ACTIVITY DEPENDENT MECHANISMS NEURAL CIRCUIT FORMATION

神经回路是神经系统的基本功能。神经电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护不当会导致神经和精神疾病，这些疾病会使人虚弱和毁灭性。了解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，神经系统有10/12的神经元和10/15的连接，构成了需要研究的最复杂的问题之一。尽管在了解神经发育的基本方面取得了相当大的进展，但对电路发育和维护中的细胞和分子机制的了解仍然有限。这里概述的研究将调查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，这些研究使用了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上表现出惊人的精确度。表达相同气味受体基因的神经元在嗅球内大约2000个局部固定的肾小球中汇聚成两个。嗅觉神经元的这种精确靶向被认为部分是由气味受体介导的，但机制尚不清楚。通过与神经元的类比，可能在建立精确的嗅觉地图方面发挥重要作用。这项研究的重点是阻断神经活动，并检查神经元沉默对回路形成的影响。为了实现这一目标，将使用遗传方法创造转基因小鼠，这些转基因小鼠可以被诱导以组织和时间特异性的方式表达钾通道。这种钾通道的表达将大大抑制神经兴奋性和抑制电活动。沉默神经元的投射模式可以通过报告基因的活性直接可视化，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.