JW, Yoo SB, Ryu V, Lee JH (2012) Hyperphagia and depression-like behavior by adolescence social isolation in female rats. Int J Dev Neurosci 30: 47–53. https://doi.org/10.1016/J.IJDEVNEU.2011.10.001Dulabi AN, Shakerin Z, Mehranfard N, Ghasemi M (2020) Vitamin C protects against chronic social isolation stress-induced weight gain and depressive-like behavior in adult male rats. Endocr Regul 54: 266–274. https://doi.org/10.2478/ENR-2020-0030Belardo C, Alessio N, Pagano M, De Dominicis E, Infantino R, Perrone M, Iannotta M, Galderisi U, Rinaldi B, Scuteri D, Bagetta G, Palazzo E, Maione S, Luongo L (2022) PEA-OXA ameliorates allodynia, neuropsychiatric and adipose tissue remodeling induced by social isolation. Neuropharmacology 208: 108978. https://doi.org/10.1016/J.NEUROPHARM.2022.108978Filaretova LP, Morozova OY, Yarushkina NI (2021) Peripheral corticotropin-releasing hormone may protect the gastric musosa against indometacin-induced injury through involvement of glucocorticoids. J Physiol Pharmacol 72: 1–10. https://doi.org/10.26402/JPP.2021.5.06Filaretova L, Komkova O, Sudalina M, Yarushkina N (2021) Non-Invasive Remote Ischemic Preconditioning May Protect the Gastric Mucosa Against Ischemia-Reperfusion-Induced Injury Through Involvement of Glucocorticoids. Front Pharmacol 12: 682643. https://doi.org/10.3389/FPHAR.2021.682643Filaretova L, Podvigina T, Yarushkina N (2020) Physiological and pharmacological effects of glucocorticoids on the gastrointestinal tract. Curr Pharm Des 26(25): 2962–2970. https://doi.org/10.2174/1381612826666200521142746Yarushkina NI, Komkova OP, Filaretova LP (2020) Influence of forced treadmill and voluntary wheel running on the sensitivity of gastric mucosa to ulcerogenic stimuli in male rats. J Physiol Pharmacol 71: 1–13. https://doi.org/10.26402/JPP.2020.6.04Filaretova LP, Filaretov AA, Makara GB (1998) Corticosterone increase inhibits stress-induced gastric erosions in rats. Am J Physiol 274: G1024-G1030.Filaretova L, Bagaeva T, Makara GB (2002) Aggravation of nonsteroidal antiinflammatory drug gastropathy by glucocorticoid deficiency or blockade of glucocorticoid receptors in rats. Life Sci 71: 2457–2468.Filaretova L (2006) The hypothalamic-pituitary-adrenocortical system: Hormonal brain-gut interaction and gastroprotection. Auton Neurosci 125: 86–93. https://doi.org/10.1016/j.autneu.2006.01.005Подвигина ТТ, Комкова ОП, Ветровой ОВ, Ярушкина НИ, Филаретова ЛП (2023) Сравнение влияния содержания крыс в горах и на равнине на развитие стрептозотоцин-индуцированного диабета и язвообразование в желудке. Рос физиол журн им ИМ Сеченова 109(10): 1457–1475. [Podvigina TT, Komkova OP, Vetrovoy OV, Yaruskina NI, Filaretova LP (2023) Comparison of the Effect of Keeping Rats in the Mountains and on the Plain on the Development of Streptozotocin-Induced Diabetes and Gastric Ulceration. Rus Phisiol J 109(10): 1457–1475. (In Russ)].Yarushkina NI, Podvigina TT, Komkova OP, Morozova OYu, Punina PV, Filaretova LP (2023) Comparative Analysis of the Effects of Insulin and Metformin on the Ulcerogenic Action of Indomethacin in Rats with Streptozotocin-Induced Diabetes. J Evol Biochem Physiol 59(6): 2399–2412. https://doi.org/10.1134/s0022093023060406Filaretova LP, Bagaeva TR, Morozova OY, Zelena D (2014) A wider view on gastric erosion: detailed evaluation of complex somatic and behavioral changes in rats treated with indomethacin at gastric ulcerogenic dose. Endocr Regul 48: 163–172. https://doi.org/10.4149/ENDO_2014_04_163Gamallo A, Villanua A, Trancho G, Fraile A (1986) Stress adaptation and adrenal activity in isolated and crowded rats. Physiol Behav 36: 217–221. https://doi.org/10.1016/0031-9384(86)90006-5Hofford RS, Prendergast MA, Bardo MT (2018) Modified single prolonged stress reduces cocaine self-administration during acquisition regardless of rearing environment. Behav Brain Res 338: 143–152. https://doi.org/10.1016/J.BBR.2017.10.023Рыбникова ЕА, Миронова ВИ, Пивина СГ, Ордян НЭ, Тюлькова ЕИ, Самойлов МО (2008) Гормональные механизмы нейропротективных эффектов гипоксического прекондиционирования у крыс. Докл РАН 421(5): 713–715. [Rybnikova EA, Mironova