The enteric nervous system of the human and mouse colon at a single-cell resolution

2019 ◽  
Author(s):  
Jessica Xie
Keyword(s):  
Nervous System ◽  
Enteric Nervous System ◽  
Single Cell ◽  
Mouse Colon ◽  
Human And Mouse

scholarly journals Homeostasis of mucosal glial cells in human gut is independent of microbiota

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Timna Inlender ◽  
Einat Nissim-Eliraz ◽  
Rhian Stavely ◽  
Ryo Hotta ◽  
Allan M. Goldstein ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nervous System ◽  
Enteric Nervous System ◽  
Single Cell ◽  
Postnatal Development ◽  
Glial Cells ◽  
Human Gut ◽  
Enteric Glial Cells ◽  
Developmental Dynamics ◽  
Human And Mouse

AbstractIn mammals, neural crest cells populate the gut and form the enteric nervous system (ENS) early in embryogenesis. Although the basic ENS structure is highly conserved across species, we show important differences between mice and humans relating to the prenatal and postnatal development of mucosal enteric glial cells (mEGC), which are essential ENS components. We confirm previous work showing that in the mouse mEGCs are absent at birth, and that their appearance and homeostasis depends on postnatal colonization by microbiota. In humans, by contrast, a network of glial cells is already present in the fetal gut. Moreover, in xenografts of human fetal gut maintained for months in immuno-compromised mice, mEGCs persist following treatment with antibiotics that lead to the disappearance of mEGCs from the gut of the murine host. Single cell RNAseq indicates that human and mouse mEGCs differ not only in their developmental dynamics, but also in their patterns of gene expression.

scholarly journals The Human and Mouse Enteric Nervous System at Single-Cell Resolution

Cell ◽  
2020 ◽  
Vol 182 (6) ◽  
pp. 1606-1622.e23 ◽  
Author(s):  
Eugene Drokhlyansky ◽  
Christopher S. Smillie ◽  
Nicholas Van Wittenberghe ◽  
Maria Ericsson ◽  
Gabriel K. Griffin ◽  
...  
Keyword(s):  
Nervous System ◽  
Enteric Nervous System ◽  
Single Cell ◽  
Human And Mouse

scholarly journals The enteric nervous system of the human and mouse colon at a single-cell resolution

2019 ◽  
Author(s):  
Eugene Drokhlyansky ◽  
Christopher S. Smillie ◽  
Nicholas Van Wittenberghe ◽  
Maria Ericsson ◽  
Gabriel K. Griffin ◽  
...  
Keyword(s):  
Nervous System ◽  
Enteric Nervous System ◽  
Single Cell ◽  
Molecular Mechanisms ◽  
Current Model ◽  
Human Colon ◽  
Enteric Neurons ◽  
Stem Cell Maintenance ◽  
Reference Map ◽  
Human And Mouse

AbstractAs the largest branch of the autonomic nervous system, the enteric nervous system (ENS) controls the entire gastrointestinal tract, but remains incompletely characterized. Here, we develop RAISIN RNA-seq, which enables the capture of intact single nuclei along with ribosome-bound mRNA, and use it to profile the adult mouse and human colon to generate a reference map of the ENS at a single-cell resolution. This map reveals an extraordinary diversity of neuron subsets across intestinal locations, ages, and circadian phases, with conserved transcriptional programs that are shared between human and mouse. These data suggest possible revisions to the current model of peristalsis and molecular mechanisms that may allow enteric neurons to orchestrate tissue homeostasis, including immune regulation and stem cell maintenance. Human enteric neurons specifically express risk genes for neuropathic, inflammatory, and extra-intestinal diseases with concomitant gut dysmotility. Our study therefore provides a roadmap to understanding the ENS in health and disease.

scholarly journals Transplantation of enteric nervous system stem cells rescues nitric oxide synthase deficient mouse colon

