Skip to main content

Advertisement

SpringerLink
Log in

Environmental Enrichment Prevent the Juvenile Hypoxia-Induced Developmental Loss of Parvalbumin-Immunoreactive Cells in the Prefrontal Cortex and Neurobehavioral Alterations Through Inhibition of NADPH Oxidase-2-Derived Oxidative Stress

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

We compared the expression of phenotype of parvalbumin (PV)-immunoreactive cells in the prefrontal cortex (PFC) of juvenile rats reared in enriched environment (EE) after daily intermittent hypoxia (IH) exposure to those reared in standard environment (SE) and investigated the involvement of NADPH oxidase-2 (NOX2)-derived oxidative stress in the IH-induced neurodevelopmental and neurobehavioral consequences in a juvenile rat model of obstructive sleep apnea. Postnatal day 21 (P21) rats were exposed to IH or room air 8 h daily for 14 consecutive days. After the daily exposure, the rats were raised in SE or EE. In the PFC of P34 rats, we determined the impact (i) of IH exposures on NOX2-derived oxidative stress and PV immunoreactivity, (ii) of pharmacological NOX2 inhibition on IH-induced oxidative stress and PV immunoreactivity, and (iii) of EE on the IH-induced oxidative stress and PV immunoreactivity. Behavioral testing of psychiatric anxiety was carried out consecutively in the open-field test and elevated plus maze at P35 and P36. The results showed IH exposures increased NOX2 expression in the PFC of P34 rats, which was accompanied with elevation of NOX activity and indirect markers of oxidative stress (4-HNE). IH exposures increased 4-HNE immunoreactivity in cortical PV cells, which was accompanied with reduction of PV immunoreactivity. Treatment of IH rats with the antioxidant/NOX inhibitor apocynin prevented the PV cells loss in the PFC and reversed the IH-induced psychiatric anxiety. EE attenuated the NOX2-derived oxidative stress and reversed the PV-immunoreactivity reduction in the PFC induced by IH. Our data suggest that EE might prevent the juvenile hypoxia-induced developmental loss of PV cells in the PFC and attenuate the neurobehavioral alterations through inhibition of NOX2-derived oxidative stress.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Dempsey JA, Veasey SC, Morgan BJ, O'Donnell CP (2010) Pathophysiology of sleep apnea. Physiol Rev 90(1):47–112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Nair D, Dayyat EA, Zhang SX, Wang Y, Gozal D (2011) Intermittent hypoxia-induced cognitive deficits are mediated by NADPH oxidase activity in a murine model of sleep apnea. PLoS ONE 6(5), e19847

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Nair D, Zhang SX, Ramesh V, Hakim F, Kaushal N, Wang Y, Gozal D (2011) Sleep fragmentation induces cognitive deficits via nicotinamide adenine dinucleotide phosphate oxidase–dependent pathways in mouse. Am J Respir Crit Care Med 184(11):1305–1312

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Al-Qahtani JM, Abdel-Wahab BA, El-Aziz SMA (2014) Long-term moderate dose exogenous erythropoietin treatment protects from intermittent hypoxia-induced spatial learning deficits and hippocampal oxidative stress in young rats. Neurochem Res 39(1):161–171

    Article  CAS  PubMed  Google Scholar 

  5. Yuan L, Wu J, Liu J, Li G, Liang D (2015) Intermittent Hypoxia-Induced Parvalbumin-Immunoreactive Interneurons Loss and Neurobehavioral Impairment is Mediated by NADPH-Oxidase-2. Neurochem Res:1–11

  6. Nair D, Ramesh V, Li RC, Schally AV, Gozal D (2013) Growth hormone releasing hormone (GHRH) signaling modulates intermittent hypoxia‐induced oxidative stress and cognitive deficits in mouse. J Neurochem 127(4):531–540

    Article  CAS  PubMed  Google Scholar 

  7. Komitova M, Xenos D, Salmaso N, Tran KM, Brand T, Schwartz ML, Ment L, Vaccarino FM (2013) Hypoxia-induced developmental delays of inhibitory interneurons are reversed by environmental enrichment in the postnatal mouse forebrain. J Neurosci 33(33):13375–13387

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Juliano C, Sosunov S, Niatsetskaya Z, Isler JA, Utkina-Sosunova I, Jang I, Ratner V, Ten V (2015) Mild intermittent hypoxemia in neonatal mice causes permanent neurofunctional deficit and white matter hypomyelination. Exp Neurol 264:33–42

    Article  CAS  PubMed  Google Scholar 

  9. Nanduri J, Makarenko V, Reddy VD, Yuan G, Pawar A, Wang N, Khan SA, Zhang X et al (2012) Epigenetic regulation of hypoxic sensing disrupts cardiorespiratory homeostasis. Proc Natl Acad Sci U S A 109(7):2515–2520

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wang Y, Zhang SX, Gozal D (2010) Reactive oxygen species and the brain in sleep apnea. Respir Physiol Neurobiol 174(3):307–316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Xie H, Yung W-H (2012) Chronic intermittent hypoxia-induced deficits in synaptic plasticity and neurocognitive functions: a role for brain-derived neurotrophic factor. Acta Pharmacol Sin 33(1):5–10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. van Winkel R, Stefanis NC, Myin-Germeys I (2008) Psychosocial stress and psychosis. A review of the neurobiological mechanisms and the evidence for gene-stress interaction. Schizophr Bull 34(6):1095–1105

