Metabotropic Glutamate Receptor-Mediated Neuromodulation in Sound Localization Circuits

项目摘要 代谢性谷氨酸受体(MGluRs)介导的神经调节调节多种脑功能。 MGluR调节功能障碍与多发性脑疾病相关，靶向mGluR的药物 是为他们的治疗而开发的。然而，mGluRs在听觉系统中的功能很差 明白了。在缺乏这种知识的情况下，对潜在的听觉机制的理解 针对mGluRs预防或治疗听力的处理和开发临床有用策略的可能性 混乱仍将是有限的。本应用程序的目标是确定mGluRs在 分析耳间时差(ITD)以进行声音定位的听觉脑干回路。已制定 根据以前的工作和申请人实验室产生的强有力的初步数据，中央 假设1)mGluRs通过调节突触和内源性神经元改善听觉处理 特性；2)听力剥夺导致mGluR调节可塑性；3)mGluR功能障碍 调制会导致听觉处理功能受损。这些假说将在Avive和 哺乳动物模型，利用每种动物模型的优点，而其他动物模型并不突出。 此外，我们将利用脆性X综合征(FXS)的小鼠模型，这是一种遗传性 神经发育障碍，其中mGluRs的活动过度是核心潜在机制， 测试mGluR调节功能障碍导致听觉处理受损的假设。在……里面 体外生理学(全细胞、穿孔脑片和脑片尖电极记录)， 结合药理工具的光学成像(电压敏感染料和钙成像)，以及 免疫组织化学将用于确定mGluR在正常人群ITD回路中的调节作用 听力和听力剥夺的雏鸟，以及听力正常和FXS的小鼠。成功地完成了 拟议的研究将提供对mGluRs在声音定位电路中的作用的深入理解， 并可为听力障碍治疗干预的分子靶点的识别提供信息。

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.