Elucidating cutaneous mechanosensory circuits, from development to disease

摘要 触觉使我们能够感知和回应物理世界-我们认识物体 拿在我们手中，区分不同的纹理和形状， 反馈回路协调我们的身体动作。触觉也是 社会交换，因此是人类经验的重要组成部分。第一步 导致触觉感知的是一组被称为低- 阈值机械感受器（LTMR）。有几种LTMR类型，每种类型都有一个独特的 敏感性、形态学、生理学特性以及可能的功能。了解 每种LTMR类型的独特功能，以及LTMR活动的集合如何集成， 在CNS中加工以形成触觉感知是该领域中突出的问题。因此 我的实验室的总体目标，因此这个R35提案，是：1）阐明敏感性， 兴奋的机制，和独特的功能，主要类别的哺乳动物皮肤 LTMR; 2）定义脊髓和脑干中LTMR回路组织的逻辑，以及 通往大脑的上升路径的本质，是辨别和情感触摸的基础 感知; 3）建立外周体感系统如何组装期间， 发展;和4）以确定是否和如何触摸电路功能障碍及其 发育是自闭症谱系障碍和神经性疼痛期间触觉缺陷的基础。 我们正在使用一系列强大的小鼠分子遗传工具来实现这些目标， 通过复杂的电生理学解剖学行为和发育分析 成功完成这一R35的目标将揭示躯体感觉神经的机制， 系统的发展和功能，以及脊髓触摸信息处理的基础 在正常和疾病条件下的感知。

Abstract The sense of touch allows us to perceive and respond to the physical world –we recognize objects held in our hands, discriminate between different textures and shapes, and sensory-motor feedback circuits coordinate our body movements. The sense of touch also underlies forms of social exchange and is thus an essential component of the human experience. The first step leading to touch perception is activation of a group of cutaneous sensory neurons called low- threshold mechanoreceptors (LTMRs). There are several LTMR types, and each has a unique sensitivity, morphology, physiological property and, presumably, function. Understanding the unique functions of each LTMR type, and how ensembles of LTMR activities are integrated and processed in the CNS to form touch percepts are outstanding questions in the field. Therefore, the overall goals of my laboratory, and thus this R35 proposal, are: 1) to elucidate the sensitivities, mechanisms of excitation, and unique functions of the major classes of mammalian cutaneous LTMRs; 2) to define the logic of LTMR circuit organization in the spinal cord and brainstem, and the nature of ascending pathways to the brain that underlie discriminative and affective touch perception; 3) to establish how the peripheral somatosensory system assembles during development; and 4) to determine whether and how dysfunction of touch circuits and their development underlies tactile deficits in autism spectrum disorders and during neuropathic pain. We are achieving these goals using an array of powerful mouse molecular genetic tools, combined with sophisticated electrophysiological, anatomical, behavioral and developmental assays. Successful completion of this R35's goals will thus reveal mechanisms of somatosensory nervous system development and function, and spinal cord touch information processing underlying perception, under normal and disease conditions.