Identification of Cellular Phenotypes in the Auditory Forebrain

 描述（由申请人提供）：在中枢听觉系统研究中，已经生成了最广泛使用的模型物种中主要脑区的基本布局和接线图。神经解剖学的努力现在主要集中在特定回路的表征上。在这个过程中，一个重要的和基本的组成部分是（1）识别组成每个大脑区域的功能不同的细胞表型;（2）确定它们在通路中的精确位置。现在已经有了获取这些数据的工具。在这个建议中，我们已经使用的转录组（mRNA测序数据库）的听觉前脑，以确定72（140）神经递质受体基因，显着表达的初级听觉皮层和内侧膝状体。使用多重荧光原位杂交测定，这些基因中的每一个将定位于5种主要细胞类型中的每一种（神经元：谷氨酸能、GABA能）（神经胶质细胞：星形胶质细胞、少突胶质细胞、小神经胶质细胞）。共表达模式的分析将使我们能够识别和定位不同的神经元和神经胶质细胞的表型在每个大脑区域的基础上，他们的基因表达谱。这些数据将扩大在细胞水平上对神经传递和可塑性机制的理解，并允许在神经生理学研究中更特异地靶向功能不同的细胞类型。更一般地说，测序引导的方法为大脑结构和功能的研究增加了一个新的维度，并为正在进行的表征与所有类型的交流障碍相关的神经生物学机制的努力提供了一个扩展的基础。全面了解控制听觉系统功能的分子机制对于构思和改进现有的治疗方法至关重要，这些方法可以解决临床人群（听力损失，自闭症，衰老和中风）中听觉功能受损的问题。

 DESCRIPTION (provided by applicant): In central auditory systems research, the basic layout and wiring diagrams of major brain areas in the most widely used model species have been generated. Neuroanatomical efforts are now primarily focused on the characterization of specific circuits. An important and rudimentary component in that process is to (1) identify the functionally-distinct cellular phenotypes that comprise each brain region; and (2) determine their precise locations in the pathway. The tools to acquire these data are now available. In this proposal, we have used the transcriptome (mRNA sequencing database) of the auditory forebrain to identify 72 (of 140) neurotransmitter receptor genes that are significantly expressed in the primary auditory cortex and medial geniculate body. Using multiplexed fluorescence in situ hybridization assays, each of those genes will be localized to each of 5 major cell types (neurons: glutamatergic, GABAergic)(glia: astrocytes, oligodendrocytes, microglia). Analyses of the co-expression patterns will permit us to identify and localize distinct neuronal and glial phenotypes in the each brain region based on their gene expression profiles. These data will expand understanding of the mechanisms that govern neurotransmission and plasticity at the cellular level, and permit greater specificity in the targeting of functionally-distinct cell typesfor neurophysiological study. More generally, the sequencing- guided approach adds a new dimension to studies of brain structure and function, and provides an expanded foundation for ongoing efforts to characterize the neurobiological mechanisms associated with communication disorders of all types. A comprehensive understanding of the molecular mechanisms that govern function in the auditory system is essential for conceiving of and improving existing therapeutic approaches that address impaired auditory function in clinical populations (hearing loss, autism, aging and stroke).