Alterations of Neurohumoral Response to Acute Stress in Spontaneously Hypertensive Rats Subjected to Long-Term Isolation

Cover Page

Cite item

Full Text

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

Abstract

Hypertension is a serious disease characterized by a sustained or recurrent increase in blood pressure, which can lead to various complications. Here, we studied the effect of genetically determined arterial hypertension in rats on their adaptation to long-term isolation and subsequent response to acute restraint stress. Male SHR rats with spontaneous hypertension were maintained in individual cages for 14 weeks. The serum levels of corticosterone, glucose, and pro- and anti-inflammatory cytokines and salivary α-amylase activity were studied, and the expression of genes associated with the regulation of steroidogenesis in the adrenal glands was evaluated. There were no significant changes in the parameters of the hypothalamic-pituitary-adrenocortical and sympatho-adrenal systems after isolation. Nevertheless, the preliminary isolation significantly affected the response to moderate restraint stress, including the expression of the regulatory genes Fkbp5 and Star in the adrenal glands and the content of proinflammatory cytokines IL-1β and IL-6 in the blood, although the changes in these indices were relatively subtle. This may reflect the predisposition of animals in isolation to develop quite specific stress-related changes.

Full Text

Restricted Access

About the authors

L. V. Tretyakova

Institute of Higher Nervous Activity and Neurophysiology of the RAS

Email: m_stepanichev@ihna.ru
Russian Federation, Moscow

A. A. Kvichansky

Institute of Higher Nervous Activity and Neurophysiology of the RAS

Email: m_stepanichev@ihna.ru
Russian Federation, Moscow

Yu. V. Moiseeva

Institute of Higher Nervous Activity and Neurophysiology of the RAS

Email: m_stepanichev@ihna.ru
Russian Federation, Moscow

V. O. Ovchinnikova

Institute of Higher Nervous Activity and Neurophysiology of the RAS

Email: m_stepanichev@ihna.ru
Russian Federation, Moscow

D. I. Mamedova

Institute of Higher Nervous Activity and Neurophysiology of the RAS

Email: m_stepanichev@ihna.ru
Russian Federation, Moscow

O. A. Nedogreeva

Institute of Higher Nervous Activity and Neurophysiology of the RAS

Email: m_stepanichev@ihna.ru
Russian Federation, Moscow

N. A. Lazareva

Institute of Higher Nervous Activity and Neurophysiology of the RAS

Email: m_stepanichev@ihna.ru
Russian Federation, Moscow

M. V. Onufriev

Institute of Higher Nervous Activity and Neurophysiology of the RAS

Email: m_stepanichev@ihna.ru
Russian Federation, Moscow

N. V. Gulyaeva

Institute of Higher Nervous Activity and Neurophysiology of the RAS

Email: m_stepanichev@ihna.ru
Russian Federation, Moscow

M. Yu. Stepanichev

Institute of Higher Nervous Activity and Neurophysiology of the RAS

Author for correspondence.
Email: m_stepanichev@ihna.ru
Russian Federation, Moscow

