The role of mechanosensory activity in the transcriptional maturation of primary somatosensory neurons

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PROJECT SUMMARY Sensory experience sculpts neural circuits over the course of postnatal development and throughout life. A key question in developmental neurobiology is how sensory-driven neuronal activity cooperates with intrinsic gene expression programs to assemble functional neural circuits during development. While this question is relatively well-studied in central neural circuits, the role sensory activity plays in regulating gene expression in primary sensory neurons remains poorly understood. I propose to address this question in the somatosensory neurons of the dorsal root ganglia (DRG). Sensory experience has long been known to exert a profound effect on the development and function of mammalian sensory systems such as the visual and auditory systems. Likewise, sensory experience has long been presumed to regulate the wiring and function of somatosensory circuits, but only limited suggestive evidence supports such presumptions. Our lab has produced genetic tools that enable visualization and functional manipulation of the major light touch-detecting DRG neuron subtypes in the mouse and recently discovered that disrupting sensory activity changes gene expression programs in these neurons. However, the ways in which sensory activity shapes the gene expression programs that dictate DRG neuron development and function have not been characterized. Aim 1 features joint chromatin-RNA single-nucleus sequencing approaches to describe the DRG neuron gene regulatory landscape across development. Aim 2 uses a combination of the same sequencing approaches and a somatosensory stimulation paradigm to describe how sensory activity establishes DRG neuron subtype-specific gene expression programs. Aim 3 uses mouse genetic tools and physiological and morphological analyses to determine the role of mechanosensation in development of DRG sensory neuron functional properties. Together, these aims will begin to reveal how sensory activity shapes the gene expression programs that dictate DRG neuron development and function, and such findings will inform the study of DRG neuron malfunctions in peripheral neuropathies such as diabetic peripheral neuropathy.