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Chronic combined stress induces selective and long-lasting inflammatory response evoked by changes in corticosterone accumulation and signaling in rat hippocampus

Abstract

Hippocampus is believed to be selectively vulnerable to stress. We hypothesized that this phenomenon may be mediated by relatively high vulnerability to neuroinflammation related to impairments of local glucocorticoid metabolism and signaling. We have evaluated inflammatory responses induced by acute or chronic combined stress in the cerebral cortex and hippocampus as well as circulating and brain corticosterone (CS) levels as well as expression of corticosterone target genes. The hippocampus showed higher stress-induced expression of the proinflammatory cytokine IL-1β as compared to the cerebral cortex. A month after the termination of the chronic stress, IL-1β mRNA in the cerebral cortex reached control level, while in the hippocampus it remained significantly increased. Under chronic stress, the maladaptive inflammatory response in hippocampus was accompanied by a significant increase in local CS levels, as compared to cerebral cortex. Under acute stress, the increased CS level induced changes in CS-regulated genes expression (CRF and IGF1), while this phenomenon was not observed after chronic stress. Thus, the hippocampus appears to be more vulnerable to stress-induced inflammation as compared to the neocortex and demonstrates persistent inflammatory response induced by chronic stress. Stress-induced maladaptive inflammatory response is associated with a selective increase in hippocampal CS accumulation and changes in CS signaling.

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References

  • Adzic M, Djordjevic H, Djordjevic A, Niciforovic A, Demonacos C, Radojcic M, Krstic-Demonacos M (2009) Acute or chronic stress induce cell compartment-specific phosphorylation of glucocorticoid receptor and alter its transcriptional activity in Wistar rat brain. J Endocrinol 202:87–97

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Barnum CJ, Pace TWW, Hu F, Neigh GN, Tansey MG (2012) Psychological stress in adolescent and adult mice increases neuroinflammation and attenuates the response to LPS challenge. J Neuroinflammation 9:9

    Article  PubMed  PubMed Central  Google Scholar 

  • Baumann R, Hecht K (1977) Stress, Neurose und Herz-Kreislauf. Berlin, VEB Deutscher Verlag der Wissenschaften

  • Blandino P Jr, Barnum CJ, Solomon LG, Larish Y, Lankow BS, Deak T (2009) Gene expression changes in the hypothalamus provide evidence for regionally-selective changes in IL-1 and microglial markers after acute stress. Brain Behav Immun 23:958–968

    CAS  Article  PubMed  Google Scholar 

  • Buchanan JB, Sparkman NL, Chen J, Johnson RW (2008) Cognitive and neuroinflammatory consequences of mild repeated stress are exacerbated in aged mice. Psychoneuroendocrinology 33:755–765

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Chourbaji S, Urani A, Inta I, Sanchis-Segura C, Brandwein C, Zink M, Schwaninger M, Gass P (2006) IL-6 knockout mice exhibit resistance to stress-induced development of depression-like behaviors. Neurobiol Dis 23:587–594

    CAS  Article  PubMed  Google Scholar 

  • Connor TJ, Song C, Leonard BE, Merali Z, Anisman H (1998) An assessment of the effects of central interleukin-1beta, −2, −6, and tumor necrosis factor-alpha administration on some behavioural, neurochemical, endocrine and immune parameters in the rat. Neuroscience 84:923–33

    CAS  Article  PubMed  Google Scholar 

  • de Pablos RM, Villarán RF, Argüelles S, Herrera AJ, Venero JL, Ayala A, Cano J, Machado A (2006) Stress increases vulnerability to inflammation in the rat prefrontal cortex. J Neurosci 26:5709–5719

    Article  PubMed  Google Scholar 

  • D’Ercole AJ, Ye P, Calikoglu AS, Gutierrez-Ospina G (1996) The role of the insulin-like growth factors in the central nervous system. Mol Neurobiol 13:227–255

