Peripheral Activity-Dependent and Molecular Mechanisms that Control Somatosensory System Development

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Project Summary The sense of touch is essential for life, and alterations in tactile sensory inputs early in development may cause long-term consequences on health and behavior. In mammals, non-painful touch is detected by low- threshold mechanoreceptors (LTMRs), peripheral sensory neurons that innervate the skin and relay tactile information to the central nervous system (CNS) by forming synapses in the spinal cord and brainstem. How mechanical or molecular cues from the periphery influence the development of LTMRs and their downstream circuits remains poorly understood. In particular, the developmental mechanisms underlying the central circuitry engaged by LTMRs and the brain's somatotopically organized and disproportionate responses to touch of different body regions remain unclear. The proposed work will use mouse genetic, anatomical, electrophysiological, and molecular approaches to investigate the role of developmental neural activity and skin type-specific signals that shape the structural and functional development of somatosensory neurons and their downstream circuits. In Aim 1, Dr. Santiago will use conditional ion channel mutants to define the role of spontaneous and evoked activity during the maturation of mechanosensory end organ structures in the periphery. Aim 2 will move into the CNS and assess the requirement for peripherally-mediated activity during LTMR central targeting and synapse formation, as well as during somatotopic map formation. Dr. Santiago will use a new mouse transgenic line to transiently silence somatosensory neurons during defined developmental periods, before restoring touch sensation and measuring the responses of central neurons to tactile stimuli. In Aim 3, Dr. Santiago will use target-specific RNA sequencing of somatosensory neurons, surgical manipulations, and genetic approaches to identify target-dependent molecular mechanisms by which cues in the skin control LTMR identity and connectivity. These proposed experiments will be paired with a scientific training plan in electrophysiology and the analysis of bioinformatic data, as well as a career development plan preparing Dr. Santiago to become an independent researcher. Technical and conceptual guidance on designing and performing electrophysiological and RNA sequencing experiments will be provided by the team of consultants that the candidate has assembled that includes Drs. Bruce Bean, Chinfei Chen, Lisa Goodrich, and Michael Greenberg. The candidate's mentor, Dr. David Ginty, will supervise the mentored phase of the award through regular meetings and ensure that Dr. Santiago's training fully prepares her to transition to an independent position. Together, the proposed research and training plan will enable Dr. Santiago to make important discoveries concerning the role of peripherally-mediated activity and molecular cues in somatosensory system development and prepare her to lead an independent research group addressing outstanding questions in neural development.