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

描述(申请人提供)：大脑功能是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接收，在那里由树突的特定形态及其电压门控离子通道的分布来处理。众所周知，棘突、树突和通道的分布随着年龄的增长而变化--无论是在正常衰老期间，还是由于与衰老相关的神经退行性疾病，如阿尔茨海默病。 对于中枢神经系统中的大多数神经元来说，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。这在很大程度上是因为神经元之间的连接具有大规模并行的性质--不可能通过实验来大量刺激具有明确定义的空间和时间模式的神经元突触，这些模式模仿神经元的生理输入。在这里，我们提出了一种新的方法，它将使用一种新型的成像工作站，允许通过笼子中神经递质的多点光解，在树突的空间范围内激活数百个单独的突触。 该项目将建立并广泛利用我们现有的协作基础设施，这些基础设施允许获取大脑切片中神经元的结构，重建神经元的形态，构建隔室模型，以及光学高速多点功能记录。我们将使用形态重建来确定刺激和记录的确切位置。对神经元的计算机模拟将通过在线识别符合实验依赖规格的神经元区域来优化实验，并将离线用于帮助理解神经元对刺激反应中非线性的潜在离子机制。- 本项目的目标是确定海马区CA1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： -实施并行光学多点刺激和记录的工作站。 -改进结构成像和形态重建，以识别树突棘。 -通过对小分支中的实验数据进行迭代拟合来改进神经元模拟。产生最佳的多突触激活模式，并研究由这些模式产生的神经元的活动。

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.