CRCNS: Computational and Optical Studies of Neural Input/Output Relationship

描述（由申请人提供）：大脑功能基于神经细胞内和神经细胞之间的并行计算。在单个神经细胞的水平上，来自数千个突触输入的信息在树突棘上被接收，在那里它被树突的特定形态及其电压门控离子通道的分布处理。众所周知，棘突、树突和通道的分布随着年龄的变化而变化--在正常衰老期间以及作为与衰老相关的神经退行性疾病（如阿尔茨海默病）的结果。 对于中枢神经系统中的大多数神经元，树突如何在正常和病理状态下转换信息的细节仍然知之甚少。在很大程度上，这是因为神经元之间的连接具有大规模并行的性质--用模拟神经元生理输入的明确定义的空间和时间模式来实验性地大量刺激神经元突触是不可能的。在这里，我们提出了一种新的方法，将采用一种新的成像工作站，允许数百个单独的突触被激活的树突的空间范围内的多站点光解的笼状神经递质。 该项目将建立在我们现有的合作基础设施的基础上，并广泛利用这些基础设施，这些基础设施允许在脑切片中获取神经元的结构，重建神经元的形态，构建房室模型，以及光学高速多站点功能记录。我们将使用形态学重建来确定刺激和记录的确切部位。神经元的计算机模拟将用于在线优化实验，通过识别神经元满足实验相关规范的区域，并离线帮助理解神经元对刺激反应的非线性的潜在离子机制。- 本研究的目的是探讨海马CA 1区锥体神经元的输入输出功能。为了实现这一目标，本提案的研究目标是： - 实现一个工作站，用于同时进行光学多部位刺激和记录。 - 改进结构成像和形态重建以识别树突棘。 - 通过迭代拟合小分支中的实验数据来改进神经元模拟。生成最佳的多突触激活模式，并研究由这些模式产生的神经元活动。

DESCRIPTION (provided by applicant): Brain function is based on the concurrent computation within and among nerve cells. At the level of the single nerve cell, information from thousands of synaptic inputs is received at dendritic spines, where it is processed by the dendrites' specific morphology and its distribution of voltage-gated ion channels. It is well established that the distributions of spines, dendrites and channels change with age -- both during normal aging and as a result of neurodegenerative diseases associated with aging such as Alzheimer's disease. For most neurons in the central nervous system, the details of how the dendrites transform information in normal and pathological states remain poorly understood. In large part this is because of the massively parallel nature of the connectivity between neurons -- it has not been possible to experimentally stimulate neuronal synapses in large numbers with well-defined spatial and temporal patterns that mimic the physiological input to the neuron. Here, we propose a new approach that will employ a novel imaging workstation allowing hundreds of individual synapses to be activated across the spatial extent of the dendrites by multi-site photolysis of caged neurotransmitter. This project will build on and make extensive use of our existing collaborative infrastructure that allows acquisition of the structure of a neuron in a brain slice, reconstruction of the neuron's morphology, construction of a compartmental model, and optical high-speed multi-site functional recording. We will use the morphological reconstruction to identify the exact sites for stimulation and recording. Computer simulations of the neuron will be used online to optimize experiments by identifying regions of the neuron meeting experiment-dependent specifications, and offline to aid in understanding the underlying ionic mechanisms of nonlinearities in the neuron's response to stimulation. - The goal of this project is to determine the input/output function of pyramidal neurons in the hippocampal area CA1. In order to accomplish this goal, the research objectives of this proposal are to: - Implement a workstation for concurrent optical multi-site stimulation and recording. - Refine structural imaging and morphological reconstruction to identify dendritic spines. - Improve neuronal simulations by iterative fitting of experimental data in small branches. Generate optimal multi-synapse activation patterns and investigate the neuron's activity generated by these patterns.