The 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 stressor

Cover Page

Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription Access

Abstract

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.

Full Text

Restricted Access

About the authors

N. I. Yaruskina

Pavlov Institute of Physiology

Email: yarushkinani@infran.ru
Russian Federation, St. Petersburg

M. Yu. Zenko

Pavlov Institute of Physiology

Email: yarushkinani@infran.ru
Russian Federation, St. Petersburg

O. Yu. Morozova

Pavlov Institute of Physiology

Email: yarushkinani@infran.ru
Russian Federation, St. Petersburg

O. P. Komkova

Pavlov Institute of Physiology

Email: yarushkinani@infran.ru
Russian Federation, St. Petersburg

K. A. Baranova

Pavlov Institute of Physiology

Author for correspondence.
Email: yarushkinani@infran.ru
Russian Federation, St. Petersburg

S. E. Zhuikova

Pavlov Institute of Physiology

Email: yarushkinani@infran.ru
Russian Federation, St. Petersburg

E. A. Rybnikova

Pavlov Institute of Physiology

Email: yarushkinani@infran.ru
Russian Federation, St. Petersburg

L. P. Filaretova

Pavlov Institute of Physiology

Email: yarushkinani@infran.ru
Russian Federation, St. Petersburg

References

  1. Holt-Lunstad J (2021) A pandemic of social isolation? World Psychiatry 20: 55–56. https://doi.org/10.1002/WPS.20839
  2. Fang 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.2019.04.002
  3. Mikocka-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/S10880-021-09818-9
  4. Xiong 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-W
  5. Zhang 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.2023.10.080
  6. Bannon 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.2021.01.009
  7. Лобов 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/S0301179824010045
  8. Golaszewski 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.2021.46461
  9. Bu 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.2020.06.036
  10. Guven 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-Y
  11. Leemhuis 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/IJERPH18041819
  12. Sihvonen 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.2022.01.003
  13. Crofton 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.2014.11.017
  14. Brown RE (2020) Donald O. Hebb and the organization of behavior: 17 years in the writing. Mol Brain 13. https://doi.org/10.1186/S13041-020-00567-8
  15. Diamond 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.901230110
  16. Wang 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/S11064-020-03102-2
  17. Braun 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/DDZ235
  18. Popa 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.2020.101790
  19. Lopez 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.2014.11.012
  20. Vannan 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.2018.07.005
  21. Zhao 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.2021.03.018
  22. Guarnieri 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/S41398-020-0701-5
  23. Крупина 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/S0301179823040045
  24. Filaretova 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-W
  25. Солнушкин 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)].
  26. 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.2011.10.001
  27. Dulabi 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-2020-0030
  28. Belardo 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.2022.108978
  29. Filaretova 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.2021.5.06
  30. Filaretova 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.2021.682643
  31. Filaretova 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/10.2174/1381612826666200521142746
  32. Yarushkina 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.2020.6.04
  33. Filaretova LP, Filaretov AA, Makara GB (1998) Corticosterone increase inhibits stress-induced gastric erosions in rats. Am J Physiol 274: G1024-G1030.
  34. 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.
  35. 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.2006.01.005
  36. Подвигина 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)].
  37. 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/s0022093023060406
  38. Filaretova 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_163
  39. Gamallo 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)90006-5
  40. Hofford 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.2017.10.023
  41. Рыбникова 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/S0012496608040054
  42. Filaretova L (2017) Gastroprotective Effect of Stress Preconditioning: Involvement of Glucocorticoids. Curr Pharm Des 23: 3923–3927. https://doi.org/10.2174/1381612823666170215145125
  43. Grigoryan 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/S11055-022-01297-1
  44. Pritchard 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.2012.12.048
  45. Brenes 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.2020.00804
  46. Silveira 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.
  47. 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.2020.04.029
  48. Falkowska 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.2023.1139205
  49. Wang 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/S00213-019-5187-6
  50. Wang 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/S10194-024-01779-2
  51. Horiguchi 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.2013.10.017
  52. Bravo 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.2013.06.021
  53. Filaretov 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/BF02359502
  54. Metcalf 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.2019.00277
  55. Kimura 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.2017.11.012
  56. Orock 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

