Russian Journal of PhysiologyRussian Journal of PhysiologyРоссийский физиологический журнал им. И.М. Сеченова0869-81392658-655XThe Russian Academy of Sciences67930710.31857/S0869813925020046UIWJEUEXPERIMENTAL ARTICLESЭКСПЕРИМЕНТАЛЬНЫЕ СТАТЬИResearch ArticleAlterations of Neurohumoral Response to Acute Stress in Spontaneously Hypertensive Rats Subjected to Long-Term IsolationИзменения нейрогуморального ответа на острый стресс у спонтанно-гипертензивных крыс, перенесших длительную изоляциюTretyakovaL. V.ТретьяковаЛ. В.
Russian Federation
m_stepanichev@ihna.ruKvichanskyA. A.КвичанскийА. А.
Russian Federation
m_stepanichev@ihna.ruMoiseevaYu. V.МоисееваЮ. В.
Russian Federation
m_stepanichev@ihna.ruOvchinnikovaV. O.ОвчинниковаВ. О.
Russian Federation
m_stepanichev@ihna.ruMamedovaD. I.МамедоваД. И.
Russian Federation
m_stepanichev@ihna.ruNedogreevaO. A.НедогрееваО. А.
Russian Federation
m_stepanichev@ihna.ruLazarevaN. A.ЛазареваН. А.
Russian Federation
m_stepanichev@ihna.ruOnufrievM. V.ОнуфриевМ. В.
Russian Federation
m_stepanichev@ihna.ruGulyaevaN. V.ГуляеваН. В.
Russian Federation
m_stepanichev@ihna.ruStepanichevM. Yu.СтепаничевМ. Ю.
Russian Federation
m_stepanichev@ihna.ruInstitute of Higher Nervous Activity and Neurophysiology of the RASИнститут высшей нервной деятельности и нейрофизиологии РАН16022025111224926509052025Copyright ©; 2025, Russian Academy of SciencesCopyright ©; 2025, Российская академия наук2025Russian Academy of SciencesРоссийская академия наукhttps://journals.eco-vector.com/0869-8139/article/view/679307

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.

Артериальная гипертензия – это серьезное заболевание, характеризующееся устойчивым или периодическим повышением артериального давления, которое может привести к различным осложнениям. В этой работе мы изучали влияние генетически обусловленной артериальной гипертензии у крыс на их адаптацию к длительной изоляции и последующую реакцию на острый стресс, вызванный ограничением подвижности. Самцов крыс линии SHR со спонтанной гипертензией содержали в индивидуальных клетках в течение 14 недель. В сыворотке крови исследовали уровень кортикостерона, глюкозы, про- и противовоспалительных цитокинов, а также оценивали экспрессию генов, связанных с регуляцией стероидогенеза, в надпочечниках. Существенных изменений показателей гипоталамо-гипофизарно-адренокортикальной и симпато-адреналовой систем после изоляции выявлено не было. Тем не менее предварительное изолированное содержание значительно повлияло на реакцию на умеренный иммобилизационный стресс, включая экспрессию регуляторных генов Fkbp5 и Star в надпочечниках и содержание провоспалительных цитокинов ИЛ-1β и ИЛ-6 в крови, хотя изменения этих показателей были достаточно слабыми. Это может отражать предрасположенность животных, находившихся в условиях изоляции, к развитию умеренных изменений, связанных со стрессом.

social isolationhypothalamic-pituitary-adrenocortical systemsympatho-adrenal systemadrenalsstressspontaneously hypertensive ratsсоциальная изоляциягипоталамо-гипофизарно-адренокортикальная системасимпато-адреналовая системанадпочечникистрессспонтанно-гипертензивная крысаРоссийский научный фондRussian Science Foundation22-15-00132McEwen 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.00041.2006Elsaid 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/10.52586/5057Cuffee 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/s11906-014-0483-3Liu 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/10.1080/01616412.2017.1317904Yadav 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.2023.105504Oken 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.2024.1380002Hawkley 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/A0017805Yadav 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.2023.105504Oken 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.2024.1380002Yang 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/10.1186/1471-2458-13-1210Steptoe 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.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 5Cacioppo 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)00049-5Hackett 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.2012.03.016Čater 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.15238Ferreira 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.2023.06.013Pournajafi-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.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.2010.10.015Klein 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.1997.1402McNeal 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.2013.10.001McNeal 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/10.1080/17470919.2016.1276473Gavrilovic 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.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/s0100-879x2006000600011Djordjevic 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/10.1159/000338605Filipović 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.22687Filipović 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/s00702-012-0776-0Zlatković 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.2013.06.002Ferland 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.2010.12.006Turner 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.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.2018.02.013Cacioppo 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-010814-015240Gavrilovic 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.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/s41398-018-0223-6Vavřínová 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.934687Moll 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-96-2-416Gądek-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.2017.08.011Gądek-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/s12640-019-00067-1Djordjevic 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.2007.02.004Konkle 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_17Matsuura 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/s12576-012-0219-6Yao 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.2023.1149671Sim 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/s12272-010-1018-3Freiman 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/S1819712415020051Nedogreeva 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.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)90357-4Paré 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/BF02964537Paré 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)90203-5Roman 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.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-wStepanichev 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/S0006297924040102Kenyon 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-DKomanicky 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-111-1-219Zannas 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.2015.235Bolshakov 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/S0006297921020048Codagnone 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/s41380-022-01755-9Binder 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.299.11.1291Binder 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/ng1479Riggs 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/10.1080/10409230490892513Clark BJ (2016) ACTH action on StAR biology. Front Neurosci 10: 547. https://doi.org/10.3389/fnins.2016.00547Selvaraj 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/ioy102Stocco 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.2016.07.036Raje 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