    Article  PubMed  PubMed Central  Google Scholar 

  13. Nguyen R, Morrissey MD, Mahadevan V, Cajanding JD, Woodin MA, Yeomans JS, Takehara-Nishiuchi K, Kim JC (2014) Parvalbumin and GAD65 Interneuron Inhibition in the Ventral Hippocampus Induces Distinct Behavioral Deficits Relevant to Schizophrenia. J Neurosci 34(45):14948–14960

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Caballero A, Flores-Barrera E, Cass DK, Tseng KY (2014) Differential regulation of parvalbumin and calretinin interneurons in the prefrontal cortex during adolescence. Brain Struct Funct 219(1):395–406

    Article  CAS  PubMed  Google Scholar 

  15. Behrens MM, Ali SS, Dao DN, Lucero J, Shekhtman G, Quick KL, Dugan LL (2007) Ketamine-induced loss of phenotype of fast-spiking interneurons is mediated by NADPH-oxidase. Science 318(5856):1645–1647

    Article  CAS  PubMed  Google Scholar 

  16. Stevens HE, Jiang GY, Schwartz ML, Vaccarino FM (2012) Learning and memory depend on fibroblast growth factor receptor 2 functioning in hippocampus. Biol Psychiatry 71(12):1090–1098

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Nithianantharajah J, Hannan AJ (2006) Enriched environments, experience-dependent plasticity and disorders of the nervous system. Nat Rev Neurosci 7(9):697–709

    Article  CAS  PubMed  Google Scholar 

  18. Salmaso N, Silbereis J, Komitova M, Mitchell P, Chapman K, Ment LR, Schwartz ML, Vaccarino FM (2012) Environmental enrichment increases the GFAP+ stem cell pool and reverses hypoxia-induced cognitive deficits in juvenile mice. J Neurosci 32(26):8930–8939

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Walf AA, Frye CA (2007) The use of the elevated plus maze as an assay of anxiety-related behavior in rodents. Nat Protoc 2(2):322–328

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yuan G, Khan SA, Luo W, Nanduri J, Semenza GL, Prabhakar NR (2011) Hypoxia-inducible factor 1 mediates increased expression of NADPH oxidase-2 in response to intermittent hypoxia. J Cell Physiol 226(11):2925–2933. doi:10.1002/jcp.22640

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wang Q, Tompkins KD, Simonyi A, Korthuis RJ, Sun AY, Sun GY (2006) Apocynin protects against global cerebral ischemia–reperfusion-induced oxidative stress and injury in the gerbil hippocampus. Brain Res 1090(1):182–189

    Article  CAS  PubMed  Google Scholar 

  22. Serrano F, Kolluri NS, Wientjes FB, Card JP, Klann E (2003) NADPH oxidase immunoreactivity in the mouse brain. Brain Res 988(1):193–198

    Article  CAS  PubMed  Google Scholar 

  23. Zhan G, Serrano F, Fenik P, Hsu R, Kong L, Pratico D, Klann E, Veasey SC (2005) NADPH oxidase mediates hypersomnolence and brain oxidative injury in a murine model of sleep apnea. Am J Respir Crit Care Med 172(7):921–929

    Article  PubMed  PubMed Central  Google Scholar 

  24. Young J, McKinney S, Ross B, Wahle K, Boyle S (2007) Biomarkers of oxidative stress in schizophrenic and control subjects. Prostaglandins Leukot Essent Fatty Acids 76(2):73–85

    Article  CAS  PubMed  Google Scholar 

  25. Maneen MJ, Cipolla MJ (2007) Peroxynitrite diminishes myogenic tone in cerebral arteries: role of nitrotyrosine and F-actin. Am J Physiol Heart Circ Physiol 292(2):H1042–H1050

    Article  CAS  PubMed  Google Scholar 

  26. Nanetti L, Taffi R, Vignini A, Moroni C, Raffaelli F, Bacchetti T, Silvestrini M, Provinciali L et al (2007) Reactive oxygen species plasmatic levels in ischemic stroke. Mol Cell Biochem 303(1–2):19–25

    Article  CAS  PubMed  Google Scholar 

  27. Vallet P, Charnay Y, Steger K, Ogier-Denis E, Kovari E, Herrmann F, Michel J-P, Szanto I (2005) Neuronal expression of the NADPH oxidase NOX4, and its regulation in mouse experimental brain ischemia. Neuroscience 132(2):233–238

    Article  CAS  PubMed  Google Scholar 

  28. Hui-guo L, Kui L, Yan-ning Z, Yong-jian X (2010) Apocynin attenuate spatial learning deficits and oxidative responses to intermittent hypoxia. Sleep Med 11(2):205–212

    Article  PubMed  Google Scholar 

  29. Infanger DW, Sharma RV, Davisson RL (2006) NADPH oxidases of the brain: distribution, regulation, and function. Antioxid Redox Signal 8(9–10):1583–1596

