ACTIVITY DEPENDENT MECHANISMS NEURAL CIRCUIT FORMATION

神经回路是神经系统基本功能的基础。神经回路的发展是高度有组织和精确的。神经发育异常和神经连接维持不当导致神经和精神疾病，使人衰弱和毁灭性。了解神经回路形成的机制是我们理解神经疾病病理的基础，并可能导致发现适当的治疗方法。然而，有10/12个神经元和10/15个连接在它们之间，神经系统提出了最复杂的研究问题之一。尽管在理解神经发育的基本方面取得了相当大的进展，但对神经回路发育和维持的细胞和分子机制的了解仍然有限。这里概述的研究将探讨内在神经活动在形成和维持适当的神经元连接中的作用。特别是，这些研究使用小鼠嗅觉系统作为模型系统。嗅觉感受器神经元在其投射模式中表现出非凡的精确性。在嗅球中大约2000个地形固定的肾小球中，表达相同气味受体基因的神经元收敛为两个。嗅觉神经元的这种精确定位被认为部分是由气味受体介导的，但其机制尚不清楚。神经元的类似物可能在建立精确的嗅觉图谱中发挥重要作用。本研究的重点是阻断神经活动，并研究神经元沉默对神经回路形成的影响。为了实现这一目标,遗传方法将用于创建转基因老鼠可以诱导表达钾通道组织和特定时间的方式。钾离子通道的表达将显著抑制神经兴奋性和抑制电活动。通过报告基因活性可以直接观察沉默神经元的投射模式，并可以直接评估神经活动在模式形成中的作用。

Neural circuitry underlies the fundamental functions of the nervous system. The development of neural circuitry is highly organized and precise. Abnormal neural development and improperly maintained neural connections lead to neurological and mental diseases, which are debilitating and devastating. To understand the mechanisms that underlie circuit formation is fundamental to our understanding of the pathology of neural diseases and may lead to discovery of proper cures. Yet with 10/12 neurons and 10/15 connections amongst them, the nervous system poses one of the most complex problems to study. Despite considerable progress in understanding fundamental aspects of neural development, knowledge of the cellular and molecular mechanisms in circuit development and maintenance are limited. The studies outlined here will investigate the role of intrinsic neural activity in the formation and maintenance of proper neuronal connections. In particular, the studies use the mouse olfactory system as a model system. Olfactory receptor neurons show remarkable precision in their projection patterns. Neurons expressing the same odorant receptor gene converge to two among approximately 2000 topograpically fixed glomeruli in the olfactory bulb. Such precise targeting by olfactory neurons is believed to be partly mediated by the odorant receptors, but the mechanism is unknown. By analogs with neurons may play an important role in setting up a precise olfactory map. The focus of this study is to block neural activity and examine the effect of neuronal silencing on circuit formation. To achieve this goal, genetic methods will be used to create transgenic mice that can be induced to express a potassium channel in a tissue and temporal specific fashion. The expression of this potassium channel will substantially dampen neural excitability and suppress electrical activity. The projection patterns of silenced neurons can be directly visualized through reporter gene activity, and the role of neural activity in pattern formation can be directly assessed.