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Conor J. McCann ◽  
Julie E. Cooper ◽  
Dipa Natarajan ◽  
Benjamin Jevans ◽  
Laura E. Burnett ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Stem Cells ◽  
Nervous System ◽  
Nitric Oxide Synthase ◽  
Enteric Nervous System ◽  
Deficient Mouse ◽  
Mouse Colon ◽  
Oxide Synthase

Diversity of neurogenic smooth muscle electrical rhythmicity in mouse proximal colon

2020 ◽  
Vol 318 (2) ◽  
pp. G244-G253 ◽  
Author(s):  
Nick J. Spencer ◽  
Lee Travis ◽  
Lukasz Wiklendt ◽  
Timothy J. Hibberd ◽  
Marcello Costa ◽  
...  
Keyword(s):  
Nervous System ◽  
Smooth Muscle ◽  
Enteric Nervous System ◽  
Extracellular Recording ◽  
Proximal Colon ◽  
Proximal Region ◽  
Muscle Membrane ◽  
Mouse Colon ◽  
Cross Correlation Analysis

The mechanisms underlying electrical rhythmicity in smooth muscle of the proximal colon are incompletely understood. Our aim was to identify patterns of electrical rhythmicity in smooth muscle of the proximal region of isolated whole mouse colon and characterize their mechanisms of origin. Two independent extracellular recording electrodes were used to record the patterns of electrical activity in smooth muscle of the proximal region of whole isolated mouse colon. Cross-correlation analysis was used to quantify spatial coordination of these electrical activities over increasing electrode separation distances. Four distinct neurogenic patterns of electrical rhythmicity were identified in smooth muscle of the proximal colon, three of which have not been identified and consisted of bursts of rhythmic action potentials at 1–2 Hz that were abolished by hexamethonium. These neurogenic patterns of electrical rhythmicity in smooth muscle were spatially and temporally synchronized over large separation distances (≥2 mm rosto-caudal axis). Myogenic slow waves could be recorded from the same preparations, but they showed poor spatial and temporal coordination over even short distances (≤1 mm rostro-caudal axis). It is not commonly thought that electrical rhythmicity in gastrointestinal smooth muscle is dependent upon the enteric nervous system. Here, we identified neurogenic patterns of electrical rhythmicity in smooth muscle of the proximal region of isolated mouse colon, which are dependent on synaptic transmission in the enteric nervous system. If the whole colon is studied in vitro, recordings can preserve novel neurogenic patterns of electrical rhythmicity in smooth muscle. NEW & NOTEWORTHY Previously, it has not often been thought that electrical rhythmicity in smooth muscle of the gastrointestinal tract is dependent upon the enteric nervous system. We identified patterns of electrical rhythmicity in smooth muscle of the mouse proximal colon that were abolished by hexamethonium and involved the temporal synchronization of smooth muscle membrane potential over large spatial fields. We reveal different patterns of electrical rhythmicity in colonic smooth muscle that are dependent on the ENS.

scholarly journals Molecular and Functional Diversity of GABA-A Receptors in the Enteric Nervous System of the Mouse Colon

2014 ◽  
Vol 34 (31) ◽  
pp. 10361-10378 ◽  
Author(s):  
M. Seifi ◽  
J. F. Brown ◽  
J. Mills ◽  
P. Bhandari ◽  
D. Belelli ◽  
...  
Keyword(s):  
Nervous System ◽  
Enteric Nervous System ◽  
Functional Diversity ◽  
Gaba A ◽  
Mouse Colon

Positive allosteric modulation of endogenous delta opioid receptor signaling in the enteric nervous system is a potential treatment for gut motility disorders

2021 ◽  
Author(s):  
Jesse J DiCello ◽  
Simona Elisa Carbone ◽  
Ayame Saito ◽  
Vi Pham ◽  
Agata Szymaszkiewicz ◽  
...  
Keyword(s):  
Nervous System ◽  
Enteric Nervous System ◽  
Opioid Receptor ◽  
Allosteric Modulation ◽  
Enteric Neurons ◽  
Delta Opioid Receptor ◽  
Motility Disorders ◽  
Myenteric Neurons ◽  
Mouse Colon ◽  
Promising Therapeutic Approach

