Dendritic Integration and Cerebellar Synaptic Plasticity

描述(申请人提供)：小脑，一种存在于所有脊椎动物中的大脑结构，被认为根据感觉输入指导运动学习。这个项目的总体目标是在基础水平上了解浦肯野神经元如何整合感觉信息。浦肯野神经元之所以令人感兴趣，是因为它们是小脑两条主要输入流的汇合点，苔藓纤维/平行纤维通路和下橄榄/攀援纤维通路。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方面发挥着关键作用。双光子显微镜可以在脑组织深处进行光学切片和成像，这将使我们能够观察大脑切片中的树突处理，并同时观察活动物的许多神经元。笼子里的神经递质和第二信使的图案化光解将允许以毫秒级的分辨率操纵空间复杂的树突活动。这项提议将考验以下三个想法。(1)复杂的颗粒细胞输入模式由浦肯野细胞根据两种规则进行整合，即局部变化的树突整合规则和决定放电输出的体细胞规则。(2)浦肯野细胞具有单一的突触水平机制来检测颗粒细胞相对于两种指导性输入的活动时序：攀升纤维活动和局部树突去极化。(3)浦肯野细胞在体内以树突状细胞下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。综上所述，这三个想法有助于建立一个模型，在该模型中，颗粒细胞中的活动模式经历了可塑性，并且本身可以驱动可塑性，从而塑造浦肯野细胞的输出。

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.