Simulations of Myenteric Neuron Dynamics in Response to Mechanical Stretch

Background. Intestinal sensitivity to mechanical stimuli has been studied intensively in visceral pain studies. The ability to sense different stimuli in the gut and translate these to physiological outcomes relies on the mechanosensory and transductive capacity of intrinsic intestinal nerves. However, the nature of the mechanosensitive channels and principal mechanical stimulus for mechanosensitive receptors are unknown. To be able to characterize intestinal mechanoelectrical transduction, that is, the molecular basis of mechanosensation, comprehensive mathematical models to predict responses of the sensory neurons to controlled mechanical stimuli are needed. This study aims to develop a biophysically based mathematical model of the myenteric neuron with the parameters constrained by learning from existing experimental data. Findings. The conductance-based single-compartment model was selected. The parameters in the model were optimized by using a combination of hand tuning and automated estimation. Using the optimized parameters, the model successfully predicted the electrophysiological features of the myenteric neurons with and without mechanical stimulation. Conclusions. The model provides a method to predict features and levels of detail of the underlying physiological system in generating myenteric neuron responses. The model could be used as building blocks in future large-scale network simulations of intrinsic primary afferent neurons and their network.

Diversification of molecularly defined myenteric neuron classes revealed by single cell RNA-sequencing

ABSTRACTAutonomous functions of the gastrointestinal tract require the combined activity of functionally distinct neurons of the enteric nervous system (ENS). However, the range of enteric neuron diversity and how it emerges during development remain largely unknown. We here make a novel molecular definition of 12 enteric neuron classes (ENCs) within the myenteric plexus of the mouse small intestine. We identify communication features and provide histochemical markers for discrete motor, sensory, and interneurons together with genetic tools for class-specific targeting. Transcriptome analysis of embryonic ENS reveals a largely post-mitotic principle of diversification, where only ENC1 or ENC8 phenotypic traits arise through a binary neurogenic trajectory, and other identities form through subsequent differentiation. We propose generic and class-specific transcriptional regulators and functionally connect the transcription factor Pbx3 to one post-mitotic identity conversion. Our results offers a conceptual and molecular resource for dissecting ENS circuits, and predicting key regulators for the directed differentiation of distinct enteric neuron classes.