References

  1. McEwen BS (2007) Physiology and neurobiology of stress and adaptation: Central role of the brain. Physiol Rev 87(3): 873–904. https://doi.org/10.1152/physrev.00041.2006
  2. Elsaid N, Saied A, Kandil H, Soliman A, Taher F, Hadi M, Giridharan G, Jennings R, Casanova M, Keynton R, El-Baz A (2021) Impact of stress and hypertension on the cerebrovasculature. Front Biosci (Landmark Ed) 26(12): 1643–1652. https://doi.org/10.52586/5057
  3. Cuffee Y, Ogedegbe C, Williams NJ, Ogedegbe G, Schoenthaler A (2014) Psychosocial risk factors for hypertension: an update of the literature. Curr Hypertens Rep 16(10): 483. https://doi.org/10.1007/s11906-014-0483-3
  4. Liu MY, Li N, Li WA, Khan H (2017) Association between psychosocial stress and hypertension: A systematic review and meta-analysis. Neurol Res 39(6): 573–580. https://doi.org/10.1080/01616412.2017.1317904
  5. Yadav RSP, Ansari F, Bera N, Kent C, Agrawal P (2024) Lessons from lonely flies: Molecular and neuronal mechanisms underlying social isolation. Neurosci Biobehav Rev 156: 105504. https://doi.org/10.1016/J.NEUBIOREV.2023.105504
  6. Oken BS, Kaplan J, Klee D, Gallegos AM (2024) Contributions of loneliness to cognitive impairment and dementia in older adults are independent of other risk factors and Alzheimer’s pathology: a narrative review. Front Hum Neurosci 18: 1380002. https://doi.org/10.3389/FNHUM.2024.1380002
  7. Hawkley LC, Thisted RA, Masi CM, Cacioppo JT (2010) Loneliness predicts increased blood pressure: five-year cross-lagged analyses in middle-aged and older adults. Psychol Aging 25(1): 132. https://doi.org/10.1037/A0017805
  8. Yadav RSP, Ansari F, Bera N, Kent C, Agrawal P (2024) Lessons from lonely flies: Molecular and neuronal mechanisms underlying social isolation. Neurosci Biobehav Rev 156: 105504. https://doi.org/10.1016/J.NEUBIOREV.2023.105504
  9. Oken BS, Kaplan J, Klee D, Gallegos AM (2024) Contributions of loneliness to cognitive impairment and dementia in older adults are independent of other risk factors and Alzheimer’s pathology: a narrative review. Front Human Neurosci 18: 1380002. https://doi.org/10.3389/FNHUM.2024.1380002
  10. Yang YC, Li T, Ji Y (2013) Impact of social integration on metabolic functions: evidence from a nationally representative longitudinal study of US older adults. BMC Public Health 13: 1210. https://doi.org/10.1186/1471-2458-13-1210
  11. Steptoe A, Owen N, Kunz-Ebrecht SR, Brydon L (2004) Loneliness and neuroendocrine, cardiovascular, and inflammatory stress responses in middle-aged men and women. Psychoneuroendocrinology 29(5): 593–611. https://doi.org/10.1016/S0306-4530(03)00086-6.
  12. Grant N, Hamer M, Steptoe A (2009) Social isolation and stress-related cardiovascular, lipid, and cortisol responses. Ann Behav Med 37(1): 29–37. https://doi.org/10.1007/s12160-009-9081-z. Epub 2009 Feb 5
  13. Cacioppo JT, Ernst JM, Burleson MH, McClintock MK, Malarkey WB, Hawkley LC, Kowalewski RB, Paulsen A, Hobson JA, Hugdahl K, Spiegel D, Berntson GG (2000) Lonely traits and concomitant physiological processes: The MacArthur social neuroscience studies. Int J Psychophysiol 35(2–3): 143–154. https://doi.org/10.1016/s0167-8760(99)00049-5
  14. Hackett RA, Hamer M, Endrighi R, Brydon L, Steptoe A (2012) Loneliness and stress-related inflammatory and neuroendocrine responses in older men and women. Psychoneuroendocrinology 37(11): 1801–1809. https://doi.org/10.1016/j.psyneuen.2012.03.016
  15. Čater M, Majdič G (2022) How early maternal deprivation changes the brain and behavior? Eur J Neurosci 55(9–10): 2058–2075. https://doi.org/10.1111/ejn.15238
  16. Ferreira de Sá N., Camarini R, Suchecki D (2023) One day away from mum has lifelong consequences on brain and behaviour Neuroscience 525: 51–66. https://doi.org/10.1016/j.neuroscience.2023.06.013
