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Chronic Stress Causes Sex-Specific and Structure-Specific Alterations in Mitochondrial Respiratory Chain Activity in Rat Brain

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Abstract

Chronic restraint stress (CRS) induces a variety of changes in brain function, some of which are mediated by glucocorticoids. The response to stress occurs in a sex-specific way, and may include mitochondrial and synaptic alterations. The synapse is highly dependent on mitochondrial energy supply, and when mitochondria become dysfunctional, they orchestrate cell death. This study aimed to investigate the CRS effects on mitochondrial respiratory chain activity, as well as mitochondrial potential and mass in cell body and synapses using hippocampus, cortex and striatum of male and female rats. Rats were divided into non-stressed (control) and stressed group (CRS during 40 days). Results showed that CRS increased complex I–III activity in hippocampus. We also observed an interaction between CRS and sex in the striatal complex II activity, since CRS induced a reduction in complex II activity in males, while in females this activity was increased. Also an interaction was observed between stress and sex in cortical complex IV activity, since CRS induced increased activity in females, while it was reduced in males. Glucocorticoid receptor (GR) content in cortex and hippocampus was sexually dimorphic, with female rats presenting higher levels compared to males. No changes were observed in GR content, mitochondrial potential or mass of animals submitted to CRS. It was concluded that CRS induced changes in respiratory chain complex activities, and some of these changes are sex-dependent: these activities are increased in the striatal mitochondria by CRS protocol mainly in females, while in males it is decreased.

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Abbreviations

GR:

Glucocorticoid receptor

MR:

Mineralocorticoid receptor

GC:

Glucocorticoid

ROS:

Reactive oxygen species

AD:

Alzheimer’s disease

CRS:

Chronic restraint stress

References

  1. Popoli M, Yan Z, McEwen BS, Sanacora G (2011) The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. Nat Rev Neurosci 13(1):22–37. doi:10.1038/nrn3138

    Article  PubMed  PubMed Central  Google Scholar 

  2. Shirazi SN, Friedman AR, Kaufer D, Sakhai SA (2015) Glucocorticoids and the brain: neural mechanisms regulating the stress response. Adv Exp Med Biol 872:235–252. doi:10.1007/978-1-4939-2895-8_10

    Article  CAS  PubMed  Google Scholar 

  3. Wang Y, Kan H, Yin Y, Wu W, Hu W, Wang M, Li W, Li W (2014) Protective effects of ginsenoside Rg1 on chronic restraint stress induced learning and memory impairments in male mice. Pharmacol Biochem Behav 120:73–81. doi:10.1016/j.pbb.2014.02.012

    Article  CAS  PubMed  Google Scholar 

  4. Buynitsky T, Mostofsky DI (2009) Restraint stress in biobehavioral research: Recent developments. Neurosci Biobehav Rev 33:1089–1098. doi:10.1016/j.neubiorev.2009.05.004

    Article  PubMed  Google Scholar 

  5. Ahmad A, Rasheed N, Chand K, Maurya R, Banu N, Palit G (2012) Restraint stress-induced central monoaminergic & oxidative changes in rats & their prevention by novel Ocimum sanctum compounds. Indian J Med Res 135(4):548–554

    PubMed  PubMed Central  Google Scholar 

  6. Gadek-Michalska A, Tadeusz J, Rachwalska P, Bugajski J (2015) Chronic stress adaptation of the nitric oxide synthases and IL-1β levels in brain structures and hypothalamic-pituitary-adrenal axis activity induced by homotypic stress. J Physiol Pharmacol 66(3):427–440

    CAS  PubMed  Google Scholar 

  7. Vyas S, Rodrigues AJ, Silva JM, Tronche F, Almeida OF, Sousa N, Sotiropoulos I (2016) Chronic stress and glucocorticoids: from neuronal plasticity to neurodegeneration. Neural Plast 2016:6391686. doi:10.1155/2016/6391686

