CRCNS: Modeling Impact of Receptor Arrangement on Spike Initiation in Touch

CRCNS：模拟受体排列对接触中尖峰起始的影响

• 批准号: 8055160
• 负责人: Gregory John Gerling
• 金额: $ 31.86万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8055160
• 关键词: Action Potentials; Afferent Neurons; Amputees; Anatomy; Aphorisms; Architecture; Awareness; Behavior; Biological; Biological Models; Brain; Burn injury; Cell Count; Child Rearing; Code; Complex; Computer Simulation; Computing Methodologies; Confocal Microscopy; Coupled; Dermatology; Educational process of instructing; Elements; Engineering; Environment; Equation; Goals; Human; Imagery; Immunohistochemistry; Journals; Mammals; Manuscripts; Measures; Mechanics; Mediating; Medicine; Merkel Cells; Microscopy; Modality; Modeling; Molecular Models; Morphology; Mus; Nerve; Nervous system structure; Neurites; Neurobiology; Neurons; Neurosciences; Noise; Output; Pain; Paper; Pattern; Peer Review; Peripheral; Physiological; Physiology; Positioning Attribute; Preparation; Property; Psychophysics; Receptor Cell; Relative (related person); Research; Research Infrastructure; Research Personnel; Research Proposals; Robotics; Sensory; Sensory Receptors; Shapes; Signal Transduction; Skin; Social Interaction; Solid; Space Models; Speed; Structure; System; Techniques; Testing; Tissue Model; Touch sensation; Training; Transgenic Mice; Work; biological systems; braille; career; computer studies; design; graduate student; haptics; molecular modeling; mouse model; neurophysiology; novel; predictive modeling; receptive field; receptor; reconstruction; relating to nervous system; research study; response; sensor; statistics; symposium; tool

DESCRIPTION (provided by applicant): The long-term goal of this research is to determine how mammalian touch receptors transduce forces into neural signals that inform the brain about objects in our dynamic environment. The sense of touch is essential for behaviors that range from avoiding bodily harm to vital social interactions such as child rearing. The touch receptors that innervate the skin are likewise diverse in their peripheral morphologies and physiological outputs. Previous studies demonstrate that different classes of touch receptors produce distinctive firing patterns that encode spatial and temporal features of objects. Despite past progress, the principles that govern neural output in mammalian touch receptors have not been defined. The objective of this application is to elucidate cellular and systems-level mechanisms that generate neural signals in mouse Merkel cell-neurite complexes, which we use as a model for molecular, physiological and computational studies. These complexes mediate slowly adapting type I (SAI) touch responses, which resolve fine spatial details, such as Braille patterns. Our ability to extract edges and object curvature with high speed and fidelity may relate directly to the SAI afferent's distinctive biphasic firing pattern. The SAI afferent's morphology is also unique among touch receptors because it is synaptically coupled to sensory receptor cells. Each SAI afferent has a branching arbor that contacts ~10-40 Merkel cells. The evolutionary maxim 'form follows function' leads to our central hypothesis that the SAI afferent's unique architecture is fundamental to its distinctive firing properties. This new collaborative project will test this hypothesis by combining computational models, microscopy and neurophysiology. We will build novel computational models using solid mechanics, differential equations and statistics to define the key principles that dictate biphasic SAI firing patterns. To inform the modeling, we will elucidate the three dimensional architecture of mouse SAI afferents, including the quantity and arrangement of Merkel cells and action potential initiation zones. The resulting models will make specific predictions about biological mechanisms that underlie touch-evoked responses in mammals. These predictions will then be experimentally tested with neurophysiological recordings from transgenic mice that allow direct visualization of Merkel cells in receptive fields. The intellectual merit of the proposed research lies in our means of joining computational and experimental techniques to determine how touch-receptor anatomy governs physiology. The power of computation allows us to evaluate thousands of possibilities that would be virtually impossible to empirically test one by one. The power of experimental observation allows us to construct realistic models by visualizing specific anatomical structures and molecules, as well as by measuring neuronal outputs. This strategy fits into an emerging paradigm of biological exploration - that of building predictive models to first explore questions in a modeling space and to subsequently test predictions in empirical space. This project is a new venture between researchers in systems engineering and neurobiology whose careers are dedicated to understanding touch. This research proposal describes a new collaborative project that will benefit from infrastructure developed through our recent study of skin mechanics, which resulted in peer-review manuscripts and conference papers [1, 2, 3, 4]. The broader impacts resulting from the proposed research will be to advance the understanding of force transduction mechanisms in biological systems. This project will support teaching and graduate student training in systems engineering, neuroscience and physiology. The biological principles elucidated in this work may further the understanding of neural signaling in other sensory modalities including pain. We expect the models to be critical for engineering artificial touch sensors that can interface with the human nervous system to restore touch sensitivity (e.g., in burn victims and amputees), as well as for applications in human-robotic manipulation in medicine. We expect the experimental results to impact researchers in fields of sensor design, tissue modeling, neurobiology, psychophysics, haptics, and dermatology. Results will be disseminated in appropriate peer-reviewed journals and conference presentations.

