BIOPHYSICS--MODELING VELOCITY STORAGE NEURAL INTEGRATION

这项研究的主要目标是确定前庭-动眼系统中速度储存神经积分器(VSNI)的生物物理和细胞底物。现有的前庭积分器神经模型在很大程度上依赖于递归正反馈网络来实现集成。然而，在金鱼和哺乳动物中识别的整合神经元中，缺乏必要的经常性轴突侧支反馈的解剖学证据。初步分析表明，VSNI神经元表现为分数阶积分器；然而，目前还不能在神经水平上理解分数或积分的动力学行为。这项拟议的研究将发展数学、分析和方法论技术，用于随后更大规模的研究，即细胞和网络特性对速度存储神经集成的相对贡献。具体目的是(1)检验金鱼VSNI神经元是分数阶积分器的假设，并量化其综合性质；(2)检验II区神经元分支几何范围和树突类型的异质性与观察到的反应动力学多样性之间的因果关系；(3)通过VSNI神经元的生物物理模拟，提取树突分支拓扑、树突不均匀和本征膜电流对分数和综合反应动力学的贡献。预期的结果是：表征VSNI神经元的综合反应动力学的范围；分形结构特性与可能的分数综合反应动力学之间的关联；以及对内在结构和细胞因素在产生这些动力学过程中的相对作用的估计。该项目的独特之处在于：(1)使用易于识别速度存储神经元的金鱼制剂，用于现实建模和结构-功能实验的数量有限，其中包括单细胞尖锐和贴片电极记录；(2)使用新的数学方法将分数积分动力学与分形树枝结构联系起来，包括计算3-D分维和从物理底物推导分数微分方程式的新分析技术。这项研究将为未来基于模型的速度存储和角VOR空间定向的神经基础研究提供方法论和初步结果。这些结果将影响当前系统水平的前庭-眼功能模型，以及神经科学多个领域中持续神经活动和短期记忆的一般理论模型。

The broad objective of this research program is to determine the biophysical and cellular substrate of the velocity storage neural integrator (VSNI) in the vestibulo-oculomotor system. Existing neural models of vestibular integrators rely largely on recurrent positive feedback networks to implement the integration. Anatomic evidence for the requisite recurrent axon collateral feedback in identified integrator neurons in goldfish and in mammals, however, is lacking. Preliminary analyses suggest that VSNI neurons behave as fractional order integrators; however, neither fractional nor integrative dynamical behaviors is presently understood at the neural level. The proposed research will develop the mathematical, analytic and methodological techniques to be used in a subsequent larger study of the relative contributions of cellular and network properties to velocity storage neural integration. The specific aims are (1) to test the hypothesis that VSNI neurons in goldfish are fractional order integrators, and quantify their integrative properties; (2) to test the hypothesis that the observed range of branching geometries and heterogeneity of dendritic process types in Area II neurons is causally related to the diversity of observed response dynamics; (3) to abstract the contributions of dendritic branching topology, dendritic nonuniformity and intrinsic membrane currents to fractional and integrative response dynamics via biophysically realistic modeling of VSNI neurons. The expected results are: characterization of the range of integrative response dynamics in VSNI neurons; correlation between fractal structural properties and possibly fractional integrative response dynamics and an estimate of the relative roles of intrinsic structural and cellular factors in producing these dynamics. The unique features of this project are (1) use of the goldfish preparation in which velocity storage neurons are easily identified, finite in number for realistic modeling and structure-function experiments that include both single cell sharp and patch electrode recordings; (2) use of new mathematical methods for relating fractional integrative dynamics to fractal dendritic structures, including computation of 3-D fractal dimension and new analytic techniques for deriving fractional differential equations from their physical substrates. This research will provide the methodology and pilot results for future model-based studies of the neural basis of velocity storage and angular VOR spatial orientation. These results will impact on current system-level models of vestibulo-ocular function, and on general theoretical models of persistent neural activity and short-term memory in multiple areas of neuroscience.