Formation and Development of an Auditory Brainstem Nucleus: the MNTB

描述（由申请人提供）：在胚胎大脑发育过程中，感觉系统建立了模式连接，神经元定位和合作信号。这个时间窗口可以用来研究单个突触的特征如何与功能相关，以及不同核内和核间的神经元集合如何共同支持感觉。不幸的是，在这段时间里，对感觉系统的检查在很大程度上没有系统地进行。本研究的重点是听觉脑干中一个明显的突触连接的早期发育，即trapazoid body （MNTB）内侧核的Held终端花萼。尽管已经确定了中枢听觉系统成熟连接中涉及神经元和突触生理学的许多细节，但有关胚胎MNTB核形成、初始突触连接阶段、与听觉功能相关的模式形成以及这些神经元功能性突触信号的开始的信息仍然不清楚。通过将形态学和功能突触特征的光学记录与全细胞记录的生理数据相结合的实验策略，将表征这种听觉中继的初始功能连通性。这些研究将提供关于早期连接的性质和时间的基本信息，这些连接后来会转化为大的、成熟的神经末梢。在MNTB形成的发育期间（胚胎第14天至出生后第4天），详细的共聚焦成像观察将确定萼前轴突终末和突触后MNTB主神经元的特征和结构模式。分析和量化早期连接的形态和功能特征也将为指导MNTB形态发生、突触形成和功能输入模式的机制提供线索。最后，本实验将开始研究gaba能系统的抑制信号在指导MNTB早期发育和功能模式中的作用。

DESCRIPTION (provided by applicant): During embryonic brain development, patterned connectivity, neuronal positioning, and cooperative signaling are established for sensory systems. This temporal window can be utilized to investigate how features of individual synapses relate to function and how neuronal ensembles within and between separate nuclei collectively support sensation. Unfortunately examination of sensory systems during this time period has, for the most part, not been systematically undertaken. The proposed investigations focus upon early development of a conspicuous synaptic connection of the auditory brainstem, the Calyx of Held terminals at the medial nucleus of the trapazoid body (MNTB). Although many details involving neuronal and synaptic physiology at mature connections of the central auditory system have been determined, information regarding embryonic MNTB nucleus formation, initial synaptic connectivity phases, formation of patterning as it relates to auditory function, and onset of functional synaptic signaling at these neurons remains obscure. Through experimental strategies that combine optical recording of morphologic and functional synaptic features with physiologic data from whole-cell recording, initial functional connectivity of this auditory relay will be characterized. These studies will provide fundamental information regarding the nature and timing of early connections that later transform into large, mature nerve terminals. Detailed confocal imaging observations over the developmental period of MNTB formation (embryonic day 14 - postnatal day 4) will identify characteristics and structural patterns of both pre-calyx axonal terminals and postsynaptic MNTB principal neurons. Analysis and quantification of morphologic and functional features of early connections will also yield clues regarding mechanisms that guide MNTB morphogenesis, synaptic formation, and functional input patterning. Finally, the proposed experiments will begin to examine the role that the inhibitory signaling of the GABAergic system plays in guiding the early development and functional patterning of the MNTB. PUBLIC HEALTH RELEVANCE: The proposed experiments will provide a fundamental understanding of how brain connections of a particular auditory system circuit first form at junctions known as synapses, and how these many connections are precisely coordinated during development. The long term goal of these and future studies is to gain a detailed understanding of the process and mechanisms involved in auditory synapse formation to understand how neurons organize into groups and select partners for cooperative signaling that supports normal hearing function. Information gained in this study could be of direct relevance for understanding certain sensory disturbances associated with autism.