Optogenetic control of the enteric nervous system and gastrointestinal transit

Abstract

Introduction: There are limited effective therapies available for improving gastrointestinal (GI) transit in mammals with intractable or chronic constipation. Current therapeutics to improve GI-transit usually require oral ingestion of therapeutic drugs, such as the serotonin receptor agonist prucalopride. However, most receptors are distributed all over the body and unsurprisingly drugs like prucalopride stimulate multiple organs, often leading to unwanted side effects. There is a desperate need in the community to improve GI-transit selectively without effects on other organs. Areas covered: We performed a systematic review of the literature on Pubmed and report significant technical advances in optogenetic control of the GI-tract. We discuss recent demonstrations that optogenetics can be used to potently control the activity of subsets of enteric neurons. Special focus is made of the first recent demonstration that wireless optogenetics can be used to stimulate the colon in conscious, freely-moving, untethered mice causing a significant increase in fecal pellet output. This is a significant technical breakthrough with a major therapeutic potential application to improve GI-transit. Expert opinion: The ability to selectively stimulate the ENS to modulate GI-transit in live mammals using light, avoids the need for oral consumption of any drugs and side effects; by stimulating only the GI-tract.

Similarities and differences between nigral and enteric dopaminergic neurons unravel distinctive involvement in Parkinson’s disease

“…Dynamic changes of Ca 2+ uptake, traceable via high-resolution imaging in myenteric neurons, combined with extracellular or intracellular recordings of the underlying innervated smooth muscle in the murine colon, have beautifully demonstrated that generation and coordination of the CMMCs are consequent to the rhythmic and synchronized firing of populations of myenteric neurons located in different ganglia and propagated along the colon. During prolonged neurogenic firing bursts, large numbers of cholinergic and nitrergic myenteric neurons are synchronously active as well as CGRP-expressing intrinsic primary sensory neurons, resulting in the contraction of smooth muscles at about 2 Hz frequency 111 , 112 . Thus, use of mice genetically modified to express fluorescent proteins (i.e., GFP or channel rhodopsin2 or GCaMP3) on promoters of genes specifically expressed by dopaminergic neurons (TH, DAT, Drd2, Drd3) could identify them and define their function within the ganglionic plexuses.…”

Motor behavior of mouse large intestine: A Minireview

“…Their objective was to take advantage of optogenetics to selectively fire identified populations of enteric neurons in terms of their histology, electrophysiology, synaptology, inmmunohistochemistry, and physiological roles in colonic propulsive motility. Their published results are proof of what the great advantage of optogenetics is at present and will be in future ability to bypass the clumsy organ bath pharmacological methodologies and techniques that are showcased in this minireview 28‐31 …”

“…the great advantage of optogenetics is at present and will be in future ability to bypass the clumsy organ bath pharmacological methodologies and techniques that are showcased in this minireview. [28][29][30][31] Feasibility and value of application of optogenetics to study intestinal motility have been reported for mouse ileum, and for the colon.…”

Enlightening the frontiers of neurogastroenterology through optogenetics

“…These advances will permit the unobstructed study of behavioral or functional changes in response to manipulation of the affected system. Recent reviews provide more detailed discussion about the potential for wireless optogenetic manipulation of GI sensation and motility (93,94), with the goal of developing clinically applicable technologies to treat GI disorders. There are also many opsins with different channel properties for circuit excitation or inhibition that can be used in addition to ChR or HR.…”