Dexras1调控焦虑行为的作用及机制研究

Anxiety has become a serious issue to human health. However, the underlying pathological mechanisms of anxiety disorders are still poorly understood. Recently, our study reveals that chronic mild stress (CMS) significantly increased the expression and activity of Dexras1 in the hippocampus. On the other hand, knock-down of Dexras1 in hippocampus produced significant anxiolytic-like effects in mice. For the mechanism study, our preliminary results showed that over-expression of Dexras1 decreased p-ERK, p-CREB, BDNF and synapsin in the hippocampus, while knock-down of Dexras1 activated these signals. Thus, we propose that hippocampal Dexras1 might regulate anxiety-related behaviors through interacting with ERK-CREB-BDNF-mediated structural synaptic plasticity. Here, we will manipulate Dexras1 by knockout, knockdown, overexpression and activity regulation of target molecular, and investigate (1) whether Dexras1 in the hippocampus plays an important role in the regulation of anxiety-related behaviors, and (2) whether Dexras1-BDNF signaling-mediated structural synaptic plasticity accounts for the regulation of anxiety by Dexras1. Our study will reveal significant importance of Dexras1 in anxiety disorders, take insight into the underlying mechanism of anxiety, and more importantly, identify a target for developing novel anxiolytics.

焦虑症诱发的自杀行为对人类健康的危害性日趋严重，但其病理生理机制迄今未明。我们前期研究发现应激诱导小鼠海马组织Dexras1表达及活性增强，而敲减海马Dexras1具有显著抗焦虑样作用。此外，动物海马组织过表达Dexras1明显降低p-ERK、p-CREB、BDNF及synapsin水平，相反，敲减Dexras1则增加它们的水平。因而，我们猜测Dexras1可能通过ERK-CREB-BDNF通路影响突触结构可塑性调控焦虑行为。本项目拟运用基因敲除、敲减或过表达目的基因以及抑制目的基因活性，正向和反向干预靶分子等技术重点研究：1）Dexras1调控焦虑行为的作用及意义；2）Dexras1-BDNF信号通路介导的突触结构可塑性是否能够解释Dexras1调控焦虑行为的分子和细胞机制。旨在明确Dexras1在焦虑症发病进程中的作用，探明其调控焦虑行为的机制，为焦虑性情感障碍类疾病提供新的干预靶标。

焦虑症诱发的自杀行为对人类健康的危害性日趋严重，我们研究发现海马Dexras1参与调控焦虑行为。增加海马DG区Dexras1诱导小鼠出现焦虑行为，慢性应激能诱导小鼠海马组织Dexras1表达及活性增强。而敲减海马DG区Dexras1能够逆转慢性应激诱导的焦虑行为。我们还发现海马DG区Dexras1影响神经干细胞增殖和神经元树突发育，以及ERK–CREB-BDNF信号。同时，我们发现海马NF-κB通过上调nNOS、CAPON和Dexras1表达，进而增强三者相互作用，调控应激诱导的焦虑行为。此外，我们还发现海马nNOS来源的NO通过下调5-HT1A受体表达，参与焦虑行为的调控。这些发现在情感障碍疾病中可能具有重要意义。