Peripheral Mechanisms Governing Tactile Encoding During Normal Target Remodeling

描述(由申请者提供)：触摸是基本行为不可或缺的一部分，如进食、社交和避免身体伤害。在哺乳动物中，触觉是由嵌入皮肤的感觉感受器编码的。哺乳动物的皮肤结构和机械性能是动态的，会随着许多生理和外部条件的变化而变化，包括营养、体重、衰老和暴露在环境因素中，如紫外线照射。关于这些生理变化如何改变来自触摸感受器的神经元信号，我们知之甚少。这项应用的目的是阐明在正常生理靶器官变化过程中控制触觉传入放电特性的外周机制。该项目的重点是小鼠缓慢适应类型I(SAI)传入作为一个模型系统，具有无与伦比的可访问性，用于计算和实验研究。与有髓皮肤传入接触的默克尔细胞形成温和的触觉受体，介导SAI反应。该项目与人类健康高度相关，因为1)皮肤中的SAI反应是人类高触觉敏锐度的基础，但人们对生理性皮肤重塑如何改变其信号知之甚少；2)了解正常神经元重塑的机制可以确定治疗病理或年龄相关触摸敏感性变化的靶点。解剖学研究表明，在小鼠的正常毛发生长过程中，皮肤神经密度会发生变化。这项应用将解决关键的开放问题：1)在毛囊周期中支配神经变化的机制是什么，以及2)神经变化是否会导致感觉信号的变化？中心假设是，在正常的皮肤重塑过程中，触觉传入的结构可塑性控制着触摸诱发的放电特性。这一假说将通过一种创新的多学科方法进行验证，该方法结合了实验技术，包括神经生理学、3D显微镜、定量形态计量学、组织生物力学和新的老鼠模型，以及计算工具，如神经动力学的新网络模型、微分方程式和固体力学。目的是1)明确皮肤更新过程中神经元重塑的时间动力学和细胞机制，2)分析神经元重塑对机械编码的功能影响，3)识别驱动神经元重塑的靶细胞类型和候选分子线索。这个项目在概念上是创新的，因为它解决了基础神经生物学中的一个新问题，这个问题对触摸刺激的编码至关重要。技术创新在于其独特的跨学科方法，将实验生物学与计算研究相结合，以回答这些基本问题。通过确定在健康皮肤中控制触摸诱发信号可靠性的机制，这些研究将为确定这些机制在衰老和病理生理状态下如何失效奠定基础。

DESCRIPTION (provided by applicant): Touch is integral to essential behaviors such as feeding, social bonding and avoiding bodily harm. In mammals, touch is encoded by sensory receptors embedded in the skin. Mammalian skin structure and mechanical properties are dynamic, changing in response to numerous physiological and external conditions, including nutrition, body weight, aging and exposure to environmental factors, such as UV irradiation. Little is known about how these physiologic changes alter neuronal signaling from touch receptors. The objective of this application is to elucidate peripheral mechanisms that govern the firing properties of tactile afferents during normal physiological target-organ changes. The project focuses on mouse slowly adapting type I (SAI) afferents as a model system with unparalleled accessibility for computational and experimental studies. Merkel cells in contact with myelinated cutaneous afferents form gentle-touch receptors that mediate SAI responses. This project is highly relevant to human health because 1) SAI responses in the skin underlie high tactile acuity in humans but little is known about how physiological skin remodeling alters their signaling; and 2) understanding mechanisms of normal neuronal remodeling could identify targets for treating pathological or age-related changes in touch sensitivity. Anatomical studies have shown that skin innervation density changes during normal hair growth in mice. This application will address key open questions: 1) what are the mechanisms that govern innervation changes during hair-follicle cycling, and 2) do changes in innervation lead to altered sensory signaling? The central hypothesis is that structural plasticity of tactile afferents govern touch-evoked firing properties during normal skin remodeling. The hypothesis will be tested with an innovative multidisciplinary approach combining experimental techniques, including neurophysiology, 3D microscopy, quantitative morphometry, tissue biomechanics and novel mouse models, with computational tools such as novel network models of neuronal dynamics, differential equations and solid mechanics. Aims are to 1) define temporal dynamics and cellular mechanisms of neuronal remodeling during skin renewal, 2) analyze the functional consequences of neuronal remodeling on mechanical encoding, and 3) identify the target cell type and candidate molecular cues that drive neuronal remodeling. This project is conceptually innovative because it tackles a novel question in basic neurobiology that is central to the encoding of touch stimuli. Technically innovation lies in its unique, interdisciplinary approaches to combine experimental biology with computational studies to answer these fundamental questions. By identifying mechanisms that govern the reliability of touch-evoked signals in healthy skin, these studies will set the stage to determine how these mechanisms fail in aging and pathophysiological states.