  17. Pournajafi-Nazarloo H, Partoo L, Sanzenbacher L, Esmaeilzadeh M, Paredes J, Hashimoto K, Azizi F, Carter CS (2009) Social isolation modulates corticotropin-releasing factor type 2 receptor, urocortin 1 and urocortin 2 mRNAs expression in the cardiovascular system of prairie voles. Peptides 30(5): 940–946. https://doi.org/10.1016/j.peptides.2009.01.003.
  18. Pournajafi-Nazarloo H, Partoo L, Yee J, Stevenson J, Sanzenbacher L, Kenkel W, Mohsenpour SR, Hashimoto K, Carter CS (2011) Effects of social isolation on mRNA expression for corticotrophin-releasing hormone receptors in prairie voles. Psychoneuroendocrinology 36(6): 780–789. https://doi.org/10.1016/j.psyneuen.2010.10.015
  19. Klein SL, Hairston JE, Devries AC, Nelson RJ (1997) Social environment and steroid hormones affect species and sex differences in immune function among voles. Horm Behav 32(1): 30–39. https://doi.org/10.1006/hbeh.1997.1402
  20. McNeal N, Scotti MA, Wardwell J, Chandler DL, Bates SL, Larocca M, Trahanas DM, Grippo AJ (2014) Disruption of social bonds induces behavioral and physiological dysregulation in male and female prairie voles. Auton Neurosci 180: 9–16. https://doi.org/10.1016/j.autneu.2013.10.001
  21. McNeal N, Anderson EM, Moenk D, Trahanas D, Matuszewich L, Grippo AJ (2018) Social isolation alters central nervous system monoamine content in prairie voles following acute restraint. Soc Neurosci 13(2): 173–183. https://doi.org/10.1080/17470919.2016.1276473
  22. Gavrilovic L, Dronjak S (2005) Activation of rat pituitary-adrenocortical and sympatho-adrenomedullary system in response to different stressors. Neuro Endocrinol Lett 26(5): 515–520.
  23. Dronjak S, Gavrilovic L (2006) Effects of stress on catecholamine stores in central and peripheral tissues of long-term socially isolated rats. Braz J Med Biol Res 39(6): 785–790. https://doi.org/10.1590/s0100-879x2006000600011
  24. Djordjevic J, Djordjevic A, Adzic M, Radojcic M (2012). Effects of chronic social isolation on Wistar rat behavior and brain plasticity markers. Neuropsychobiology 66(2): 112–119. https://doi.org/10.1159/000338605
  25. Filipović D, Zlatković J, Inta D, Bjelobaba I, Stojiljkovic M, Gass P (2011) Chronic isolation stress predisposes the frontal cortex but not the hippocampus to the potentially detrimental release of cytochrome c from mitochondria and the activation of caspase-3. J Neurosci Res 89(9): 1461–1470. https://doi.org/10.1002/JNR.22687
  26. Filipović D, Zlatković J, Pavićević I, Mandić L, Demajo M (2012) Chronic isolation stress compromises JNK/c-Jun signaling in rat brain. J Neural Transmis 119(11): 1275–1284. https://doi.org/10.1007/s00702-012-0776-0
  27. Zlatković J, Filipović D (2013) Chronic social isolation induces NF-κB activation and upregulation of iNOS protein expression in rat prefrontal cortex. Neurochem Int 63(3): 172–179. https://doi.org/10.1016/j.neuint.2013.06.002
  28. Ferland CL, Schrader LA (2011) Cage mate separation in pair-housed male rats evokes an acute stress corticosterone response. Neurosci Lett 489(3): 154–158. https://doi.org/10.1016/j.neulet.2010.12.006
  29. Turner PV, Sunohara-Neilson J, Ovari J, Healy A, Leri F (2014) Effects of single compared with pair housing on hypothalamic-pituitary-adrenal axis activity and low-dose heroin place conditioning in adult male Sprague-Dawley rats. J Am Assoc Lab Anim Sci 53(2): 161–167.
  30. Dong H, Keegan JM, Hong E, Gallardo C, Montalvo-Ortiz J, Wang B, Rice KC, Csernansky J (2018) Corticotrophin releasing factor receptor 1antagonists prevent chronic stress-induced behavioral changes and synapse loss in aged rats. Psychoneuroendocrinology 90: 92. https://doi.org/10.1016/J.PSYNEUEN.2018.02.013
  31. Cacioppo JT, Cacioppo S, Capitanio JP, Cole SW (2015) The neuroendocrinology of social isolation. Annu Rev Psychol 66: 733–767. https://doi.org/10.1146/annurev-psych-010814-015240
