Neural integration with active dendrites and inhibition

描述（由申请人提供）：在广泛的大脑区域中观察到持续的神经活动，并涉及从信息存储和处理到运动控制的功能。大脑工作记忆区持续神经活动的缺陷被认为是精神分裂症的核心特征。拟议的工作旨在揭示持续的神经活动的神经机制，表现出持续的神经活动的模型系统，金鱼眼神经积分器的计算建模。眼神经整合器接收速度编码的眼球运动命令，并将其转换为控制眼球位置的信号。在没有速度指令的情况下，积分器中的神经元在数十秒内保持稳定的放电速率。神经整合受损的患者无法保持稳定的凝视，并且在眼动追踪行为和眼反射方面存在缺陷。先前的眼神经系统模型忽略了一些重要的特征，这些特征使得它们无法通过实验进行明确的测试。使用一种新的框架，允许数据被直接纳入，实验约束和验证模型的金鱼眼神经积分器将被构建。该模型将用于分析网络和细胞对持续神经活动的贡献。突触兴奋，突触抑制和内在神经元兴奋性的贡献将通过模拟最近的解剖学和药理学操作的持续神经活动的系统进行评估。在网络水平上的初步建模表明，细胞之间的经常性相互作用介导的一个树突状的过程，假设是一个树突平台电位。一个网络模型与树突状分支结构和电压敏感的突触和内在电导将被构建来测试的假设，电压依赖性的树突特性增加了网络的鲁棒性扰动。该模型将受到切片和体内细胞内记录的限制，并将与顾问实验室目前正在进行的树突状成像实验进行比较。通过在一个特征良好的系统中产生一个实验约束和可验证的模型，这项工作有望揭示产生持续神经活动的核心机制。

DESCRIPTION (provided by applicant): Persistent neural activity has been observed in a wide range of brain regions and has been implicated in functions ranging from information storage and processing to motor control. Deficits in persistent neural activity in working memory areas of the brain have been suggested as a core feature of schizophrenia. The proposed work seeks to reveal the neural mechanisms underlying persistent neural activity by computational modeling of a model system exhibiting persistent neural activity, the goldfish oculomotor neural integrator. The oculomotor neural integrator receives velocity-coded eye movement commands and converts these into signals that control the position of the eyes. In the absence of velocity commands, neurons in the integrator maintain a steady rate of firing for tens of seconds. Patients with impaired neural integrators are unable to maintain a steady gaze and have deficits in eye tracking behavior and ocular reflexes. Previous models of the oculomotor system have neglected important features that have made them unable to be tested explicitly by experiment. Using a novel framework that allows data to be directly incorporated, an experimentally constrained and verifiable model of the goldfish oculomotor neural integrator will be constructed. The model will be used to analyze network and cellular contributions to persistent neural activity. The contributions of synaptic excitation, synaptic inhibition, and intrinsic neuronal excitability will be assessed by modeling recent anatomical and pharmacological manipulations of persistent neural activity in the system. Preliminary modeling at the network level suggests that recurrent interactions between cells are mediated by a bistable dendritic process that is hypothesized to be a dendritic plateau potential. A network model with dendritic branching structures and voltage-sensitive synaptic and intrinsic conductances will be constructed to test the hypothesis that voltage-dependent dendritic properties increase the robustness of the network to perturbations. The model will be constrained by intracellular recordings in slice and in vivo and will be compared to dendritic imaging experiments currently being conducted in the consultants' laboratories. By producing an experimentally constrained and verifiable model in a well-characterized system, this work promises to reveal core mechanisms by which persistent neural activity is generated.