Circuit Analysis by Rapid Silencing of Specific Interneuron Populations In Vivo

描述(由申请人提供)：该项目是神经回路功能解剖的系统研究计划的初始阶段。该实验方法使用了一些最新的转基因技术来快速和可逆地灭活不同类别的中间神经元，并分析了这种干预对神经回路和行为中的信号的影响。这一策略应该会对电路的架构如何塑造神经计算产生更深层次和更全面的理解。拟议中的实验特别侧重于分析小脑的神经回路功能，小脑是一种在运动学习和动作协调中发挥核心作用的大脑结构。该项目的第一个目标是产生转基因动物，这种动物可以在不干扰大脑中任何其他神经元的情况下，快速且可逆地灭活小脑有限区域中一种名为高尔基细胞的小脑中间神经元。该项目的第二个目标是利用第一个目标中产生的小鼠来分析高尔基细胞对神经计算的贡献，以支持产生适当幅度和时机的运动。这些实验是系统分析小脑和其他神经回路中不同类别的神经元如何支持支持感知和行动的计算功能的第一步。神经系统的许多疾病涉及由特定类别的神经元退化引起的神经网络故障。这项拟议的研究开发了一种实验方法，用于分析特定神经元群体的丧失如何扰乱神经网络的功能。这一结果将有助于开发合理的治疗干预措施，以治疗因特定类别神经元退化而导致的神经系统病理状态。

DESCRIPTION (provided by applicant): This project is the initial phase of a systematic research program for the functional dissection of a neural circuit. The experimental approach employs some of the latest transgenic techniques to rapidly and reversibly inactivate distinct classes of interneurons and analyzes the impact of this intervention on both signaling in the neural circuit and behavior. This strategy should yield a deeper and more comprehensive understanding of how a circuit's architecture shapes neural computations. The proposed experiments focus specifically on analysis of neural circuit function in the cerebellum, a brain structure that plays a central role in motor learning and the coordination of movements. The first Aim of the project is to generate transgenic animals that can be used to rapidly and reversibly inactivate a class of cerebellar interneurons called Golgi cells in a restricted region of the cerebellum, without perturbing any other neurons in the brain. The second Aim of the project is to use the mice generated in the first Aim to analyze the contribution of the Golgi cells to the neural computations supporting the generation of movements with appropriate amplitude and timing. These experiments represent the first step in a systematic analysis of how the different classes of neurons in the cerebellum and other neural circuits support the computational functions supporting perception and action. Many diseases of the nervous system involve the malfunction of neural networks caused by the degeneration of specific classes of neurons. This proposed research develops an experimental approach for analyzing how the function of neural networks is disrupted by the loss of specific populations of neurons. The results will aid in the development of rational therapeutic interventions for pathological states of the nervous system resulting from the degeneration of specific classes of neurons.