Anatomical and Functional Characterization of Gastrointestinal to Spinal Cord Circuits

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Project Summary/Abstract: Viscerosensation is the communication between internal organs and the nervous system. Viscerosensory signals are transmitted from the gastrointestinal (GI) tract to the central nervous system by both vagal and dorsal root ganglia (DRG) neurons. While vagal innervation of the GI tract is considerably well-studied, far less is known about GI-innervating DRG neurons. Colon-innervating DRG neurons are critical for normal GI function. These neurons detect the chemical/gut microbial contents of the GI tract, modulate long- range control of GI motility, and are responsible for transmitting innocuous (non-painful) and noxious (painful) sensations from the GI tract. Recent studies have identified five major subtypes of colon-innervating DRG neurons, defined by their anatomical innervation patterns in the colon and ex vivo responses to stimuli. Colon-innervating DRG neurons transmit GI-relevant information to the spinal cord. These neurons project to multiple laminae of the spinal cord dorsal horn and are proposed to transmit information from the GI tract to a range of spinal cord interneurons and projection neurons, including postsynaptic dorsal column (PSDC) projection neurons. However, few studies have explored the anatomical organization of colon-innervating DRG neuron central arbors in the spinal cord. Further, a comprehensive understanding of the spinal cord neuron types to which colon-innervating DRG neurons send their diverse signals has yet to be explored. Finally, few studies have investigated the in vivo responses of spinal cord neurons across dorsal horn laminae to non-painful and painful GI stimuli. The goal of this proposal is to characterize the central morphologies and postsynaptic partners of colon- innervating DRG neurons. I hypothesize that colon-innervating DRG neuron central arbors will form distinct morphological subtypes based on the types of sensory information they transmit. I predict that colon-innervating DRG neurons that express the mechanosensitive ion channel, Piezo2, will project to deeper laminae of the dorsal horn to transmit innocuous sensations to multiple spinal cord neuron types. Conversely, I predict that peptidergic, colon-innervating DRG neurons that express the alpha form of Calcitonin Gene-Related Peptide (Calca) will transmit painful stimuli to laminae I/II interneurons. I further hypothesize that PSDC neurons will receive innocuous and noxious sensory information from the colon, through direct and indirect connections with colon- innervating DRG neurons. Using conditional mouse genetics, surgical, viral labeling, imaging, optogenetic and in vivo electrophysiological approaches, I will: 1) characterize the central arbors and postsynaptic partners of colon-innervating DRG neuron types in the spinal cord, and 2) identify the in vivo response properties of spinal cord neurons to innocuous and noxious colon stimuli. These experiments will advance our fundamental understanding of DRG to spinal cord circuits responsible for detecting, transmitting, and processing sensations from the colon. This research will provide critical insight, and may identify novel therapeutic targets, for GI pain.