    Article  PubMed  PubMed Central  Google Scholar 

  8. Arp JM, Horst JP, Kanatsou S, Fernández G, Joëls M, Krugers HJ, Oitzl MS (2014) Mineralocorticoid receptors guide spatial and stimulus-response learning in mice. PLoS ONE 9(1):e86236. doi:10.1371/journal.pone.0086236.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Chiba S, Numakawa T, Ninomiya M, Richards MC, Wakabayashi C, Kunugi H (2012) Chronic restraint stress causes anxiety- and depression-like behaviors, downregulates glucocorticoid receptor expression, and attenuates glutamate release induced by brain-derived neurotrophic factor in the prefrontal cortex. Prog Neuropsychopharmacol Biol Psychiatry 39(1):112–119. doi:10.1016/j.pnpbp.2012.05.018

    Article  CAS  PubMed  Google Scholar 

  10. Kitraki E, Kremmyda O, Youlatos D, Alexis M, Kittas C (2004) Spatial performance and corticosteroid receptor status in the 21-day restraint stress paradigm. Ann NY Acad Sci 1018:323–327. doi:10.1196/annals.1296.039

    Article  CAS  PubMed  Google Scholar 

  11. Adzic M, Lukic I, Mitic M, Djordjevic J, Elaković I, Djordjevic A, Krstic-Demonacos M, Matić G, Radojcic M (2013) Brain region- and sex-specific modulation of mitochondrial glucocorticoid receptor phosphorylation in fluoxetine treated stressed rats: effects on energy metabolism. Psychoneuroendocrinology 38(12):2914–2924. doi:10.1016/j.psyneuen.2013.07.019

    Article  CAS  PubMed  Google Scholar 

  12. Hunter RG, Seligsohn M, Rubin TG, Griffiths BB, Ozdemir Y, Pfaff DW, Datson NA, McEwen BS (2016) Stress and corticosteroids regulate rat hippocampal mitochondrial DNA gene expression via the glucocorticoid receptor. Proc Natl Acad Sci USA 113(32):9099–9104. doi:10.1073/pnas.1602185113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Jeanneteau F, Arango-Lievano M (2016) Linking mitochondria to synapses: new insights for stress-related neuropsychiatric disorders. Neural Plast 2016:3985063. doi:10.1155/2016/3985063

    Article  PubMed  PubMed Central  Google Scholar 

  14. Völgyi K, Gulyássy P, Háden K, Kis V, Badics K, Kékesi KA, Simor A, Györffy B, Tóth EA, Lubec G, Juhász G, Dobolyi A (2015) Synaptic mitochondria: a brain mitochondria cluster with a specific proteome. J Proteomic 120:142–157. doi:10.1016/j.jprot.2015.03.005.

    Article  Google Scholar 

  15. Malisch JL, Saltzman W, Gomes FR, Rezende EL, Jeske DR, Garland T Jr (2007) Baseline and stress-induced plasma corticosterone concentrations of mice selectively bred for high voluntary wheel running. Physiol Biochem Zool 80(1):146–156. doi:10.1086/508828

    Article  CAS  PubMed  Google Scholar 

  16. Lu J, Wu XY, Zhu QB, Li J, Shi LG, Wu JL, Zhang QJ, Huang ML, Bao AM (2015) Sex differences in the stress response in SD rats. Behav Brain Res 284:231–237. doi:10.1016/j.bbr.2015.02.009

    Article  CAS  PubMed  Google Scholar 

  17. Nilsen J, Brinton RD (2002) Impact of progestins on estradiol potentiation of the glutamate calcium response. Neuroreport 13(6):825–830

    Article  CAS  PubMed  Google Scholar 

  18. Pettenuzzo LF, Noschang C, von Pozzer Toigo E, Fachin A, Vendite D, Dalmaz C (2008) Effects of chronic administration of caffeine and stress on feeding behavior of rats. Physiol Behav 95:295–301. doi:10.1016/j.physbeh.2008.06.003

    Article  CAS  PubMed  Google Scholar 

  19. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin-Phenol reagents. J Biol Chem 193:265–275