  32. Gavrilovic L, Spasojevic N, Tanic N, Dronjak S (2008) Chronic isolation of adult rats decreases gene expression of catecholamine biosynthetic enzymes in adrenal medulla. Neuro Endocrinol Lett 29(6): 1015–1020.
  33. Jacobson ML, Kim LA, Patro R, Rosati B, McKinnon D (2018) Common and differential transcriptional responses to different models of traumatic stress exposure in rats. Transl Psychiatry 8(1): 165. https://doi.org/10.1038/s41398-018-0223-6
  34. Vavřínová A, Behuliak M, Vaněčková I, Zicha J (2021) The abnormalities of adrenomedullary hormonal system in genetic hypertension: Their contribution to altered regulation of blood pressure. Physiol Res 70(3): 307–326. https://doi.org/10.33549/physiolres.934687
  35. Moll D, Dale SL, Melby JC (1975) Adrenal steroidogenesis in the spontaneously hypertensive rat (SHR). Endocrinology 96(2): 416–420. https://doi.org/10.1210/endo-96-2-416
  36. Gądek-Michalska A, Bugajski A, Tadeusz J, Rachwalska P, Bugajsk, J (2017) Chronic social isolation in adaptation of HPA axis to heterotypic stress. Pharmacol Rep 69(6): 1213–1223. https://doi.org/10.1016/j.pharep.2017.08.011
  37. Gądek-Michalska A, Tadeusz J, Bugajski A, Bugajski J (2019) Chronic isolation stress affects subsequent crowding stress-induced brain nitric oxide synthase (NOS) isoforms and hypothalamic-pituitary-adrenal (HPA) axis responses. Neurotox Res 36(3): 523–539. https://doi.org/10.1007/s12640-019-00067-1
  38. Djordjevic J, Vuckovic T, Jasnic N, Cvijic G (2007) Effect of various stressors on the blood ACTH and corticosterone concentration in normotensive Wistar and spontaneously hypertensive Wistar-Kyoto rats. Gen Comp Endocrinol 153(1–3): 217–220. https://doi.org/10.1016/j.ygcen.2007.02.004
  39. Konkle ATM, Keith SE, McNamee JP, Michaud D (2017) Chronic noise exposure in the Spontaneously Hypertensive Rat. Noise Health 19(90): 213. https://doi.org/10.4103/NAH.NAH_15_17
  40. Matsuura T, Takimura R, Yamaguchi M, Ichinose M (2012) Estimation of restraint stress in rats using salivary amylase activity. J Physiol Sci 62(5): 421–427. https://doi.org/10.1007/s12576-012-0219-6
  41. Yao M, Hao Y, Wang T, Xie M, Li H, Feng J, Feng L, Ma D (2023) A review of stress-induced hyperglycaemia in the context of acute ischaemic stroke: Definition, underlying mechanisms, and the status of insulin therapy. Front Neurol 14: 1149671. https://doi.org/10.3389/fneur.2023.1149671
  42. Sim YB, Park SH, Kang YJ, Kim SM, Lee JK, Jung JS, Suh HW (2010) The regulation of blood glucose level in physical and emotional stress models: Possible involvement of adrenergic and glucocorticoid systems. Arch Pharmacol Res 33(10): 1679–1683. https://doi.org/10.1007/s12272-010-1018-3
  43. Freiman SV, Onufriev MV, Druzhkova TA, Yakovlev AA, Pochigaeva KI, Chepelev AV, Grishkina MN, Gudkova AA, Gekht AB, Gulyaeva NV (2015) The change in blood glucose level after a moderate stress as a parameter of stress reactivity in anxiety and depression: A pilot translational study. Neurochem J 9(2): 146–148. https://doi.org/10.1134/S1819712415020051
  44. Nedogreeva O, Mamedova D, Lazareva N, Novikova M, Moiseeva Y, Kostryukov P, Stepanichev M, Gulyaeva N (2023) Social isolation does not affect the indices of stress-responsiveness in aged rats of SHR strain. Proc XXIV Meeting IP Pavlov’s Physiol Society. 155–156.
  45. Paré WP, Schimmel GT (1986) Stress ulcer in normotensive and spontaneously hypertensive rats. Physiol Behav 36(4): 699–705. https://doi.org/10.1016/0031-9384(86)90357-4
  46. Paré WP (1989) Stress ulcer and open-field behavior of spontaneously hypertensive, normotensive, and Wistar rats. Pavlov J Biol Sci 24(2): 54–57. https://doi.org/10.1007/BF02964537
