Elucidating the molecular and functional diversity of dorsal root ganglia somatosensory neurons across mammals

About This Grant

Project Summary The somatosensory system has evolved to detect, process, and relay information from the body’s surfaces into the central nervous system. At the sensory periphery, each of a diverse repertoire of somatosensory neuron types housed in the dorsal root ganglia (DRG) expresses one or more of a small collection of sensory receptors that transduce mechanical, thermal, and/or chemical stimuli. While these cell types, the sensory receptors they express, and even the physiological responsivity of many cell types are relatively well-characterized in mice, it remains unclear whether other mammals exhibit the same cell-type-specific sensory receptor gene expression patterns and cell-type-specific physiology. My preliminary data indicate that even closely related species such as the mouse and rat frequently exhibit notably different cell-type-specific patterns of sensory receptor gene expression. Furthermore, some DRG neuron types have remained genetically inaccessible, even in mice, and thus have remained anatomically and physiologically uncharacterized. The proposed work will leverage single-nucleus RNA- and ATAC-sequencing datasets, viral engineering, and modern neuroanatomical and neurophysiological approaches to investigate the diversity, evolution, and function of DRG somatosensory neuron repertoires across different mammals. In Aim 1, I will describe interspecies differences in cell-type- specific sensory receptor gene expression patterns across mammals ranging from the widely used laboratory mouse to niche non-genetic model organisms such as the naked mole rat. In Aim 2, I will mine my single-cell ATAC-seq datasets to find enhancers that allow genetic access to specific DRG neuron types to develop new viral-genetic tools to genetically access and describe the anatomy, physiology, and function of DRG neuron types previously genetically inaccessible in mice; I will also extend these viral-genetic tools to describe the anatomy, physiology, and function of conserved DRG cell types that elicit pain and itch in rats and test whether the divergent patterns of sensory receptor gene expression indeed affect the function of these cellular orthotypes. These proposed experiments will be paired with a scientific training plan in bioinformatics and genomic analysis, enhancer- virus engineering, somatosensory neuron physiology, and animal behavior, as well as a career development plan preparing me to become an independent researcher. Technical and conceptual guidance on designing and performing bioinformatic analyses and physiological and behavioral experiments will be provided by the postdoctoral advisory committee I have assembled, including Drs. Gordon Fishell, Stephen Liberles, and Guoping Feng. My mentors, Drs. David Ginty and Michael Greenberg, will supervise the mentored phase of the award through regular meetings and ensure that my training fully prepares me to transition to an independent position. Together, the proposed research and training plan will enable me to make important discoveries concerning the diversity, evolution, and function of mammalian somatosensory neuron repertoires and prepare me to lead an independent research group addressing outstanding questions in somatosensory neuron evolution and function.