Involvement of the brain metabotropic glutamate receptor ^subtypes 5 and 7 in chronic psychosocial stress

脑代谢型谷氨酸受体（mGluR）亚型mGluR 5和mGluR 7在啮齿动物中焦虑和急性应激相关行为和生理学中的作用已得到充分确立，相反，关于它们参与慢性应激几乎一无所知。在这里，我们打算确定的影响，基因消融和本地敲低，以及药理学调制的mGluRS和mGtuR 7的行为和生理后果的慢性心理社会应激小鼠使用建立的慢性从属殖民地住房（CSC）的范例。此外，我们希望更广泛地评估CSC对大脑mGluR系统的影响。因此，定量PCR将用于确定CSC诱导的mGluRl-8及其细胞内调节蛋白的变化。此外，将评估暴露于CSC的mGluRS、mGluR 7和相应野生型的敲除小鼠组的选定应激相关行为参数、神经元和激素HPA轴反应性、选定脑mRNA水平以及免疫功能。此外，将使用mGluRS和mGtuR 7的选择性药理学试剂来研究它们对CSC后果的影响，并与基因敲除进行比较。最后，由腺相关病毒载体介导的mGluR的局部siRNA介导的敲低和过表达将进一步定义受体在特定脑区域中的关键参与，并将有助于剖析和建议mGluR亚型的哪种模式和方向调节可能是最有益的未来治疗干预与慢性心理社会压力相关的人类疾病。

The role of the brain metabotropic glutamate receptor (mGluR) subtypes mGluR5 and mGluR7 in anxiety- and acute stress-related behaviours and physiology in rodents is well established, tn contrast, virtually nothing is known about their involvement in chronic stress. Here we intend to determine the effects of genetic ablation and local knock-down, as well as pharmacological modulation of mGluRS and mGtuR7 on behavioural and physiological consequences of chronic psychosocial stress in mice using the established chronic subordinate colony housing (CSC) paradigm. Also, we want to assess more broadly the effects of CSC on the mGluR system of the brain. Thus, quantitative PCR will be used to determine CSC-induced changes of mGluRl-8 and their intracellular regulatory proteins. Further, groups of knock-out mice of mGluRS, of mGluR7, and corresponding wild-types exposed to CSC will be assessed with respect to selected stress-related behavioural parameters, neuronal and hormonal HPA-axis responsiveness, selected brain mRNA levels, as well as immune functions. Moreover, selective pharmacological agents for mGluRS and mGtuR7 will be utilized to investigate their effects on the consequences of CSC and for comparison with the genetic knock-outs. Finally, local siRNA-mediated knock-down and overexpression of mGluRs, mediated by adeno-associated viral vectors, wilt further define the criticat involvement of the receptors in specific brain regions and will assist to dissect and suggest which mode and direction of mGluR subtype-modulation could be most beneficial for future therapeutic intervention in human disorders related to chronic psychosocial stress.