  47. Paré WP (1989) Stress ulcer susceptibility and depression in Wistar Kyoto (WKY) rats. Physiol Behav 46(6): 993–998. https://doi.org/10.1016/0031-9384(89)90203-5
  48. Roman O, Seres J, Pometlova M, Jurcovicova J (2004) Neuroendocrine or behavioral effects of acute or chronic emotional stress in Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Endocr Regul 38(4): 151–155.
  49. Vavřínová A, Behuliak M, Vodička M, Bencze M, Ergang P, Vaněčková I, Zicha J (2024) More efficient adaptation of cardiovascular response to repeated restraint in spontaneously hypertensive rats: The role of autonomic nervous system. Hypertens Res 47(9): 2377–2392. https://doi.org/10.1038/s41440-024-01765-w
  50. Stepanichev MY, Mamedova DI, Gulyaeva NV (2024) Hippocampus under pressure: molecular mechanisms of development of cognitive impairments in SHR rats. Biochemistry (Mosc) 89(4): 711–725. https://doi.org/10.1134/S0006297924040102
  51. Kenyon CJ, Panarelli M, Holloway CD, Dunlop D, Morton JJ, Connell JMC, Fraser R (1993) The role of glucocorticoid activity in the inheritance of hypertension: Studies in the rat. J Steroid Biochem Mol Biol 45(1–3): 7–11. https://doi.org/10.1016/0960-0760(93)90115-D
  52. Komanicky P, Reiss DL, Dale SL, Melby JC (1982) Role of adrenal steroidogenesis in etiology of hypertension in the spontaneously hypertensive rat. Endocrinology 111(1): 219–224. https://doi.org/10.1210/ENDO-111-1-219
  53. Zannas AS, Wiechmann T, Gassen NC, Binder EB (2016) Gene–stress–epigenetic regulation of FKBP5: clinical and translational implications. Neuropsychopharmacology 41(1): 261–274. https://doi.org/10.1038/npp.2015.235
  54. Bolshakov AP, Tret’yakova LV, Kvichansky AA, Gulyaeva NV (2021) Glucocorticoids: Dr. Jekyll and Mr. Hyde of hippocampal neuroinflammation. Biochemistry (Mosc) 86(2): 156–167. https://doi.org/10.1134/S0006297921020048
  55. Codagnone MG, Kara N, Ratsika A, Levone BR, van de Wouw M, Tan LA, Cunningham JI, Sanchez C, Cryan JF, O’Leary OF (2022) Inhibition of FKBP51 induces stress resilience and alters hippocampal neurogenesis. Mol Psychiatry 27(12): 4928–4938. https://doi.org/10.1038/s41380-022-01755-9
  56. Binder EB, Bradley RG, Liu W, Epstein MP, Deveau TC, Mercer KB, Tang Y, Gillespie CF, Heim CM, Nemeroff CB, Schwartz AC, Cubells JF, Ressler KJ (2008) Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. JAMA 299(11): 1291–1305. https://doi.org/10.1001/jama.299.11.1291
  57. Binder EB, Salyakina D, Lichtner P, Wochnik GM, Ising M, Pütz B, Papiol S, Seaman S, Lucae S, Kohli MA, Nickel T, Künzel HE, Fuchs B, Majer M, Pfennig A, Kern N, Brunner J, Modell S, Baghai T, Muller-Myhsok B (2004) Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. Nat Gen 36(12): 1319–1325. https://doi.org/10.1038/ng1479
  58. Riggs DL, Cox MB, Cheung-Flynn J, Prapapanich V, Carrigan PE, Smith DF (2004) Functional specificity of co-chaperone interactions with Hsp90 client proteins. Crit Rev Biochem Mol Biol 39(5–6): 279–295. https://doi.org/10.1080/10409230490892513
  59. Clark BJ (2016) ACTH action on StAR biology. Front Neurosci 10: 547. https://doi.org/10.3389/fnins.2016.00547
  60. Selvaraj V, Stocco DM, Clark BJ (2018) Current knowledge on the acute regulation of steroidogenesis. Biol Reproduct 99(1): 13–26. https://doi.org/10.1093/biolre/ioy102
  61. Stocco DM, Zhao AH, Tu LN, Morohaku K, Selvaraj V (2017) A brief history of the search for the protein(s) involved in the acute regulation of steroidogenesis. Mol Cell Endocrinol 441: 7–16. https://doi.org/10.1016/j.mce.2016.07.036
  62. Raje V, Ahern KW, Martinez BA, Howell NL, Oenarto V, Granade ME, Kim JW, Tundup S, Bottermann K, Gödecke A, Keller SR, Kadl A, Bland ML, Harris TE (2020) Adipocyte lipolysis drives acute stress-induced insulin resistance. Sci Rep 10(1): 18166. https://doi.org/10.1038/s41598-020-75321-0