    Article  PubMed  Google Scholar 

  • Dinkel K, MacPherson A, Sapolsky RM (2003) Novel glucocorticoid effects on acute inflammation in the CNS. J Neurochem 84:705–716

    CAS  Article  PubMed  Google Scholar 

  • Esch T, Stefano GB, Fricchione GL, Benson H (2002) The role of stress in neurodegenerative diseases and mental disorders. Neuro Endocrinol Lett 23:199–208

    PubMed  Google Scholar 

  • Fan J, Wojnar MM, Theodorakis M, Lang CH (1996) Regulation of insulin-like growth factor (IGF)-I mRNA and peptide and IGF-binding proteins by interleukin-1. Am J Physiol 270:R621–R629

    CAS  PubMed  Google Scholar 

  • Gądek-Michalska A, Spyrka J, Rachwalska P, Tadeusz J, Bugajski J (2013) Influence of chronic stress on brain corticosteroid receptors and HPA axis activity. Pharmacol Rep 65:1163–1175

    Article  PubMed  Google Scholar 

  • García-Fernández LF, Iñiguez MA, Eguchi N, Fresno M, Urade Y, Muñoz A (2000) Dexamethasone induces lipocalin-type prostaglandin D synthase gene expression in mouse neuronal cells. J Neurochem 75:460–470

    Article  PubMed  Google Scholar 

  • Goshen I, Kreisel T, Ben-Menachem-Zidon O, Licht T, Weidenfeld J, Ben-Hur T, Yirmiya R (2008) Brain interleukin-1 mediates chronic stress-induced depression in mice via adrenocortical activation and hippocampal neurogenesis suppression. Mol Psychiatry 13:717–728

    CAS  Article  PubMed  Google Scholar 

  • Hecht K, Poppei M (1977) Zur rolle des umweltfaktors in der dialektischen gesundheits-krankheitsbeziehung eines organismus. Forschungsverband Herz-Kreislaufkrankheiten, Berlin

    Google Scholar 

  • Hueston CM, Barnum CJ, Eberle JA, Ferraioli FJ, Buck HM, Deak T (2011) Stress-dependent changes in neuroinflammatory markers observed after common laboratory stressors are not seen following acute social defeat of the Sprague Dawley rat. Physiol Behav 104:187–198

    CAS  Article  PubMed  Google Scholar 

  • Jung SH, Wang Y, Kim T, Tarr A, Reader B, Powell N, Sheridan JF (2015) Molecular mechanisms of repeated social defeat-induced glucocorticoid resistance: role of microRNA. Brain Behav Immun 44:195–206

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Klieber MA, Underhill C, Hammond GL, Muller YA (2007) Corticosteroid-binding globulin, a structural basis for steroid transport and proteinase-triggered release. J Biol Chem. 282:29594–29603.

  • Kubera M, Obuchowicz E, Goehler L, Brzeszcz J, Maes M (2010) In animal models, psychosocial stress-induced (neuro)inflammation, apoptosis and reduced neurogenesis are associated to the onset of depression. Prog Neuropsychopharmacol Biol Psychiatry 35:744–759

    Article  PubMed  Google Scholar 

  • Lee SW, Tsou AP, Chan H, Thomas J, Petrie K, Eugui EM, Allison AC (1988) Glucocorticoids selectively inhibit the transcription of the interleukin 1 beta gene and decrease the stability of interleukin 1 beta mRNA. Proc Natl Acad Sci U S A 85:1204–1208

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Lightman SL, Harbuz MS (1993) Expression of corticotropin-releasing factor mRNA in response to stress. Ciba Found Symp 172:173–187

    CAS  PubMed  Google Scholar 

  • Linthorst AC, Flachskamm C, Holsboer F, Reul JM (1994) Local administration of recombinant human interleukin-1 beta in the rat hippocampus increases serotonergic neurotransmission, hypothalamic-pituitary-adrenocortical axis activity, and body temperature. Endocrinology 135:520–32