    Article  CAS  PubMed  Google Scholar 

  30. Sorce S, Krause K-H (2009) NOX enzymes in the central nervous system: from signaling to disease. Antioxid Redox Signal 11(10):2481–2504

    Article  CAS  PubMed  Google Scholar 

  31. Schiavone S, Sorce S, Dubois-Dauphin M, Jaquet V, Colaianna M, Zotti M, Cuomo V, Trabace L et al (2009) Involvement of NOX2 in the development of behavioral and pathologic alterations in isolated rats. Biol Psychiatry 66(4):384–392

    Article  CAS  PubMed  Google Scholar 

  32. Jiang Z, Rompala GR, Zhang S, Cowell RM, Nakazawa K (2013) Social isolation exacerbates schizophrenia-like phenotypes via oxidative stress in cortical interneurons. Biol Psychiatry 73(10):1024–1034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Gonzalez-Liencres C, Tas C, Brown EC, Erdin S, Onur E, Cubukcoglu Z, Aydemir O, Esen-Danaci A et al (2014) Oxidative stress in schizophrenia: a case–control study on the effects on social cognition and neurocognition. BMC Psychiatry 14(1):268

    Article  PubMed  PubMed Central  Google Scholar 

  34. Salinas E, Sejnowski TJ (2001) Correlated neuronal activity and the flow of neural information. Nat Rev Neurosci 2(8):539–550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Bartos M, Vida I, Jonas P (2007) Synaptic mechanisms of synchronized gamma oscillations in inhibitory interneuron networks. Nat Rev Neurosci 8(1):45–56

    Article  CAS  PubMed  Google Scholar 

  36. Gonzalez-Burgos G, Cho RY, Lewis DA (2015) Alterations in Cortical Network Oscillations and Parvalbumin Neurons in Schizophrenia. Biol Psychiatry

  37. Wischhof L, Irrsack E, Osorio C, Koch M (2015) Prenatal LPS-exposure–a neurodevelopmental rat model of schizophrenia–differentially affects cognitive functions, myelination and parvalbumin expression in male and female offspring. Prog Neuropsychopharmacol Biol Psychiatry 57:17–30

    Article  CAS  PubMed  Google Scholar 

  38. Inácio AR, Ruscher K, Wieloch T (2011) Enriched environment downregulates macrophage migration inhibitory factor and increases parvalbumin in the brain following experimental stroke. Neurobiol Dis 41(2):270–278

    Article  CAS  PubMed  Google Scholar 

  39. Urakawa S, Takamoto K, Hori E, Sakai N, Ono T, Nishijo H (2013) Rearing in enriched environment increases parvalbumin-positive small neurons in the amygdala and decreases anxiety-like behavior of male rats. BMC Neurosci 14(1):13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Harte MK, Powell S, Swerdlow N, Geyer M, Reynolds G (2007) Deficits in parvalbumin and calbindin immunoreactive cells in the hippocampus of isolation reared rats. J Neural Transm 114(7):893–898

    Article  CAS  PubMed  Google Scholar 

  41. Schiavone S, Jaquet V, Sorce S, Dubois-Dauphin M, Hultqvist M, Bäckdahl L, Holmdahl R, Colaianna M et al (2012) NADPH oxidase elevations in pyramidal neurons drive psychosocial stress-induced neuropathology. Transl Psychiatry 2(5), e111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by the grants from the National Natural Science Foundation of China (Nos. 31071085, 81471105) and by Grant no. 2013-ZX03 from the Major Special Project of Medical Scientific Research Fund for Nanjing Military Area Command.

Author information

Author notes

    Authors and Affiliations

    1. Department of Anaesthesiology, Teaching Hospital of Chengdu University of T.C.M, 39 twelve bridge road, Jinniu district, Chengdu, 610072, People’s Republic of China

      Mingqiang Zhang, Lan Huo, Liang Luo, Xi Song & Fei Fan

    2. Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210093, People’s Republic of China

      Jing Wu

    3. Department of emergency, Ruijin Hospital North, School of Medicine, Shanghai Jiaotong University, 999 Xiwang road, Jiading district, Shanghai, 201801, People’s Republic of China

      Yiming Lu & Dong Liang

    Authors
    1. Mingqiang Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Jing Wu
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Lan Huo
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Liang Luo
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Xi Song
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Fei Fan
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Yiming Lu
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Dong Liang
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to Mingqiang Zhang or Dong Liang.

    Ethics declarations

    Conflict of interest

    We declare that we have no competing interests.

    Additional information

    Mingqiang Zhang and Jing Wu contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Zhang, M., Wu, J., Huo, L. et al. Environmental Enrichment Prevent the Juvenile Hypoxia-Induced Developmental Loss of Parvalbumin-Immunoreactive Cells in the Prefrontal Cortex and Neurobehavioral Alterations Through Inhibition of NADPH Oxidase-2-Derived Oxidative Stress. Mol Neurobiol 53, 7341–7350 (2016). https://doi.org/10.1007/s12035-015-9656-6

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s12035-015-9656-6

    Keywords

    Search

    Navigation