Supplementary files

Supplementary Files
Action
1. JATS XML
Download
2. Fig. 1. Effect of social isolation on biochemical indices of stress-responsiveness in blood and saliva: (a) and (b) - changes in blood glucose and CORT in SHR rats during 60 min of acute moderate immobilisation stress, (c) - α-amylase activity in saliva from SHR rats before and after 60 min of acute moderate immobilisation stress. Data are presented as boxes (Me [Q1-Q3]) with whiskers (range min - max). * - p < 0.05, ** - p < 0.01, *** - p < 0.001 and **** - p < 0.0001 by Dunnett's criterion for multiple comparisons.

Download (163KB)
Indexing metadata
3. Fig. 2. Effect of acute moderate immobilisation stress on the content of pro-inflammatory and anti-inflammatory cytokines and C-reactive protein in the blood of rats of SOC and WPI groups. "Control" - rats not exposed to acute stressor. Data are presented as boxes (Me [Q1-Q3]) with whiskers (min-max spread). * - p < 0.012 and ** - p < 0.01 by Mann-Whitney test for independent variables.

Download (176KB)
Indexing metadata
4. Fig. 3. Effect of acute moderate immobilisation stress on relative adrenal mass (a) and mRNA transcript content of genes encoding the adrenocorticotropin receptor Mc2r (b) and glucocorticoid receptor Nr3c1 (c), associated with synthesis and metabolism of corticosteroids Hsd11b1 (d), Cyp11a1 (e), Cyp11b1 (f), transcription factor Fkbp5 (g) and steroid hormone synthesis regulatory protein Star (h) in adrenal glands of rats of SOC and IZO groups. ‘Control’ - rats not exposed to acute stressor. Data are presented as boxes (Me [Q1-Q3]) with whiskers (min-max difference). * - p < 0.012 and ** - p < 0.01 by Mann-Whitney test for independent variables.

Download (332KB)
Indexing metadata

Copyright (c) 2025 Russian Academy of Sciences