Synaptic integration and firing patterns of the midbrain dopaminergic neuron

中脑多巴胺能神经元的突触整合和放电模式

• 批准号: 0817717
• 负责人: Alexey Kuznetsov
• 金额: $ 20万
• 依托单位: Indiana University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0817717&HistoricalAwards=false
• 关键词: Synaptic; integration; firing; patterns; midbrain

This project involves computational and mathematical studies to elucidate signal processing performed by the midbrain dopaminergic (DA) neuron. The central dopamine system has implications in many behavioral and cognitive tasks. A high-frequency response of the DA neuron is one of a few cellular events for which a clear physiological meaning has been proposed, and an immediate behavioral implication is the main determinant for great interest in properties of this cell. In a two-compartmental model of the DA cell, the canard and singular perturbation analysis will be applied to the bifurcation transition that corresponds to the onset of high-frequency oscillations. Timescale separations will be introduced to make the analysis possible. Then, the accuracy of proposed asymptotic approximations will be evaluated by comparison with simulations. In a morphological reconstruction, the investigators will reproduce distinctive properties of the spike generation mechanism of DA cells: 1. Its dependence on the subthreshold currents; 2. the contribution of active dendritic properties; 3. axonal initiation and presence of two components of a spike. Modeling will combine data on identified currents. Functional criteria will be applied to validate the model. Using the constructed model, synaptic integration properties of the DA neuron will be identified. Attenuation properties for a single spike and spike trains evoked at different dendritic locations will be measured in simulations. The dendritic tree is expected to be compartmentalized in such a way that synaptic inputs at certain locations elicit only somatic or only axonal spiking due to a significant spatial separation of the axon origin from the soma in DA neurons. Additionally, compartmentalization of the neuron may depend on the stimulation frequency because distal dendrites and the axon have much higher natural frequencies than the soma. Synchronization of spontaneously-evoked dendritic spikes and classical coincidence detection of synaptic inputs will be addressed in the model.The above research will integrate experimental data on firing patterns and spike initiation of the DA cell to make conclusions about functional properties of the neuron. The project will open new possibilities to move the investigation of various behavioral functions involving the DA cells from the abstract to the biophysical context. It will layout the groundwork for further experiments. In its analytical part, the research will advance dynamical explanations to nontrivial biological phenomena and contribute to the extension of singular perturbation techniques to the vicinity of a bifurcation boundary. In the long perspective, understanding of DA cell functions will advance the development of new therapies to cure numerous disorders in which the central dopamine system is impaired. This interdisciplinary study will promote the usage of mathematical and modeling methods in biosciences. The models will be submitted in a public domain database to be used for educational and scientific purposes. The project will involve graduate students and postdocs, both through mentoring and by seminar activities. The project has a potential for attracting female students and scholars from biology to mathematical sciences, were women are underrepresented.

这个计画包括计算和数学研究，以阐明中脑多巴胺能神经元所执行的讯号处理。中枢多巴胺系统在许多行为和认知任务中都有意义。DA神经元的高频反应是已经提出了明确的生理意义的少数细胞事件之一，并且直接的行为暗示是对该细胞的性质产生极大兴趣的主要决定因素。在DA细胞的两室模型中，鸭翼和奇异摄动分析将被应用于对应于高频振荡的开始的分叉过渡。将引入时间尺度分离，以使分析成为可能。然后，建议的渐近近似的准确性将通过与模拟的比较进行评估。在形态重建中，研究人员将再现DA细胞锋电位产生机制的独特特性：1。其对亚阈值电流的依赖性; 2.活性枝晶特性的贡献; 3.轴突起始和尖峰的两个组成部分的存在。建模将结合联合收割机识别电流的数据。将应用功能标准来验证模型。使用构建的模型，DA神经元的突触整合特性将被识别。在模拟中将测量在不同树突位置诱发的单个尖峰和尖峰序列的衰减特性。树突树预期以这样一种方式进行区室化，即在某些位置处的突触输入仅引起体细胞或仅引起轴突尖峰，这是由于DA神经元中轴突起源与索马的显著空间分离。此外，神经元的区室化可能取决于刺激频率，因为远端树突和轴突具有比索马高得多的自然频率。该模型将研究自发诱发的树突棘波的同步和突触输入的经典重合检测，并结合DA细胞放电模式和棘波起始的实验数据，得出有关神经元功能特性的结论。该项目将开辟新的可能性，将涉及DA细胞的各种行为功能的研究从抽象到生物物理背景。它将为进一步的实验奠定基础。在其分析部分，研究将推进动力学解释的非平凡的生物现象，并有助于扩展奇异摄动技术的分岔边界附近。从长远来看，对DA细胞功能的了解将促进新疗法的开发，以治疗中枢多巴胺系统受损的许多疾病。这种跨学科的研究将促进数学和建模方法在生物科学中的使用。这些模型将在公共领域数据库中提交，用于教育和科学目的。该项目将通过指导和研讨会活动让研究生和博士后参与。该项目有可能吸引从生物学到数学科学的女学生和女学者，因为在这些学科中，妇女的代表性不足。