Biophysical Modeling of Neural Integration

描述(申请人提供)：速度存储神经积分器的神经元存储头部速度的短期记忆，提供头部和身体在空间中的方向的中央表示，允许动物相对于惯性参考系导航。前庭整合者的建模主要集中在系统水平和递归反馈网络上，然而，辅助神经整合的生物物理机制仍不清楚。单个整合型神经元在整合型存储能力和树突分支结构上表现出相应的变异性，但到目前为止还没有研究试图将它们联系起来。这主要是由于在获得开始哺乳动物生物物理建模所需的结构/功能方面的技术困难，以及缺乏执行精确几何建模的计算和分析技术。结合数学、实验和成像专业知识的多学科方法将解决发展良好的金鱼模型中的这些不足之处，在该模型中，整合神经元很容易识别，而对于现实建模和结构功能实验，整合神经元的数量有限。我们的中心假设，即空间扩展的单细胞属性，包括树突拓扑结构及其与活性膜的相互作用和突触属性是神经整合的基本元素，将通过以下方式进行检验：(1)表征整合神经元的多样性及其在动眼运动行为和可塑性中的作用；(2)利用新的成像、图像分析和几何技术对上调的三维树突分支结构进行参数化；(3)通过高分辨率形态数据的隔室建模以及包含真实生物物理神经元模型的简化版本的电路模型的评估，验证目标1中的功能与目标2中的形态之间的关系。开发新的数学技术，将神经动力学与树突结构的局部和全局性质联系起来，是该项目的一个独特特点。从长远来看，我们希望了解细胞属性和现实神经元之间的相互作用对前庭神经整合者基础上的持续神经活动的贡献，以及神经科学多个领域中短期记忆或工作记忆的基本机制。对神经整合的机械性理解将产生基本信息，从而为预防、治疗和逆转平衡和平衡功能障碍以及理解障碍和短期记忆丧失的结构性决定因素提供合理的策略。

DESCRIPTION (provided by applicant): Neurons of the velocity storage neural integrator store a 'short-term memory' of head velocity that provides a central representation of head and body orientation in space, allowing animals to navigate with respect to an inertial reference frame. Much effort has been focused on modeling vestibular integrators at the systems level and by recurrent feedback networks, however the biophysical mechanisms that subserve neural integration remain unknown. Individual integrator neurons exhibit a corresponding variability in integrator storage capacity and dendritic branching structure, but to date no studies have attempted to relate these. This is primarily due to technical difficulties in obtaining the requisite structure/function to begin biophysical modeling in mammals, and lack of computational and analytic techniques to perform precise geometric modeling. A multidisciplinary approach combining mathematical, experimental and imaging expertise will address these inadequacies in the well-developed goldfish model, in which integrator neurons are easily identified, and finite in number for realistic modeling and structure-function experiments. Our central hypothesis, that spatially-extended single cell properties including dendritic topology and its interaction with active membrane and synaptic properties are essential elements of neural integration, will be tested by (1) characterizing the diversity in integrator neurons and its role in oculomotor behavior and plasticity; (2) parametrising 3-D dendritic branching structure with novel imaging, image analysis and geometric techniques; (3) verifying the relationships determined between function in Aim 1 and morphology in Aim 2 by compartment modeling of high-resolution morphologic data, and evaluation of circuit models containing reduced versions of biophysically realistic neuron models. Development of new mathematical techniques for relating neural dynamics to local and global properties of dendritic structures is a unique feature of this project. In the long term, we want to understand the contributions of cellular properties and interactions between realistic neurons to the persistent neural activity that underlies vestibular neural integrators specifically, and fundamental mechanisms of short-term or working memory in multiple areas of neuroscience. A mechanistic understanding of neural integration will yield basic information leading to rational strategies for prevention, treatment and reversal of balance and equilibrium dysfunction, and for understanding the structural determinants of disorders and loss of short-term memory.