海马RASD1调控应激诱导的焦虑行为的神经机制

Anxiety is predominant clinical expression of life-threatening and highly prevalent psychiatric disorders. However, the neural circuit underlying anxiety-related behaviors is poorly understood. Our preliminary experiments demonstrated that chronic unpredictable stress (CUS) significantly increased the expression and activity of RASD1 (RAS, dexamethasone-induced 1). On the other hand, knocking-down of RASD1 in hippocampal dentate gyrus (DG) produced significant anxiolytic-like behaviors. Thus, RASD1 in hippocampal DG might play an important role in modulating anxiety-like behaviors. In addition, our results showed that RASD1 in hippocampal DG affected neural stem cell proliferation and neuronal neurite growth. Here, we will take insight into the neural and molecular mechanism underlying the anxiety-related behaviors by using genetic and biochemical methods to selectively manipulate RASD1 in vitro and in vivo. The aim of current proposal is to answer whether RASD1 in the hippocampus regulates neurogenesis, synaptic structure plasticity and synaptogenesis via epigenetic mechanism, renews and integrates hippocampal neural circuit, thereby modifying stress-related anxiety behaviors. This project will reveal the hippocampal neural circuit underlying the pathogenesis of psychiatric disorders which are clinically expressed as anxiety behaviors, ascertain a novel target for treating anxiety disorders.

许多重大精神疾病以焦虑为主要临床表型或伴有严重的焦虑症状，但焦虑的神经环路机制迄今未明。我们预实验结果发现慢性应激（CUS）显著增加海马组织RASD1的表达和活性，而敲减海马齿状回（dentate gyrus, DG）区的RASD1具有显著的抗焦虑样作用，提示RASD1在焦虑行为调控中起重要作用。此外，我们预实验结果还发现海马DG区RASD1影响神经干细胞增殖和神经元突起生长。本项目将通过体外和在体动物实验，并运用遗传学、分子生物学等特异手段，探究RASD1调控焦虑行为的神经及分子机制，以阐明RASD1是否通过表观遗传学机制影响海马神经细胞新生和突触结构重塑，更新和整合海马神经环路，从而调控应激诱导的焦虑相关行为。本项目研究结果将从新的角度深入理解以焦虑为主要临床表型的重大精神疾病的病理机制，旨在发现抗焦虑治疗的新靶点。

焦虑症诱发的自杀行为对人类健康的危害性日趋严重，需要深入研究控制焦虑情绪的机制以发现新的干预靶标。本项目研究发现海马DG区RASD1通过影响BDNF调节突触可塑性和海马微环路参与焦虑行为调控。同时，我们发现海马NF-κB通过上调nNOS、CAPON和RASD1表达，进而增强三者相互作用，调控应激诱导的焦虑行为。在焦虑动物模型上研究发现nNOS-CAPON-RASD1解耦联剂具有抗焦虑作用。再者，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。此外，我们在前期研究基础上，设计并建立了一套稳定、敏感、高效的糖水偏爱实验装置“SPT-Z4A”，并论证了一套成熟的检测糖水偏爱实验的方案，适用于评估慢性应激相关的快感缺失行为以及吗啡诱导的依赖性的糖水偏好检测实验。以上研究发现在情感障碍疾病研究中具有重要意义。