Dendritic Integration and Cerebellar Synaptic Plasticity

描述（由申请人提供）：小脑是所有脊椎动物的大脑结构，被认为指导基于感觉输入的运动学习。这个项目的总体目标是在基础层面上理解浦肯野神经元是如何整合感觉信息的。浦肯野神经元之所以引起人们的兴趣，是因为它们是通向小脑的两条主要输入流——苔藓纤维/平行纤维通路和下橄榄/攀缘纤维通路——的汇聚点。此外，浦肯野神经元是小脑的唯一输出，被认为在调节运动和认知活动中起着关键作用。双光子显微镜可以对脑组织深处进行光学切片和成像，可以观察大脑切片中的树突处理过程，并可以同时观察活体动物的许多神经元。笼状神经递质和第二信使的模式光解将允许以毫秒分辨率操纵空间复杂的树突活动。这个提议将检验以下三个想法。(1)浦肯野细胞根据两种规则整合颗粒细胞输入的复杂模式，即局部变化的树突整合规则和决定放电输出的体细胞整合规则。(2)浦肯野细胞具有单突触水平的机制，可以检测颗粒细胞活动的时间相对于两种指导性输入：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，产生驱动输出放电和突触可塑性的信号。综上所述，这三种观点有助于形成一个模型，在这个模型中，颗粒细胞的活动模式经历了可塑性，并且可以自己驱动可塑性，从而形成浦肯野细胞的输出。

DESCRIPTION (provided by applicant): 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.