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

基本信息

批准号：
8513087
负责人：
Gregory John Gerling
金额：
$ 3.47万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
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/8513087
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 Fire - disasters 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

项目摘要

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）：这项研究的长期目标是确定哺乳动物触摸受体如何转导力到神经信号中，这些神经信号在我们的动态环境中为大脑提供了有关对象的信息。触觉对于从避免身体伤害到诸如儿童抚养等重要社交互动的行为至关重要。支配皮肤的触摸受体在其周围形态和生理输出中同样多样。先前的研究表明，不同类别的触摸受体产生独特的触发模式，编码对象的空间和时间特征。尽管取得了过去的进展，但尚未定义控制哺乳动物接触受体中神经输出的原则。该应用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级机制，我们将其用作分子，生理和计算研究的模型。这些复合物介导了慢慢适应I型（SAI）触摸响应，从而解决了良好的空间细节，例如盲文图案。我们以高速和保真度提取边缘和物体曲率的能力可能直接与SAI传入的独特双相触发模式有关。 SAI传入的形态在触摸受体中也是独特的，因为它与感觉受体细胞偶联。每个SAI传入都有一个分支乔木，接触约10-40个默克尔细胞。进化的格言“遵循功能”导致我们的核心假设，即SAI传入的独特架构是其独特的射击特性的基础。这个新的协作项目将通过结合计算模型，显微镜和神经生理学来检验这一假设。我们将使用固体力学，微分方程和统计数据来构建新颖的计算模型，以定义决定双相SAI发射模式的关键原理。为了告知建模，我们将阐明小鼠SAI传入的三维结构，包括默克尔细胞的数量和排列以及动作潜在的起始区。最终的模型将对哺乳动物中触摸诱发反应的生物学机制做出具体预测。然后将通过转基因小鼠的神经生理记录对这些预测进行实验测试，这些记录允许在接受场中直接可视化默克尔细胞。拟议研究的智力优点在于我们加入计算和实验技术以确定触摸受体解剖学如何控制生理的手段。计算的力量使我们能够评估数千个可能性，这些可能性几乎不可能一一进行经验测试。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现实模型。该策略符合生物学探索的新兴范式 - 建立预测模型，以首先探索建模空间中的问题，并随后在经验空间中测试预测。该项目是系统工程研究人员与神经生物学研究人员之间的新事业，其职业致力于理解触摸。该研究建议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开发的基础设施，这导致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提高对生物系统中力转导机制的理解。该项目将支持系统工程，神经科学和生理学的教学和研究生培训。这项工作中阐明的生物学原理可以进一步理解其他感觉方式，包括疼痛。我们希望这些模型对于可以与人工神经系统接口以恢复触摸灵敏度的工程人工触摸传感器至关重要（例如，在燃烧受害者和截肢者中），以及在医学中进行的人类动物操纵中的应用。我们预计实验结果会影响传感器设计，组织建模，神经生物学，心理物理学，触觉和皮肤病领域的研究人员。结果将在适当的同行评审期刊和会议演讲中传播。