Department of Neurology, Zhongnan Hospital, Wuhan University, No.169, Donghu Road, Wuhan, Hubei 430071, China.
Department of Neurology, Zhongnan Hospital, Wuhan University, No.169, Donghu Road, Wuhan, Hubei 430071, China.
J Affect Disord. 2019 Apr 1;248:81-90. doi: 10.1016/j.jad.2019.01.031. Epub 2019 Jan 28.
Chronic unpredictable mild stress (CUMS) is an important risk factor for depression and cognitive deficits in humans. Enriched environment (EE) showed a beneficial effect on depression and cognition by enhancing brain derived neurotrophic factor (BDNF) expression and synaptic plasticity. However, it is still not clearly understood whether an epigenetic mechanism is involved in the BDNF modulation and synaptic plasticity that occurs after EE treatment for the depressive-like behaviors and cognitive deficits elicited by CUMS. In this study, we investigated the possible mechanism of the neuroprotective effect of EE.
All rats were exposed to the 5-week CUMS procedure except the control group. After CUMS procedure, some rats were stereotaxically injected with SIRT1 pharmacologic inhibitor EX527 or SIRT1 knocking down lentivirus (sh-SIRT1) in the hippocampus followed by EE treatment for 3 weeks. Other rats were directly subjected to EE treatment without stereotaxic injection. Behavioral tests were used to appraise depression and cognition after EE treatment. Then epigenetic molecules, synaptic proteins, dendritic spine density and branches, and synaptic morphology of the dorsal hippocampus were determined.
We found that CUMS induced depressive-like behaviors including decreased sucrose preference ratio, prolonged immobility and reduced locomotor and exploratory activity; cognitive deficits including spatial learning and memory impairment; reduced dendritic spine density and number of branches; thinned postsynaptic density; downregulated SIRT1/microRNA-134 pathway, decreased BDNF and synaptic proteins including synaptophysin (SYN) and postsynaptic density protein 95 (PSD95) expression in the hippocampus. However, the CUMS-induced depressive-like behaviors, cognitive deficits, dendritic spine density and branch number reduction, postsynaptic density thinning, SIRT1/microRNA-134 pathway downregulation, BDNF and synaptic proteins reduction, including synaptophysin (SYN) and postsynaptic density protein 95 (PSD95), were reversed by EE treatment. However, depressive-like behaviors and cognitive deficits were observed again in rats subjected to stereotaxic injection with EX527 or sh-SIRT1. Furthermore, this study also found that SIRT1/microRNA-134 regulates the downstream molecules BDNF, and the synaptic proteins SYN and PSD95 in primary cultured hippocampal neurons.
This study provides evidence for the neuroprotective role of EE on depression and cognitive deficits by activating the SIRT1/microRNA-134 pathway, which accounts for the regulation of synaptic proteins, including BDNF, PSD95 and SYN, dendritic remodeling and ultrastructure changes of synapses in the hippocampus.
慢性不可预测轻度应激（CUMS）是人类抑郁和认知缺陷的重要危险因素。丰富环境（EE）通过增强脑源性神经营养因子（BDNF）表达和突触可塑性，对抑郁和认知产生有益影响。然而，EE 治疗 CUMS 诱导的抑郁样行为和认知缺陷后，BDNF 调节和突触可塑性是否涉及表观遗传机制仍不清楚。在这项研究中，我们研究了 EE 的神经保护作用的可能机制。
除对照组外，所有大鼠均接受 5 周 CUMS 程序。CUMS 程序后，一些大鼠海马立体定向注射 SIRT1 药理抑制剂 EX527 或 SIRT1 敲低慢病毒（sh-SIRT1），然后进行 3 周 EE 治疗。其他大鼠直接进行 EE 治疗，而不进行立体定向注射。EE 治疗后，通过行为测试评估抑郁和认知情况。然后测定背侧海马的表观遗传分子、突触蛋白、树突棘密度和分支以及突触形态。
我们发现 CUMS 诱导了抑郁样行为，包括蔗糖偏好比降低、不动时间延长以及运动和探索活动减少；认知缺陷，包括空间学习和记忆障碍；树突棘密度和分支数量减少；突触后密度变薄；SIRT1/微小 RNA-134 通路下调，BDNF 和突触蛋白（包括突触小体（SYN）和突触后密度蛋白 95（PSD95）表达减少。然而，EE 治疗逆转了 CUMS 诱导的抑郁样行为、认知缺陷、树突棘密度和分支数量减少、突触后密度变薄、SIRT1/微小 RNA-134 通路下调、BDNF 和突触蛋白（包括突触小体（SYN）和突触后密度蛋白 95（PSD95）减少。然而，在立体定向注射 EX527 或 sh-SIRT1 的大鼠中再次观察到抑郁样行为和认知缺陷。此外，本研究还发现 SIRT1/微小 RNA-134 调节原代培养海马神经元中的下游分子 BDNF 以及突触蛋白 SYN 和 PSD95。
本研究通过激活 SIRT1/微小 RNA-134 通路，为 EE 对抑郁和认知缺陷的神经保护作用提供了证据，该通路调节突触蛋白，包括 BDNF、PSD95 和 SYN，海马的树突重塑和突触超微结构变化。
