Developing new paradigms for mouse forelimb sensorimotor circuit analysis

开发小鼠前肢感觉运动电路分析的新范例

• 批准号: 10371764
• 负责人: Gordon M Shepherd
• 金额: $ 44万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-29 至 2024-03-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10371764
• 关键词: Anatomy; Animal Model; Area; Behavior; Clinical; Code; Communication; Complement; Complex; Computer software; Coupled; Development; Dimensions; Disease; Electrodes; Evaluation; Forelimb; Frequencies; Genetic; Goals; Hand; Health; Human; Human Activities; Impairment; Investigation; Joystick; Knowledge; Lasers; Light; Mainstreaming; Manuals; Mechanics; Mechanoreceptors; Mediating; Methodology; Methods; Mission; Modeling; Molecular; Monkeys; Motivation; Motor; Movement; Mus; Muscle; Neocortex; Nervous system structure; Neurons; Neurosciences Research; Opsin; Optics; Organism; Outcome; Pathology; Pathway interactions; Pattern; Peripheral; Physics; Primates; Property; Psychophysics; Public Health; Research; Role; Scanning; Sensorimotor functions; Sensory; Series; Signal Transduction; Speed; Spinal Cord; Standardization; Stimulus; System; Tactile; Technology; Touch sensation; United States National Institutes of Health; Variant; Vibrissae; Viral; Visual system structure; Water; Work; awake; base; biceps brachii muscle; cell type; dexterity; disability; experimental study; flexibility; improved; in vivo; insight; interest; kinematics; motor control; motor impairment; neural circuit; neurophysiology; novel strategies; optical fiber; optogenetics; prototype; relating to nervous system; response; somatosensory; spatiotemporal; stroke model; tool; visual motor

PROJECT SUMMARY Sensory-guided movements of hands involve the integration and coordination of ascending somatosensory signals and descending motor commands at multiple levels of the nervous system. A great deal of knowledge about the neurophysiology of active touch and related aspects of forelimb somatosensation and motor control has been gained from studies using humans and monkeys as subjects. More recently, studies using mice are enabling extensive molecular and cellular characterizations of somatosensory neurons mediating forelimb- related functions. However, a limitation to neurophysiological analysis of mouse forelimb functions is that the vibrotactile and other mechanical types of stimuli that are commonly used to probe the system have inherent practical limitations in their spatiotemporal precision, speed, flexibility, and complexity. These limitations reflect the small dimensions of the mouse's forelimb anatomy and the need for mechanical stimuli to be applied through direct physical contact. In contrast, in the visual system, the physics of light permits tightly controlled delivery of complex stimuli. Our overall goal in this proposal is to develop new paradigms for investigating forelimb somatosensory and motor functions in the mouse based on “light touch”: optogenetic activation of mechanosensory afferents of the forelimbs/hands, using spatiotemporally controlled light stimuli. For this, we will first use anesthetized mice to implement paradigms for optical delivery of light stimuli through optical fibers or laser-scanning photostimulation (LSPS). The stimulation technology will be used to activate the forelimbs/hands of mice expressing the excitatory opsin channelrhodopsin-2 (ChR2) in forelimb mechanoreceptor afferents, and integrated with hardware and software for recording kinematics, neuronal spiking in cortex and elsewhere, and forelimb muscular activity. In a second series of experiments we will develop multiple variants of this approach for use with awake behaving mice, enabling diverse types of experiments such as cortical silencing during peripheral activation, high-speed mapping of tactile responses, dynamic stimulus patterns, and more. The overall outcome will be to augment and expand the available experimental paradigms for investigating somatosensory-based functions of the mouse's forelimb, complementing the growing availability in mice of genetic and viral methods for accessing and manipulating in a cell-type-specific manner the somatosensory cell types and their circuits involved in sensory-guided motor control of the forelimb.

项目摘要 感觉引导的手运动涉及上升体感的整合和协调 神经系统多个级别的信号和下降电机命令。很多知识 关于主动触摸的神经生理学以及前肢节感和运动控制的相关方面 已经从使用人类和猴子作为受试者的研究中获得了研究。最近，使用小鼠的研究是 能够介导前肢的体感神经元的广泛分子和细胞特征 相关功能。但是，对小鼠前肢功能的神经生理分析的局限性是 通常用于探测系统的葡萄圆纤维和其他机械类型的刺激 其时空精度，速度，灵活性和复杂性的实际限制。这些限制反映了 小鼠的前肢解剖结构的小尺寸和需要应用机械刺激的尺寸 通过直接的身体接触。相反，在视觉系统中，光的物理学允许受到严格控制 传递复杂刺激。我们在此提案中的总体目标是开发新的范式来调查 基于“轻触摸”的小鼠的前肢体感和运动功能：光遗传激活 使用时空控制的光刺激，前肢/手的机械增强传入。为此，我们 将首先使用麻醉小鼠实施范式，以通过光纤维光递送光刺激 或激光扫描光刺激（LSP）。刺激技术将用于激活 表达兴奋性opsin ChannelRhopopsin-2（ChR2）的小鼠的前肢/手 机械感受器传入，并与硬件和软件集成用于录制运动学，神经元 在皮质和其他地方的峰值，以及前肢肌肉活动。在第二个实验中，我们将 开发这种方法的多种变体，以与行为醒着的小鼠一起使用，使潜水员类型的类型 诸如外围激活期间皮质沉默，触觉反应的高速映射等实验， 动态刺激模式等等。总体结果将是增加和扩展可用的 用于研究小鼠前肢的基于体感的功能的实验范例， 补充遗传和病毒方法的小鼠的日益增长的可用性，以获取和操纵 细胞型特异性方式的体感细胞类型及其电路涉及感官引导电动机 控制前肢。