    CAS  PubMed  Google Scholar 

  20. Fischer JC, Ruitenbeek W, Berden JA, Trijbels JM, Veerkamp JH, Stadhouders AM, Sengers RC, Janssen AJ (1985) Differential investigation of the capacity of succinate oxidation in human skeletal muscle. Clin Chim Acta 153:23–26

    Article  CAS  PubMed  Google Scholar 

  21. Schapira AH, Cooper JM, Dexter D, Clark JB, Jenner P, Marsden CD (1990) Mitochondrial complex I deficiency in Parkinson’s disease. J Neurochem 54(3):823–827

    Article  CAS  PubMed  Google Scholar 

  22. Rustin P, Chretien D, Bourgeron T, Gérard B, Rötig A, Saudubray JM, Munnich A (1994) Biochemical and molecular investigations in respiratory chain deficiencies. Clin Chim Acta 228(1):35–51

    Article  CAS  PubMed  Google Scholar 

  23. Pettenuzzo LF, Ferreira G da C, Schmidt AL, Dutra-Filho CS, Wyse AT, Wajner M (2006) Differential inhibitory effects of methylmalonic acid on respiratory chain complex activities in rat tissues. Int J Dev Neurosci 24(1):45–52. doi:10.1016/j.ijdevneu.2005.10.005

    Article  CAS  PubMed  Google Scholar 

  24. Weis SN, Pettenuzzo LF, Krolow R, Valentim LM, Mota CS, Dalmaz C, Wyse AT, Netto CA (2012) Neonatal hypoxia ischemia induces sex-related changes in rat brain mitochondria. Mitochondrion 12(2):271–279. doi:10.1016/j.mito.2011.10.002

    Article  CAS  PubMed  Google Scholar 

  25. Almeida RF, Comasseto DD, Ramos DB, Hansel G, Zimmer ER, Loureiro SO, Ganzella M, Souza DO (2016) Guanosine anxiolytic-like effect involves adenosinergic and glutamatergic neurotransmitter systems. Mol Neurobiol. doi:10.1007/s12035-015-9660-x

    Google Scholar 

  26. Benjamini Y, Drai D, Elmer G, Kafkafi N, Golani I (2001) Controlling the false discovery rate in behavior genetics research. Behav Brain Res 125(1–2):279–284

    Article  CAS  PubMed  Google Scholar 

  27. Nikiforuk A, Popik P (2013) Neurochemical modulation of stress-induced cognitive inflexibility in a rat model of an attentional set-shifting task. Pharmacol Rep 65(6):1479–1488

    Article  PubMed  Google Scholar 

  28. Quinton MS, Yamamoto BK (2007) Neurotoxic effects of chronic restraint stress in the striatum of methamphetamine-exposed rats. Psychopharmacology 193(3):341–350. doi:10.1007/s00213-007-0796-x.

    Article  CAS  PubMed  Google Scholar 

  29. Moreira PS, Almeida PR, Leite-Almeida H, Sousa N, Costa P (2016) Impact of chronic stress protocols in learning and memory in rodents: systematic review and meta-analysis. PLoS ONE 11(9):e0163245. doi:10.1371/journal.pone.0163245

    Article  PubMed  PubMed Central  Google Scholar 

  30. Mychasiuk R, Muhammad A, Kolb B (2016) Chronic stress induces persistent changes in global DNA methylation and gene expression in the medial prefrontal cortex, orbitofrontal cortex, and hippocampus. Neuroscience 322:489–499. doi:10.1016/j.neuroscience.2016.02.053

    Article  CAS  PubMed  Google Scholar 

  31. Hollis F, van der Kooij MA, Zanoletti O, Lozano L, Cantó C, Sandi C (2015) Mitochondrial function in the brain links anxiety with social subordination. Proc Natl Acad Sci USA 112(50):15486–15491. doi:10.1073/pnas.1512653112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ishii T, Yasuda K, Miyazawa M, Mitsushita J, Johnson TE, Hartman PS, Ishii N (2016) Infertility and recurrent miscarriage with complex II deficiency-dependent mitochondrial oxidative stress in animal models. Mech Ageing Dev 155:22–35. doi:10.1016/j.mad.2016.02.013

