Biology subjects

Smith-Edwards, K. M.

Publications and source records attributed to Smith-Edwards, K. M..

3 recordsLinked to original sources

bioRxiv2024

Experimental data supporting a novel hypothesis for the rhythmic initiation of proximal colon motor complexes

Current models of colon motility are largely based on studies of distal regions where distension-induced neural peristalsis predominates, but the proximal colon significantly differs in terms of cellular organization and its rhythmic motor activity that continues without external sensory input, emphasizing the need to define the unique mechanisms utilized by the proximal colon. With the long-term goal of developing a new model for the rhythmic initiation of proximal colon motor complexes (CMCs), we used in situ calcium imaging to define activity patterns in key players for colon motility [i.e., submucosal interstitial cells of Cajal (ICC-SM) and myenteric neurons of the enteric nervous system (ENS)], while simultaneously monitoring motor output in the proximal mouse colon. We observed repeated patterns of activity in ICC-SM and ENS myenteric neurons during the intervals between CMCs that could be used to predict the timing of subsequent CMC events. Based on our findings, we propose a novel hypothesis that cyclical interactions between the ENS and ICC-SM act as an intrinsic pattern generator for the rhythmic initiation of proximal CMCs.

physiology↗

bioRxiv2023

Abnormal enteric nervous system and motor activity in the ganglionic proximal bowel of Hirschsprung's disease

Hirschsprungs disease (HSCR) is a congenital defect in which the enteric nervous system (ENS) does not develop in the distal bowel, requiring surgical removal of the portions of bowel without ENS ganglia ( aganglionic) and reattachment of the normal proximal bowel with ENS ganglia. Unfortunately, many HSCR patients have persistent dysmotility (e.g., constipation, incontinence) and enterocolitis after surgery, suggesting that the remaining bowel is not normal despite having ENS ganglia. Anatomical and neurochemical alterations have been observed in the ENS-innervated proximal bowel from HSCR patients and mice, but no studies have recorded ENS activity to define the circuit mechanisms underlying post-surgical HSCR dysfunction. Here, we generated a HSCR mouse model with a genetically-encoded calcium indicator to map the ENS connectome in the proximal colon. We identified abnormal spontaneous and synaptic ENS activity in proximal colons from GCaMP-Ednrb-/- mice with HSCR that corresponded to motor dysfunction. Many HSCR-associated defects were also observed in GCaMP-Ednrb+/- mice, despite complete ENS innervation. Results suggest that functional abnormalities in the ENS-innervated bowel contribute to post-surgical bowel complications in HSCR patients, and HSCR-related mutations that do not cause aganglionosis may cause chronic colon dysfunction in patients without a HSCR diagnosis.

physiology↗

bioRxiv2020

Optogenetic inhibition of colon epithelium reduces hypersensitivity in a mouse model of inflammatory bowel disease

Visceral pain is a prevalent symptom of inflammatory bowel disease (IBD) that can be difficult to treat. Pain and hypersensitivity are mediated by extrinsic primary afferent neurons (ExPANs) that innervate the colon. Recent studies indicate that the colon epithelium contributes to initiating ExPAN firing and nociceptive responses. Based on these findings we hypothesized that the epithelium contributes to inflammation-induced hypersensitivity. A key prediction of this hypothesis is that inhibition of the epithelium would attenuate nociceptive signaling and inflammatory hypersensitivity. To test this hypothesis, the inhibitory yellow light activated protein archaerhodopsin was targeted to the intestinal epithelium (villin-Arch) or the ExPANs (TRPV1-Arch) that innervate the colon. Visceral sensitivity was assessed by measuring the visceromotor response (VMR) to colorectal distension (CRD), with and without yellow light illumination of the colon lumen. Inhibition of the colon epithelium in healthy villin-Arch mice significantly diminished the CRD-induced VMR. Direct inhibition of ExPANs during CRD using TRPV1-Arch mice showed that ExPAN and epithelial inhibition were similarly effective in reducing the VMR to CRD. We then investigated the effect of epithelial and ExPAN inhibition in the dextran sulfate sodium (DSS) model of inflammatory bowel disease (IBD). Inhibition of the colon epithelium significantly decreased DSS-induced hypersensitivity and was comparable to inhibition of ExPANS. Together these results reveal the potential of targeting the colon epithelium for treatment of pain.

neuroscience↗