Cell Type-Specific Halorhodopsin Mice for Neuronal Silencin

描述（由申请人提供）：大脑的复杂和多样的功能取决于由具有不同分子和/或电特性的各种神经元亚型形成的神经回路的独特特性。此外，许多神经和精神疾病通常是由于神经元或神经回路的特定子集的功能障碍。因此，在本发明中， 阐明每种神经元亚型在形成电路功能中的独特作用对于我们理解正常和异常的脑功能是至关重要的。将空间和时间控制纳入神经元亚群中的神经活动的遗传工具将大大提高我们精确绘制大脑中的电路功能和功能障碍的能力。以这种方式操纵活动需要一种工具，该工具可以在遗传上针对特定的神经元群体，并且允许简单快速地控制神经元放电。这已经通过最近开发的用于光活化的遗传编码的光激活阳离子通道channelrhodopsin-2（ChR 2）和用于光抑制的光驱动氯离子泵halorhodopsin（NpHR）而成为可能。最近几个实验室的研究强调了使用ChR 2和NpHR在映射神经元连接和操纵电路功能方面的巨大潜力。这项研究计划的目标是产生一系列转基因小鼠，这些小鼠在大脑中分子定义的神经元亚型中选择性地表达改进的NpHR。与我们最近产生的细胞类型特异性ChR 2转基因小鼠一起，它将提供一套强大的遗传工具，用于使用高密度聚乙烯来询问脑回路功能和功能障碍。 在脑切片和体内加速光刺激和光抑制。

DESCRIPTION (provided by applicant): The complex and diverse functions of the brain depend on the unique properties of neural circuits formed by various subtypes of neurons with distinct molecular and/or electrical properties. Furthermore, many neurological and psychiatric disorders are often due to the dysfunction of specific subsets of neurons or neural circuits. Thus, elucidating the unique roles of each subtype of neurons in shaping circuitry function is critical t our understanding of both normal and abnormal brain functions. Genetic tools that incorporating spatial and temporal control over neural activity in neuronal subsets would greatly enhance our capability to precisely map circuitry function and dysfunction in the brain. Manipulating activity n this way requires a tool that can be genetically targeted to specific populations of neurons and that allows simple and rapid control of neuronal firing. This has been made possible by the recent development of the genetically encoded light-activated cation channel channelrhodopsin-2 (ChR2) for photoactivation and the light-driven chloride pump halorhodopsin (NpHR) for photoinhibition. Recent studies from several laboratories have highlighted the tremendous potentials of using ChR2 and NpHR in mapping neuronal connectivity and manipulating circuitry function. The goal of this research proposal is to generate a series of transgenic mice that express improved NpHR selectively in molecularly defined subtypes of neurons in the brain. Together with our recently generated cell type-specific ChR2 transgenic mice, it will provide a set of powerful genetic tools for interrogating brain circuitry function and dysfunction using high speed photostimulation and photoinhibition in brain slices and in vivo.