    CAS  PubMed  Google Scholar 

  • MacPherson A, Dinkel K, Sapolsky R (2005) Glucocorticoids worsen excitotoxin-induced expression of pro-inflammatory cytokines in hippocampal cultures. Exp Neurol 94:376–383

    Article  Google Scholar 

  • Magarinos AM, McEwen BS (1995) Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons: involvement of glucocorticoid secretion and excitatory amino acid receptors. Neuroscience 69:89–98

    CAS  Article  PubMed  Google Scholar 

  • Marques AH, Silverman MN, Sternberg EM (2009) Glucocorticoid dysregulations and their clinical correlates. From receptors to therapeutics. Ann N Y Acad Sci 1179:1–18

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • McEwen BS (1997) Possible mechanisms for atrophy of the human hippocampus. Mol Psychiatry 2:255–262

    CAS  Article  PubMed  Google Scholar 

  • McEwen BS, Sapolsky RM (1995) Stress and cognitive function. Curr Opin Neurobiol 5:205–216

    CAS  Article  PubMed  Google Scholar 

  • Melik Parsadaniantz S, Dauge V, Roques BP, Kerdelhue B (1999) Acute intrahippocampal injection of human interleukin-1b stimulates the anterior pituitary POMC transcription and increases plasma levels of ACTH and corticosterone in the male rat. Neuroendocrinology 69:77–87

    CAS  Article  PubMed  Google Scholar 

  • Munhoz CD, García-Bueno B, Madrigal JL, Lepsch LB, Scavone C, Leza JC (2008) Stress-induced neuroinflammation: mechanisms and new pharmacological targets. Braz J Med Biol Res 41:1037–1046

    CAS  Article  PubMed  Google Scholar 

  • Murray CA, Lynch MA (1998) Evidence that increased hippocampal expression of the cytokine, IL-1b, is a common trigger for age- and stress-induced impairments in long-term potentiation. J Neurosci 18:2974–2981

    CAS  PubMed  Google Scholar 

  • Ownby RL (2010) Neuroinflammation and cognitive aging. Curr Psychiatr Rep 12:39–45

    Article  Google Scholar 

  • Pace TW, Heim CM (2011) A short review on the psychoneuroimmunology of posttraumatic stress disorder: from risk factors to medical comorbidities. Brain Behav Immun 25:6–13

    CAS  Article  PubMed  Google Scholar 

  • Pace TW, Hu F, Miller AH (2007) Cytokine-effects on glucocorticoid receptor function: relevance to glucocorticoid resistance and the pathophysiology and treatment of major depression. Brain Behav Immun 21:9–19

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Piskunov AK, Yakovlev AA, Stepanichev MY, Onufriev MV, Gulyaeva NV (2011) Selective vulnerability of hippocampus to interoceptive stress: impact on interleukin-1β and erythropoietin. Neurochem J 5:191–193

    CAS  Article  Google Scholar 

  • Pugh CR, Nguyen NT, Goyea JL, Fleshner M, Wakins LR, Maier SF, Rudy JW (1999) Role of interleukin-1beta in impairment of contextual fear conditioning caused by social isolation. Behav Brain Res 106:109–118

    CAS  Article  PubMed  Google Scholar 

  • Qin L, Wu X, Block ML, Liu Y, Breese GR, Hong JS, Knapp DJ, Crews FT (2007) Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia 55:453–462

    Article  PubMed  PubMed Central  Google Scholar 

  • Remus JL, Stewart LT, Camp RM, Novak CM, Johnson JD (2015) Interaction of metabolic stress with chronic mild stress in altering brain cytokines and sucrose preference. Behav Neurosci 129:321–330

    Article  PubMed  PubMed Central  Google Scholar 

  • Sapolsky R, Rivier C, Yamamoto G, Plotsky P, Vale W (1987) Interleukin-1 stimulates the secretion of hypothalamic corticotrophin-releasing factor. Science 238:522–524

