Dendritic Integration and Cerebellar Synaptic Plasticity

小脑是所有脊椎动物的大脑结构，被认为是基于感觉输入指导运动学习的。该项目的总体目标是在基本层面上了解浦肯野神经元如何整合感觉信息。浦肯野神经元是感兴趣的，因为它们是小脑的两个主要输入流的会聚点，苔藓纤维/平行纤维通路和下橄榄/攀爬纤维通路。此外，浦肯野神经元是小脑？的唯一输出，并被认为在调节运动和认知活动中起着关键作用。双光子显微镜允许在脑组织深处进行光学切片和成像，将能够观察脑切片中的树突加工，并在活体动物中同时观察许多神经元。笼状神经递质和第二信使的模式化光解将允许以毫秒分辨率操纵空间复杂的树突活动。本提案将检验以下三个想法。(1)颗粒细胞输入的复杂模式由浦肯野细胞根据两种规则整合，局部变化的树突整合规则和确定放电输出的体细胞规则。(2)浦肯野细胞具有单突触水平的机制，用于检测颗粒细胞活动相对于两种指导性输入的时间：攀爬纤维活动和局部树突去极化。(3)浦肯野细胞在体内以亚树突和多细胞模式被激活，以产生驱动输出放电和突触可塑性的信号。这三个观点结合在一起，形成了一个模型，在这个模型中，颗粒细胞的活动模式经历了可塑性，并且它们本身可以驱动可塑性，从而塑造浦肯野细胞的输出。

The cerebellum, a brain structure found in all vertebrates, is thought to guide motor learning based on sensory inputs. The overall goal of this project is to understand, at a fundamental level, how sensory information is integrated by Purkinje neurons. Purkinje neurons are of interest because they are the point of convergence for the two main input streams to the cerebellum, the mossy fiber/parallel fiber pathway and the inferior olive/climbing fiber pathway. In addition, Purkinje neurons are the cerebellum?s sole output and are thought to play a key role in modulating motor and cognitive activity. Two-photon microscopy, which allows optical sectioning and imaging deep in brain tissue, will enable the observation of dendritic processing in brain slices, and observation of many neurons at once in living animals. Patterned photolysis of caged neurotransmitters and second messengers will allow spatially complex dendritic activity to be manipulated with millisecond resolution. This proposal will test the following three ideas. (1) Complex patterns of granule cell inputs are integrated by Purkinje cells according to two kinds of rules, a dendritic integration rule for local changes and a somatic rule for determining firing output. (2) Purkinje cells have single synapse-level mechanisms for detecting the timing of granule cell activity relative to two kinds of instructive input: climbing fiber activity and local dendritic depolarization. (3) Purkinje cells are activated in vivo in subdendritic and multicellular patterns to generate signals that drive output firing and synaptic plasticity. Taken together, these three ideas contribute to a model in which patterns of activity in granule cells undergo plasticity, and can themselves drive plasticity, to shape Purkinje cell output.