Elucidating Cutaneous Mechanosensory Circuits, from Development to Disease

Abstract Our relationship with the physical world is rich, complex, and essential for life. How does the nervous system encode component dimensions of touch –pressure, texture, vibratory frequency, adhesiveness, wetness, compliance– and superimpose these with respect to location, direction, and speed of movement of a tactile stimulus. To understand the neural encoding of touch, we seek

to define the properties and functions of mechanosensory neurons whose mechanosensitive endings are embedded within the skin as well as the functional organization of the subcortical touch circuitry. We also investigate development of touch neurons and the subcortical touch circuitry, embracing the premise that if we know how it’s built, we can better understand how it

works. To achieve our goals, we have generated an array of mouse genetic tools for interrogating the physiologically distinct classes of Low-Threshold Mechanoreceptors (LTMRs) and High- Threshold Mechanoreceptors (HTMRs), which collectively mediate our sense of touch. These genetic tools are the lab’s engine of discovery that enable advanced physiological, anatomical,

molecular, developmental, and behavioral analyses of the mechanosensory system. The goals of my laboratory during the next eight years, and thus this P35 proposal, are: 1) to elucidate the properties and functions of LTMR and HTMR subtypes; 2) to define the organizational logic of the direct and indirect dorsal column pathways; 3) to establish how mechanotransduction contributes

to somatosensory system development; 4) to determine the basis of aberrant touch reactivity in nervous system disorders; and 5) to train somatosensory researchers and future mentors, with emphasis on rigor, creativity, collaboration, diversity, and inclusion. Achieving the goals of this R35 will reveal mechanisms of somatosensory neuron development and function, and the central

representation of touch, under normal and disease conditions, and help to prepare the neuroscientists of the future.