Developing new paradigms for mouse forelimb sensorimotor circuit analysis

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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.