Metabotropic Glutamate Receptor-Mediated Neuromodulation in Sound Localization Circuits

项目摘要 由代谢型谷氨酸受体（mGluRs）介导的神经调节调节许多脑功能。 mGluR调节功能障碍与多种脑部疾病相关，靶向mGluR的药物 都是为了治疗而研发的然而，mGluRs在听觉系统中的功能较差， 明白在缺乏这些知识的情况下，理解听觉系统的机制， 加工和潜在的开发临床有用的策略靶向mGluRs，以预防或治疗听力 疾病将保持有限。本申请的目的是确定mGluR在细胞凋亡中的作用。 听觉脑干电路，其分析用于声音定位的耳间时间差（ITD）。制定 根据先前的工作和申请人实验室产生的强有力的初步数据， 假设是：1）mGluRs通过调节突触和内在神经元来改善听觉加工 性质; 2）听力剥夺导致mGluR调节的可塑性;以及3）功能失调的mGluR 调制导致受损的听觉处理。这些假设将在鸟类和 哺乳动物模型，利用每种动物模型的优点，而这些优点在另一种动物模型中并不突出。 此外，我们将利用脆性X综合征（FXS）的小鼠模型， 神经发育障碍，其中mGluRs的过度活性是核心潜在机制， 测试功能失调的mGluR调制有助于受损的听觉处理的假设。在 体外生理学（全细胞和穿孔贴片记录以及脑切片中的尖电极记录）， 光学成像（电压敏感染料和Ca 2+成像）结合药理学工具，以及 免疫组织化学将用于确定正常人ITD回路中mGluR调节的作用。 听力和听力剥夺的小鸡，以及正常听力和FXS小鼠。圆满完成 拟议的研究将提供对mGluRs在声音定位回路中的作用的深入理解， 并且可以为听力障碍的治疗干预提供分子靶点的鉴定。

Project Summary Neuromodulation mediated by metabotropic glutamate receptors (mGluRs) regulates many brain functions. Dysfunction of mGluR modulation is associated with multiple brain disorders, and drugs targeting mGluRs have been developed for their treatment. However, the functions of mGluRs in the auditory system are poorly understood. In the absence of such knowledge, an understanding of the mechanisms underlying auditory processing and the potential to develop clinically useful strategies targeting mGluRs to prevent or treat hearing disorders will remain limited. The objective in this application is to determine the roles of mGluRs in the auditory brainstem circuit that analyze interaural time differences (ITD) for sound localization. Formulated based upon the previous work and strong preliminary data produced in the applicant's laboratory, the central hypotheses are that 1) mGluRs improve auditory processing by modulating synaptic and intrinsic neuronal properties; 2) hearing deprivation results in plasticity of mGluR modulation; and 3) dysfunctional mGluR modulation leads to compromised auditory processing. These hypotheses will be tested in both avian and mammalian models, utilizing the advantages of each animal model that are not prominent in the other. Furthermore, we will take advantage of a mouse model of fragile X syndrome (FXS), an inherited neurodevelopmental disorder in which exaggerated activity of mGluRs is the core underlying mechanism, to test the hypothesis that dysfunctional mGluR modulation contributes to compromised auditory processing. In vitro physiology (whole-cell and perforated patch recording and sharp electrode recording in brain slices), optical imaging (voltage-sensitive dye and Ca2+ imaging) combined with pharmacological tools, and immunohistochemistry will be used to determine the roles of mGluR modulation in the ITD circuit in normal hearing and hearing-deprived chicks, and in normal hearing and FXS mice. The successful completion of the proposed research will provide in-depth understanding of the roles of mGluRs in sound localization circuits, and may inform the identification of molecular targets for therapeutic intervention in hearing disorders.