期刊
JOURNAL OF NEUROCHEMISTRY
卷 155, 期 6, 页码 679-696出版社
WILEY
DOI: 10.1111/jnc.15043
关键词
environmental enrichment; functional recovery; histone deacetylase 2; neuroplasticity; stroke
资金
- Science and Technology Foundation of Nanjing Medical University [2017NJMUZD019]
- National Key Research and Development Program of China [2016YFC1306703]
- Science and Technology Program of Guangdong [2018B030334001]
- National Natural Science Foundation of China [31530091, 81870912, 81801221, 81901253]
Environmental enrichment (EE) is a generally accepted strategy to promote stroke recovery and its beneficial effect is positively correlated with neuroplasticity. However, the mechanisms underlying it remain elusive. Histone deacetylase 2 (HDAC2), a negative regulator of neuroplasticity, is up-regulated after stroke. Thus, we hypothesized that HDAC2 may participate in EE-mediated stroke recovery. In this study, focal stroke was induced by photothrombosis in male mice exposing to EE or standard housing (SH) conditions. Recombinant virus vectors, including Ad-HDAC2-Flag, AAV-CAG-EGFP-Cre, LV-shHDAC2, or their controls were microinjected into the motor cortex at 3 days before stroke. Grid-walking and cylinder tasks were conducted to assess motor function. Western blot and immunostaining were used to uncover the mechanisms underlying EE-mediated stroke recovery. We found that EE exposure reversed stroke-induced HDAC2 up-regulation, implicating HDAC2 in EE-mediated functional recovery. Importantly, EE-dependent stroke recovery was counteracted by over-expressing HDAC2, and HDAC2 knockdown promoted functional recovery from stroke to the similar extent as EE exposure. Moreover, the knockdown of HDAC2 epigenetically enhanced expressions of neurotrophins and neuroplasticity-related proteins, with similar effects as EE, and consequently, whole brain and corticospinal tract (CST) rewiring. Together, our findings indicate that HDAC2 is critical for EE-dependent functional restoration. Precisely targeting HDAC2 may mimic EE and serve as a novel therapeutic strategy for stroke recovery.
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