    Article  CAS  PubMed  Google Scholar 

  33. Hong IS, Lee HY, Kim HP (2014) Anti-oxidative effects of Rooibos tea (Aspalathus linearis) on immobilization-induced oxidative stress in rat brain. PLoS ONE 9(1):e87061. doi:10.1371/journal.pone.0087061

    Article  PubMed  PubMed Central  Google Scholar 

  34. Aliev G, Palacios HH, Gasimov E, Obrenovich ME, Morales L, Leszek J, Bragin V, Solís Herrera A, Gokhman D (2010) Oxidative stress induced mitochondrial failure and vascular hypoperfusion as a key initiator for the development of alzheimer disease. Pharmaceuticals 3(1):158–187. doi:10.3390/ph3010158

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Guenzel FM, Wolf OT, Schwabe L (2014) Sex differences in stress effects on response and spatial memory formation. Neurobiol Learn Mem 109:46–55. doi:10.1016/j.nlm.2013.11.020

    Article  PubMed  Google Scholar 

  36. Razmara A, Duckles SP, Krause DN, Procaccio V (2007) Estrogen suppresses brain mitochondrial oxidative stress in female and male rats. Brain Res 1176:71–81. doi:10.1016/j.brainres.2007.08.036

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Noschang CG, Krolow R, Pettenuzzo LF, Avila MC, Fachin A, Arcego D, von Pozzer Toigo E, Crema LM, Diehl LA, Vendite D, Dalmaz C (2009) Interactions between chronic stress and chronic consumption of CAFFEINE on the enzymatic antioxidant system. Neurochem Res 34(9):1568–1574. doi:10.1007/s11064-009-9945-4

    Article  CAS  PubMed  Google Scholar 

  38. Koufali MM, Moutsatsou P, Sekeris CE, Breen KC (2003) The dynamic localization of the glucocorticoid receptor in rat C6 glioma cell mitochondria. Mol Cell Endocrinol 209(1–2):51–60

    Article  CAS  PubMed  Google Scholar 

  39. 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(5):1163–1175

    Article  PubMed  Google Scholar 

  40. Simpkins JW, Dykens JA (2008) Mitochondrial mechanisms of estrogen neuroprotection. Brain Res Rev 57(2):421–430. doi:10.1016/j.brainresrev.2007.04.007

    Article  CAS  PubMed  Google Scholar 

  41. Hojo Y, Higo S, Ishii H, Ooishi Y, Mukai H, Murakami G, Kominami T, Kimoto T, Honma S, Poirier D, Kawato S (2009) Comparison between hippocampus-synthesized and circulation-derived sex steroids in the hippocampus. Endocrinology 150(11):5106–5112. doi:10.1210/en.2009-0305

    Article  CAS  PubMed  Google Scholar 

  42. Grimm A, Mensah-Nyagan AG, Eckert A (2016) Alzheimer, mitochondria and gender. Neurosci Biobehav Rev 67:89–101. doi:10.1016/j.neubiorev.2016.04.012

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was partly supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).

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Authors and Affiliations

  1. Department of Biochemistry, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Ramiro Barcellos, 2600, anexo, Porto Alegre, Rio Grande Do Sul, 90035-003, Brazil

    Carina de Souza Mota, Roberto Farina Almeida, Carla Dalmaz, Fátima Therezinha Costa Guma & Letícia Ferreira Pettenuzzo

  2. Department of Cellular Biology, Universidade de Brasília, Brasilia, Distrito Federal, Brazil

    Simone Nardin Weis

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  1. Carina de Souza Mota
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  2. Simone Nardin Weis
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Correspondence to Carina de Souza Mota.

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de Souza Mota, C., Weis, S.N., Almeida, R.F. et al. Chronic Stress Causes Sex-Specific and Structure-Specific Alterations in Mitochondrial Respiratory Chain Activity in Rat Brain. Neurochem Res 42, 3331–3340 (2017). https://doi.org/10.1007/s11064-017-2375-9

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  • DOI: https://doi.org/10.1007/s11064-017-2375-9

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