Formation and Development of an Auditory Brainstem Nucleus: the MNTB

描述(申请人提供)：在胚胎大脑发育期间，为感觉系统建立了模式连接、神经元定位和协作信号。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，以及不同核内和核之间的神经元集合如何共同支持感觉。不幸的是，在这段时间内，对感觉系统的检查在很大程度上没有被系统地进行。拟议的研究集中于听觉脑干的明显突触连接的早期发育，即斜方体体内侧核(MNTB)持有的终末的花冠。虽然关于中枢听觉系统成熟连接的神经元和突触生理学的许多细节已经确定，但关于胚胎MNTB核的形成、初始突触连接阶段、与听觉功能有关的模式的形成以及这些神经元上功能性突触信号的起始的信息仍然不清楚。通过将形态和功能突触特征的光学记录与来自全细胞记录的生理数据相结合的实验策略，将表征这一听觉继电器的初始功能连接。这些研究将提供有关早期连接的性质和时机的基本信息，这些连接后来转化为大型成熟神经末梢。在MNTB形成的发育期(胚胎第14天-出生后第4天)进行详细的共聚焦成像观察，将确定MNTB主神经元的特征和结构模式，包括服务前轴突终末和突触后MNTB主神经元。对早期连接的形态和功能特征的分析和量化也将为指导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，拟议的实验将开始检验GABA能系统的抑制信号在指导MNTB的早期发展和功能模式中所起的作用。 与公共健康相关：拟议的实验将提供一个基本的理解，即特定听觉系统电路的大脑连接是如何在称为突触的连接处首先形成的，以及这些连接在发育过程中是如何精确协调的。这些和未来研究的长期目标是详细了解听觉突触形成的过程和机制，以了解神经元如何组织成组并选择合作伙伴以支持正常听力功能的合作信号。从这项研究中获得的信息可能与理解与自闭症相关的某些感觉障碍直接相关。

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.