Supplementary files

Supplementary Files
Action
1. JATS XML
Download
2. Fig. 1. Experimental design. Thirty-day-old rats were placed for 4 weeks in different housing conditions: standard conditions (SC), social isolation (SI), or enriched environment (EE). Then they were divided into two groups, each of which was exposed to an ulcerogenic stressor (US): 3 h immobilization in the cold (10 °C). In the first group (a), the effect of housing conditions only on the sensitivity of the gastric mucosa to the action of the US was studied (experiment 1), in the second group (b), the effect of housing conditions on behavior, stress reactivity of the HPA axis, and somatic pain sensitivity after the action of the US was studied (experiment 2).

Download (124KB)
Indexing metadata
3. Fig. 2. The effect of rat housing conditions on changes in body weight in the period preceding experiments 1 and 2. Significance of differences at p < 0.05: * from the “social isolation” (SI) group. EN – enriched environment, SC – standard conditions. Number of cases in the group n = 11–12.

Download (70KB)
Indexing metadata
4. Fig. 3. Effect of rat housing conditions on plasma corticosterone levels after exposure to an ulcerogenic stressor (3 h immobilization in the cold, 10 ˚C) (a) and the average area of ​​erosions in the stomach induced by this stressor (b). EN – enriched environment, CI – isolation, SC – standard conditions. Number of rats: (a) – n = 10–11; (b) – n = 12.

Download (60KB)
Indexing metadata
5. Fig. 4. Effect of rat housing conditions on the stress reactivity of the HPA axis without an ulcerogenic stressor (a) and under its action (3 h immobilization, 10 ˚C) (b). Significance of differences at p < 0.05: * from the basal level (0 point); # from the OS group (enriched environment). SI – isolation, SU – standard conditions. Number of cases in the group n = 6.

Download (158KB)
Indexing metadata
6. Fig. 5. Motor activity in the “open field”: the number of crossed peripheral squares. US – ulcerogenic stressor. Reliability of differences at p < 0.05: * from SU, # from all other groups. SU – standard conditions, CI – isolation, OS – enriched environment. Number of cases in groups: n = 6 (SU); n = 18 (SU+US); n = 12 (SI+US) and (OS+US).

Download (93KB)
Indexing metadata
7. Fig. 6. Animal behavior in the elevated plus maze test. (a) – time in the center of the setup, (b) – number of exits to the center, (c) – time in the open arms, (d) – number of exits to the open arms. US – ulcerogenic stressor. Significance of differences at p < 0.05: * from SU, # from OS. SU – standard conditions, CI – isolation, OS – enriched environment. Number of cases in groups: n = 6 (SU); n = 18 (SU+US); n = 12 (SI+US) and (OS+US).

Download (128KB)
Indexing metadata
8. Fig. 7. Effect of housing conditions on somatic pain sensitivity of rats in the hot plate test on the next day (day 3) and on the 5th day (day 6) after exposure to an ulcerogenic stressor (3 h immobilization, 10 ˚C). Significance of differences at p < 0.05: * from the IE+US and SI+US groups; # from the SI group (standard conditions). EE – enriched environment, SI – social isolation, SI – ulcerogenic stressor. Number of cases in a group n = 10–12.

Download (55KB)
Indexing metadata
9. Fig. 8. Mean plasma corticosterone levels in rats with active and passive behavioral strategies kept in social isolation (SI) and rats kept in an enriched environment (EE) and standard conditions (SC) after exposure to an ulcerogenic stressor (US) (a), and the relationship between the plasma corticosterone level and somatic pain sensitivity in rats with active and passive behavioral strategies after the first (b) and second (c) testing of somatic pain sensitivity. Significance of differences at p < 0.05: * from the SC+SC group. Number of cases in groups: n = 5 (SI (passive)); n = 7 (SI (active)); n = 11 (SC); n = 12 (SI).

Download (255KB)
Indexing metadata

Copyright (c) 2024 Russian Academy of Sciences