描述（由申请人提供）：本研究的长期目标是确定哺乳动物触觉感受器如何将力转化为神经信号，以告知大脑我们动态环境中的物体。触觉对于从避免身体伤害到重要的社会互动（如抚养孩子）的行为至关重要。神经支配皮肤的触觉感受器在其外周形态和生理输出方面同样是多样的。先前的研究表明，不同类别的触觉感受器产生不同的放电模式，编码对象的空间和时间特征。尽管过去的进展，在哺乳动物触觉感受器的神经输出的原则还没有被定义。本申请的目的是阐明在小鼠默克尔细胞-神经突复合物中产生神经信号的细胞和系统水平机制，我们将其用作分子、生理和计算研究的模型。这些复合物介导缓慢适应I型（SAI）触摸反应，其解析精细的空间细节，例如盲文图案。我们的能力，以高速和保真度提取边缘和物体曲率可能直接涉及到SAI传入的独特的双相放电模式。SAI传入的形态在触觉感受器中也是独特的，因为它与感觉感受器细胞突触耦合。每个SAI传入神经具有接触~10-40个默克尔细胞的分支乔木。进化的格言“形式遵循功能”导致我们的中心假设，即SAI传入的独特架构是其独特的放电特性的基础。这个新的合作项目将通过结合计算模型，显微镜和神经生理学来测试这一假设。我们将使用固体力学，微分方程和统计学来建立新的计算模型，以定义决定双相SAI发射模式的关键原则。为了告知建模，我们将阐明小鼠SAI传入的三维结构，包括默克尔细胞和动作电位起始区的数量和排列。由此产生的模型将对哺乳动物触摸诱发反应的生物机制做出具体预测。然后，这些预测将通过转基因小鼠的神经生理学记录进行实验测试，这些记录允许直接观察感受野中的默克尔细胞。这项研究的智力价值在于我们将计算和实验技术结合起来，以确定触觉感受器解剖学如何支配生理学。计算的力量使我们能够评估成千上万的可能性，这些可能性几乎不可能逐一进行经验测试。实验观察的力量使我们能够通过可视化特定的解剖结构和分子以及测量神经元输出来构建逼真的模型。这一策略符合一种新兴的生物探索范式，即建立预测模型，首先在建模空间中探索问题，然后在经验空间中测试预测。这个项目是系统工程和神经生物学研究人员之间的一个新的冒险，他们的职业生涯致力于理解触摸。这项研究提案描述了一个新的合作项目，该项目将受益于我们最近对皮肤力学的研究所开发的基础设施，该研究产生了同行评审手稿和会议论文[1，2，3，4]。拟议的研究产生的更广泛的影响将是促进对生物系统中力传导机制的理解。该项目将支持系统工程、神经科学和生理学方面的教学和研究生培训。这项工作中阐明的生物学原理可能会进一步了解包括疼痛在内的其他感觉方式中的神经信号。我们预计这些模型对于工程人工触摸传感器至关重要，人工触摸传感器可以与人类神经系统连接以恢复触摸灵敏度（例如，在烧伤患者和截肢者中），以及在医学中的人机操作中的应用。我们希望实验结果能够影响传感器设计，组织建模，神经生物学，心理物理学，触觉学和皮肤病学领域的研究人员。结果将在适当的同行评审期刊和会议报告中传播。