    CAS  Article  PubMed  Google Scholar 

  • Sapolsky RM, Romero LM, Munck A (2000) How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory and preparative action. Endocr Rev 21:55–89

    CAS  PubMed  Google Scholar 

  • Schmidt MV, Sterlemann V, Ganea K, Liebl C, Alam S, Harbich D, Greetfeld M, Uhr M, Holsboer F, Müller MB (2007) Persistent neuroendocrine and behavioral effects of a novel, etiologically relevant mouse paradigm for chronic social stress during adolescence. Psychoneuroendocrinology 32:417–429

    CAS  Article  PubMed  Google Scholar 

  • Sorrells SF, Sapolsky RM (2007) An inflammatory review of glucocorticoid actions in the CNS. Brain Behav Immun 21:259–272

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Sterlemann V, Ganea K, Liebl C, Harbich D, Alam S, Holsboer F, Müller MB, Schmidt MV (2008) Long-term behavioral and neuroendocrine alterations following chronic social stress in mice: implications for stress-related disorders. Horm Behav 53:386–394

    CAS  Article  PubMed  Google Scholar 

  • Stewart JC, Rand KL, Muldoon MF, Kamarck TW (2009) A prospective evaluation of the directionality of the depression-inflammation relationship. Brain Behav Immun 23:936–944

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Streit WJ (1990) An improved staining method for rat microglial cells using the lectin from Griffonia simplicifolia (GSA I-B4). J Histochem Cytochem 38:1683–1686

    CAS  Article  PubMed  Google Scholar 

  • Tishkina AO (2009) A method of automated quantitative analysis of brain slices microphotographs. Neurochem J 3:309–313

    Article  Google Scholar 

  • Tishkina AO, Levshina IP, Lazareva NA, Passikova NV, Stepanichev MY, Ajrapetyanz MG, Gulyaeva NV (2009) Chronic stress induces nonapoptotic neuronal death in the rat hippocampus. Dokl Biol Sci 428:403–406

    CAS  Article  PubMed  Google Scholar 

  • Tishkina AO, Rukhlenko A, Stepanichev M, Levshina I, Pasikova N, Onufriev M, Yu M, Piskunov A, Gulyaeva N (2012) Region-specific changes in activities of cell death-related proteases and nitric oxide metabolism in rat brain in a chronic unpredictable stress model. Metab Brain Dis 27:431–441

    CAS  Article  PubMed  Google Scholar 

  • Uz T, Dwivedi Y, Savani PD, Impagnatiello F, Pandey G, Manev H (1999) Glucocorticoids stimulate inflammatory 5-lipoxygenase gene expression and protein translocation in the brain. J Neurochem 73:693–699

    CAS  Article  PubMed  Google Scholar 

  • Yang N, Ray DW, Matthews LC (2012) Current concepts in glucocorticoid resistance. Steroids 77(11):1041–9

    CAS  Article  PubMed  Google Scholar 

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Acknowledgments

The authors would like to thank Natalia Lazareva and Natalia Stepanicheva for excellent technical assistance as well as Alexander Yakovlev and Mikhail Onufriev for their help and valuable advice.

This study was supported by the Russian Science Foundation grant # 14-25-00136.

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Correspondence to Natalia Gulyaeva.

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Aleksey Piskunov and Mikhail Stepanichev equally contributed to this study.

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Piskunov, A., Stepanichev, M., Tishkina, A. et al. Chronic combined stress induces selective and long-lasting inflammatory response evoked by changes in corticosterone accumulation and signaling in rat hippocampus. Metab Brain Dis 31, 445–454 (2016). https://doi.org/10.1007/s11011-015-9785-7

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  • DOI: https://doi.org/10.1007/s11011-015-9785-7

Keywords

  • Neuroinflammation
  • Hippocampus
  • Stress
  • Glucocorticoid
  • Corticosterone