VI, Pivina SG, Ordyan NE, Tulkova EI, Samoilov MO (2008) Hormonal mechanisms of neuroprotective effects of the mild hypoxic preconditioning in rats. Dokl Biol Sci 421(5): 239–240. (In Russ)]. https://doi.org/10.1134/S0012496608040054Filaretova L (2017) Gastroprotective Effect of Stress Preconditioning: Involvement of Glucocorticoids. Curr Pharm Des 23: 3923–3927. https://doi.org/10.2174/1381612823666170215145125Grigoryan GA, Pavlova IV, Zaichenko MI (2022) Effects of Social Isolation on the Development of Anxiety and Depression-Like Behavior in Model Experiments in Animals. Neurosci Behav Physiol 52: 722–738. https://doi.org/10.1007/S11055-022-01297-1Pritchard LM, Van Kempen TA, Zimmerberg B (2013) Behavioral effects of repeated handling differ in rats reared in social isolation and environmental enrichment. Neurosci Lett 536: 47–51. https://doi.org/10.1016/J.NEULET.2012.12.048Brenes JC, Fornaguera J, Sequeira-Cordero A (2020) Environmental Enrichment and Physical Exercise Attenuate the Depressive-Like Effects Induced by Social Isolation Stress in Rats. Front Pharmacol 11: 804. https://doi.org/10.3389/FPHAR.2020.00804Silveira J, Oliveira D, Martins A, Costa L, Neto F, Ferreira-Gomes J, Vaz C (2024) The association between anxiety and depression symptoms and clinical and pain characteristics in patients with hip and knee osteoarthritis. ARP Rheumatol.Bravo L, Llorca-Torralba M, Suárez-Pereira I, Berrocoso E (2020) Pain in neuropsychiatry: Insights from animal models. Neurosci Biobehav Rev 115: 96–115. https://doi.org/10.1016/J.NEUBIOREV.2020.04.029Falkowska M, Ntamati NR, Nevian NE, Nevian T, Acuña MA (2023) Environmental enrichment promotes resilience to neuropathic pain-induced depression and correlates with decreased excitability of the anterior cingulate cortex. Front Behav Neurosci 17: 1139205. https://doi.org/10.3389/FNBEH.2023.1139205Wang X ming, Zhang G fen, Jia M, Xie Z min, Yang J jun, Shen J chun, Zhou Z qiang (2019) Environmental enrichment improves pain sensitivity, depression-like phenotype, and memory deficit in mice with neuropathic pain: role of NPAS4. Psychopharmacology (Berl) 236: 1999–2014. https://doi.org/10.1007/S00213-019-5187-6Wang L, Liu X, Zhu C, Wu S, Li Z, Jing L, Zhang Z, Jing Y, Wang Y (2024) Environmental enrichment alleviates hyperalgesia by modulating central sensitization in a nitroglycerin-induced chronic migraine model of mice. J Headache Pain 25(1): 74. https://doi.org/10.1186/S10194-024-01779-2Horiguchi N, Ago Y, Hasebe S, Higashino K, Asada K, Kita Y, Takuma K, Matsuda T (2013) Isolation rearing reduces mechanical allodynia in a mouse model of chronic inflammatory pain. Pharmacol Biochem Behav 113: 46–52. https://doi.org/10.1016/J.PBB.2013.10.017Bravo L, Alba-Delgado C, Torres-Sanchez S, Mico JA, Neto FL, Berrocoso E (2013) Social stress exacerbates the aversion to painful experiences in rats exposed to chronic pain: the role of the locus coeruleus. Pain 154: 2014–2023. https://doi.org/10.1016/J.PAIN.2013.06.021Filaretov AA, Bogdanov AI, Yarushkina NI (1996) Stress-induced analgesia. The role of hormones produced by the hypophyseal-adrenocortical system. Neurosci Behav Physiol 26(6): 572–578. https://doi.org/10.1007/BF02359502Metcalf CS, Huntsman M, Garcia G, Kochanski AK, Chikinda M, Watanabe E, Underwood T, Vanegas F, Smith MD, White HS, Bulaj G (2019) Music-Enhanced Analgesia and Antiseizure Activities in Animal Models of Pain and Epilepsy: Toward Preclinical Studies Supporting Development of Digital Therapeutics and Their Combinations With Pharmaceutical Drugs. Front Neurol 10: 1–16. https://doi.org/10.3389/FNEUR.2019.00277Kimura LF, Mattaraia VG de M, Picolo G (2019) Distinct environmental enrichment protocols reduce anxiety but differentially modulate pain sensitivity in rats. Behav Brain Res 364: 442–446. https://doi.org/10.1016/J.BBR.2017.11.012Orock A, Johnson AC, Mohammadi E, Greenwood-Van Meerveld B (2023) Environmental enrichment reverses stress-induced changes in the brain-gut axis to ameliorate chronic visceral and somatic hypersensitivity. Neurobiol Stress 28: 100590. https://doi.org/10.1016/J.YNSTR.2023.100590