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Cognitive Improvement Induced by Environment Enrichment in Chronic Cerebral Hypoperfusion Rats: a Result of Upregulated Endogenous Neuroprotection?

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Abstract

Environment enrichment (EE) has been demonstrated to improve the cognitive impairment that is induced by chronic cerebral hypoperfusion (CCH), but the underlying mechanism has not yet been elucidated. This study aimed to investigate the role of endogenous neuroprotection in EE-induced cognitive improvement in rats with CCH. Permanent bilateral common carotid artery occlusions (2-vessel occlusions (2VOs)) were performed to induce CCH in male adult Wistar rats. Four weeks after the surgeries, the rats were exposed to enriched environments for 4 weeks (6 h/day). Subsequently, we assessed the effects of EE on cognitive function, brain histone acetylation levels, neuroprotection-related transcription factors (i.e., cAMP response element-binding protein (CREB), phospho-CREB (p-CREB), hypoxia-inducible factor 1 (HIF-1) α, and nuclear regulatory factor 2 (Nrf2)), and oxidative stress and histological changes in the brain. After 2VO, the rats exposed to the EE treatment exhibited increased acetylation of histone 4 and increased p-CREB and Nrf2 protein levels in the brain. HIF-1α levels were increased after 2VO and reduced after EE treatment. The oxidative damage, histopathological changes in the brain, and spatial learning and memory impairments induced by 2VO were subsequently restored after EE treatment. These data indicate that EE promotes the acetylation of histone 4, regulates some neuroprotection-related transcription factors, attenuates oxidative damage, and protects against the histopathological damage to the brain induced by CCH. Together, the effects of EE in CCH rats might contribute to the recovery of spatial learning and memory.

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Abbreviations

EE:

Environment enrichment

CCH:

Chronic cerebral hypoperfusion

2VO:

2-Vessel occlusion

AD:

Alzheimer’s disease

VaD:

Vascular dementia

CREB:

cAMP response element-binding protein

p-CREB:

Phospho-CREB

Nrf2:

Nuclear regulatory factor 2

HIF-1α:

Hypoxia-inducible factor 1α

GFAP:

Glial fibrillary acidic protein

Iba-1:

Ionized calcium binding adapter molecule 1 (a marker of microglia)

4-HNE:

4-Hydroxynonenal

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (Grant number: 81171029 and 81000471)

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The authors declared that there are no conflicts of interest.

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    Authors and Affiliations

    1. Department of Neurology, Zhongnan Hospital, Wuhan University, Donghu Road 169#, Wuhan, 430071, China

      Ying Yang, Junjian Zhang, Li Xiong, Min Deng, Jing Wang, Jiawei Xin & Hui Liu

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    1. Ying Yang
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    2. Junjian Zhang
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    3. Li Xiong
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    4. Min Deng
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    5. Jing Wang
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    6. Jiawei Xin
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    7. Hui Liu
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    Correspondence to Junjian Zhang.

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    Ying Yang and Li Xiong contributed equally to this work.

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    Yang, Y., Zhang, J., Xiong, L. et al. Cognitive Improvement Induced by Environment Enrichment in Chronic Cerebral Hypoperfusion Rats: a Result of Upregulated Endogenous Neuroprotection?. J Mol Neurosci 56, 278–289 (2015). https://doi.org/10.1007/s12031-015-0529-2

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    • DOI: https://doi.org/10.1007/s12031-015-0529-2

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