The role of early postnatal activity in development of physiological properties of neurons and of nuclear organization in the auditory brainstem

在发育中的听觉系统中，通过ATP介导的内毛细胞的激活在耳蜗中产生自发性动作电位的离散爆发，然后转移到中枢听觉系统。这种爆发活动停止与听力的发病，并被认为在轴突寻路，细化地形图，树突形态发生，和轴突终末乔木的隔离中发挥作用。本实验室最近的研究表明，内源性嘌呤能信号在特定的听觉脑干神经元出生后早期发育过程中对神经元放电具有促进作用。因此，我们假设，神经元的活动，促进了嘌呤能信号在听力发作前，在组织发展中的中央听觉通路发挥了特定的作用。我们提出的项目将分析传入活动的速率和模式对耳蜗核和斜方体内侧核的生理和细胞及核形态的影响。将使用两种动物模型：Pou4f3DTR/+小鼠，其中耳蜗毛细胞可在早期发育期间通过注射白喉毒素选择性消除。缺乏嘌呤能P2X2和P2X3受体（P2X2/P2X3Db1-/-）的小鼠将用作研究传入活动模式改变的影响的模型。该项目包括切片和体内电生理学的补充使用。这样，我们就可以利用这两种实验方法中任何一种的优势来仔细研究发展的具体方面。

In the developing auditory system, discrete bursts of spontaneous action potentials are generated in the cochlea by ATP-mediated activation of the inner hair cells, and thereafter transferred to the central auditory system. Such bursting activity ceases with the onset of hearing and is believed to play a role in axonal pathfinding, refinement of topographic maps, dendritic morphogenesis, and the segregation of axonal terminal arbors. Recent studies in our lab indicate a facilitating effect of endogenous purinergic signaling on neuronal firing during early postnatal development of specific auditory brainstem neurons. Thus, we hypothesize that the neuronal activity, facilitated by purinergic signaling before hearing onset, plays a specific role in organizing the developing central auditory pathways. Our proposed project will analyze the effects of the rate and the pattern of afferent activity on the physiology and both cellular and nuclear morphology in the cochlear nucleus and in the medial nucleus of the trapezoid body. Two animal models will be used: Pou4f3DTR/+ mice in which cochlear hair cells can be selectively eliminated during early development by injection of diphtheria toxin. Mice lacking purinergic P2X2 and P2X3 receptors (P2X2/P2X3Dbl-/-) will be used as a model to study the impact of altered patterns of afferent activity. The project includes the complementary use of slice- and in vivo electrophysiology. In this way, we can make use of the strengths of either of these two experimental approaches in scrutinizing specific aspects of development.