分子組織学および医学生理学ジャーナル

The Role of Intestinal Distension in Shaping Neuronal Activity in the Enteric Nervous System of Adult Mice

Abstract

Cavin Sharkey

The Enteric Nervous System (ENS) plays a pivotal role in governing the motor, secretory, and defensive functions of the gastrointestinal tract. These enteric neurons intricately process both mechanical and chemical cues from the gut lumen, translating them into intricate motor responses. However, the precise manner in which intact enteric neural networks react to shifts within the gut environment remains a puzzle. To unravel this enigma, we conducted live-cell confocal recordings, capturing intracellular calcium activity in neurons extracted from intact portions of mouse intestine. Our aim was to investigate how neurons respond to various luminal mechanical and chemical stimuli. Utilizing specialized Wnt1, ChAT, and Calb1-GCaMP6 mice, we focused on neurons residing in the jejunum and colon. Our experimental design encompassed an examination of neuronal calcium responses triggered by diverse stimuli, including KCl (75 mM), veratridine (10 μM), 1,1-dimethyl-4-phenylpiperazinium (DMPP; 100 μM), and luminal nutrients (Ensure®), all under conditions of either intraluminal distension or its absence. The outcomes were particularly intriguing: in both the jejunum and colon, the presence of luminal content (chyme in the jejunum and faecal pellets in the colon) induced distension, rendering the underlying enteric circuit unresponsive to depolarizing stimuli. Notably, in the distal colon, heightened levels of distension displayed an inhibitory effect on neuronal reactions to KCl. Moreover, intermediary distension levels orchestrated a reconfiguration of Ca²⁺ responses, particularly influencing the circumferential propagation of slow waves. Our experimentation also revealed the key role of mechanosensitive channels; the inhibition of these channels effectively suppressed distension-induced Ca²⁺ elevations. Furthermore, we uncovered that inhibiting calciumactivated potassium channels restored neuronal responses to KCl in the distended colon, but not to DMPP. In a novel discovery, distension in the jejunum halted a tetrodotoxin-resistant neuronal response to luminal nutrient stimulation. In summation, our findings demonstrate that intestinal distension operates as a regulator of ENS circuit excitability, with mechanosensitive channels acting as key mediators. The dynamic interplay between physiological levels of distension and neural synchronicity or suppression showcases the ENS's ability to fine-tune its responses based on the gut's luminal content.