Cell Type-Specific Halorhodopsin Mice for Neuronal Silencin

描述(申请人提供)：大脑的复杂和多样化的功能取决于由具有不同分子和/或电学属性的不同类型的神经元组成的神经电路的独特属性。此外，许多神经和精神障碍往往是由于特定的神经元亚群或神经回路的功能障碍所致。因此， 阐明每种亚型神经元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大脑功能都是至关重要的。基因工具结合了对神经元亚群中神经活动的空间和时间控制，将极大地增强我们精确绘制大脑回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，这种工具可以从基因上针对特定的神经元群体，并允许简单而快速地控制神经元的放电。这是由于最近开发的用于光激活的基因编码的光激活阳离子通道-视紫红质-2(ChR2)和用于光抑制的光驱动氯泵卤视紫红质(NpHR)。最近来自几个实验室的研究强调了使用ChR2和NpHR在绘制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，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。与我们最近开发的针对特定细胞类型的chr2转基因小鼠一起，它将提供一套强大的遗传工具，用于询问大脑回路功能和功能障碍。 在脑片和体内的光刺激和光抑制的速度。 与公共卫生相关：大脑中异常的神经元连接和神经元活动导致许多神经和神经精神疾病，如癫痫和自闭症。这项研究计划的目标是开发新的遗传工具，使神经科学家能够在人类疾病的小鼠模型中操纵神经元活动，从而帮助阐明神经和神经精神疾病的致病机制。

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. PUBLIC HEALTH RELEVANCE: Abnormal neuronal connectivity and neuronal activity in the brain contribute to many neurological and neuropsychiatric disorders such as epilepsy and autism. The goal of this research proposal is to develop new genetic tools that will allow neuroscientists to manipulate neuronal activity in mouse models of human diseases, thus helping to elucidate the pathogenic mechanisms of neurological and neuropsychiatric disorders.