CRCNS: Mechanistic Modeling and Inference of Neuronal Synaptic Transmission

CRCNS：神经元突触传递的机制建模和推断

• 批准号: 10206091
• 负责人: Abhyudai Singh
• 金额: $ 11.1万
• 依托单位: UNIVERSITY OF DELAWARE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10206091
• 关键词: Action Potentials; Acute; Address; Adolescent; Age; Auditory; Auditory system; Biological Models; Biological Process; Brain; Brain Stem; Cells; Central Auditory Processing Disorder; Communication; Computer Models; Coupled; Data; Derivation procedure; Development; Docking; Electrophysiology (science); Engineering; Event; Frequencies; Genetic; Goals; Hearing; Hippocampus (Brain); Hybrids; Instruction; Interneurons; Investigation; Joints; Knowledge; Literature; Mathematics; Membrane Potentials; Methods; Modeling; Mus; Names; Neurons; Neurotransmitters; Noise; Pharmacology; Play; Process; Protocols documentation; Recovery; Research; Role; Sensory; Shapes; Slice; Sound Localization; Source; Synapses; Synaptic Transmission; Synaptic Vesicles; System; Time; Training; Variant; Vesicle; Work; base; data exchange; experimental study; hearing impairment; information processing; interdisciplinary approach; mathematical model; neurotransmission; neurotransmitter release; neurotransmitter uptake; novel; patch clamp; postsynaptic neurons; presynaptic neurons; response; socioeconomics; synaptic depression; tool; uptake; vesicular release

Action potential-triggered transmitter release forms a hallmark of interneuronal communication. The release is critically impacted by diverse noise mechanisms, such as random arrival of action potentials, probabilistic vesicle release, and random replenishment of vesicle pools. How these noise mechanisms combine to impact fidelity of interneuronal communication is an intriguing fundamental problem. A key focus of this project is to use the mathematical formalism of Stochastic Hybrid Systems (SHS) that combine continuous dynamics with discrete random events for modeling synaptic transmission. The SHS-based formalism will be used to derive analytical results connecting synaptic noise mechanisms to randomness in the neurotransmitter levels, and its impact on temporal precision of the responses in the postsynaptic neuron. The project will also develop novel inference methods for inferring neurotransmission parameters from whole-cell patch-clamp recordings in acute brain slices of juvenile mice. Integration of mathematical models with experimental data on long-lasting high-frequency activation of input neurons will be used to characterize neurotransmission at various auditory and non-auditory synapse types. This interdisciplinary approach--coupled with genetic and pharmacological manipulation of neurotransmitter release, re-uptake, and vesicle replenishment--will systematically uncover the role of these processes in information processing at the single-cell level and how auditory brainstem synapses achieve exquisitely high fidelity during prolonged stimulation. Altogether, the project will reveal the extraordinary capabilities of auditory synapses and thus form a basis for a better understanding of central auditory processing disorders. RELEVANCE (See instructions): Hearing impairment is the most prevalent sensory deficit, with major socioeconomic impact. In order to understand how hearing happens, we must obtain a comprehensive knowledge about neuronal information processing in the central auditory system. The project will thoroughly address synaptic processes involved in sound localization by combining empirical work with computational modeling, and we will achieve hitherto unreached synergistic effects towards our goal.

动作电位触发的递质释放形成了神经元间交流的标志。这 释放受到多种噪声机制的严重影响，例如动作电位的随机到达， 概率囊泡释放和囊泡池的随机补充。这些噪音机制如何 结合起来影响神经元间交流的保真度是一个有趣的基本问题。一把钥匙 该项目的重点是使用随机混合系统（SHS）的数学形式 将连续动态与离散随机事件相结合来建模突触传递。这 基于 SHS 的形式主义将用于导出将突触噪声机制与 神经递质水平的随机性及其对反应时间精度的影响 突触后神经元。该项目还将开发新的推理方法来推断 青少年急性脑切片全细胞膜片钳记录的神经传递参数 老鼠。将数学模型与持久高频激活的实验数据相结合 输入神经元的数量将用于表征各种听觉和非听觉的神经传递 突触类型。这种跨学科的方法——结合遗传和药理学操作 神经递质释放、再摄取和囊泡补充——将系统地揭示 单细胞水平信息处理的这些过程以及听觉脑干突触如何 在长时间的刺激过程中实现极高的保真度。总而言之，该项目将揭示 听觉突触的非凡能力，从而为更好地理解中枢奠定了基础 听觉处理障碍。 相关性（参见说明）： 听力障碍是最普遍的感觉缺陷，具有重大的社会经济影响。为了 了解听觉是如何发生的，我们必须获得关于神经元的全面知识 中枢听觉系统的信息处理。该项目将彻底解决突触问题 通过将经验工作与计算模型相结合来参与声音定位的过程，以及 我们将在实现我们的目标方面实现前所未有的协同效应。