Journal
GASTROENTEROLOGY
Volume 155, Issue 2, Pages 514-+Publisher
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2018.05.029
Keywords
Peristalsis; Gut Motility; Colonic Migrating Motor Complex; Myoelectric Complex
Categories
Funding
- National Institutes of Health (NIH) [R01GM101218, R01DK103901]
- Washington University School of Medicine Digestive Disease Research Core Center [NIDDK P30 DK052574]
- Center for the Study of Itch of Department of Anesthesiology at Washington University School of Medicine
- NIH SPARC Award [NIBIB U18EB021793]
- NIH Director's Transformative Research Award [TR01 NS081707]
- National Health and Medical Research Council of Australia [1127140]
- Urology Care Foundation Research Scholars Program
- Kailash Kedia Research Scholar Award
- NATIONAL INSTITUTE OF BIOMEDICAL IMAGING AND BIOENGINEERING [U18EB021793] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [P30DK052574, R01DK103901] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM101218] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS081707] Funding Source: NIH RePORTER
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BACKGROUND & AIMS: Strategies are needed to increase gastrointestinal transit without systemic pharmacologic agents. We investigated whether optogenetics, focal application of light to control enteric nervous system excitability, could be used to evoke propagating contractions and increase colonic transit in mice. METHODS: We generated transgenic mice with Cre-mediated expression of light-sensitive channelrhodopsin-2 (ChR2) in calretinin neurons (CAL-ChR2 Crethorn mice); Cre-littermates served as controls. Colonic myenteric neurons were analyzed by immunohistochemistry, patchclamp, and calcium imaging studies. Motility was assessed by mechanical, electrophysiological, and video recording in vitro and by fecal output in vivo. RESULTS: In isolated colons, focal light stimulation of calretinin enteric neurons evoked classic polarized motor reflexes (50/58 stimulations), followed by premature anterograde propagating contractions (39/58 stimulations). Light stimulation could evoke motility from sites along the entire colon. These effects were prevented by neural blockade with tetrodotoxin (n = 2), and did not occur in control mice (n = 5). Light stimulation of proximal colon increased the proportion of natural fecal pellets expelled over 15 minutes in vitro (75% +/- 17% vs 32% +/- 8% for controls) (P < .05). In vivo, activation of wireless light-emitting diodes implanted onto the colon wall significantly increased hourly fecal pellet output in conscious, freely moving mice (4.2 +/- 0.4 vs 1.3 +/- 0.3 in controls) (P < .001). CONCLUSIONS: In studies of mice, we found that focal activation of a subset of enteric neurons can increase motility of the entire colon in vitro, and fecal output in vivo. Optogenetic control of enteric neurons might therefore be used to modify gut motility.
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