Molecular Neurobiology

, Volume 53, Issue 10, pp 7341–7350 | Cite as

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

  • Mingqiang Zhang
  • Jing Wu
  • Lan Huo
  • Liang Luo
  • Xi Song
  • Fei Fan
  • Yiming Lu
  • Dong Liang


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.


Intermittent hypoxia Enriched environment NADPH oxidase-2 Oxidative stress Parvalbumin-immunoreactive cells Anxiety 



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.

Compliance with Ethical Standards

Conflict of interest

We declare that we have no competing interests.


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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of AnaesthesiologyTeaching Hospital of Chengdu University of T.C.MChengduPeople’s Republic of China
  2. 2.Jiangsu Key Laboratory of Molecular MedicineMedical School of Nanjing UniversityNanjingPeople’s Republic of China
  3. 3.Department of emergency, Ruijin Hospital North, School of MedicineShanghai Jiaotong UniversityShanghaiPeople’s Republic of China

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