Background and Purpose: Allosteric modulators (AMs) are molecules that can fine-tune signaling by G protein-coupled receptors (GPCRs). Although they are a promising therapeutic approach for treating a range of disorders, allosteric modulation of GPCRs in the context of the enteric nervous system (ENS) and digestive dysfunction remains largely unexplored. This study examined allosteric modulation of the delta opioid receptor (DOR) in the ENS and assessed the suitability of DOR AMs for the treatment of irritable bowel syndrome (IBS) symptoms using mouse models. Experimental Approach: The effects of the positive allosteric modulator (PAM) of DOR, BMS-986187, on neurogenic contractions of the mouse colon and on DOR internalization in enteric neurons were quantified. The ability of BMS-986187 to influence colonic motility was assessed both in vitro and in vivo. Key Results: BMS-986187 displayed DOR selective PAM-agonist activity and orthosteric agonist probe-dependence in the mouse colon. BMS-986187 augmented the inhibitory effects of DOR agonists on neurogenic contractions and enhanced reflex-evoked DOR internalization in myenteric neurons. BMS-986187 significantly increased DOR endocytosis in myenteric neurons in response to the weakly internalizing agonist ARM390. BMS-986187 reduced the generation of complex motor patterns in the isolated intact colon. BMS-986187 reduced fecal output and diarrhea onset in the novel environment stress and castor oil models of IBS symptoms, respectively. Conclusion and Implications: DOR PAMs enhance DOR-mediated signaling in the ENS and have potential benefit for the treatment of dysmotility. This study provides proof of concept to support the use of GPCR AMs for treatment of gastrointestinal motility disorders.

scholarly journals Inflammation-associated changes in DOR expression and function in the mouse colon

2018 ◽  
Vol 315 (4) ◽  
pp. G544-G559 ◽  
Author(s):  
Jesse J. DiCello ◽  
Ayame Saito ◽  
Pradeep Rajasekhar ◽  
Emily M. Eriksson ◽  
Rachel M. McQuade ◽  
...  
Keyword(s):  
Nervous System ◽  
Enteric Nervous System ◽  
Relative Proportion ◽  
Colonic Motility ◽  
Significant Proportion ◽  
Circular Muscle ◽  
Nerve Fibers ◽  
Endogenous Opioids ◽  
Myenteric Neurons ◽  
Mouse Colon

Endogenous opioids activate opioid receptors (ORs) in the enteric nervous system to control intestinal motility and secretion. The μ-OR mediates the deleterious side effects of opioid analgesics, including constipation, respiratory depression, and addiction. Although the δ-OR (DOR) is a promising target for analgesia, the function and regulation of DOR in the colon are poorly understood. This study provides evidence that endogenous opioids activate DOR in myenteric neurons that may regulate colonic motility. The DOR agonists DADLE, deltorphin II, and SNC80 inhibited electrically evoked contractions and induced neurogenic contractions in the mouse colon. Electrical, chemical, and mechanical stimulation of the colon evoked the release of endogenous opioids, which stimulated endocytosis of DOR in the soma and proximal neurites of myenteric neurons of transgenic mice expressing DOR fused to enhanced green fluorescent protein. In contrast, DOR was not internalized in nerve fibers within the circular muscle. Administration of dextran sulfate sodium induced acute colitis, which was accompanied by DOR endocytosis and an increased density of DOR-positive nerve fibers within the circular muscle. The potency with which SNC80 inhibited neurogenic contractions was significantly enhanced in the inflamed colon. This study demonstrates that DOR-expressing neurons in the mouse colon can be activated by exogenous and endogenous opioids. Activated DOR traffics to endosomes and inhibits neurogenic motility of the colon. DOR signaling is enhanced during intestinal inflammation. This study demonstrates functional expression of DOR by myenteric neurons and supports the therapeutic targeting of DOR in the enteric nervous system. NEW & NOTEWORTHY DOR is activated during physiologically relevant reflex stimulation. Agonist-evoked DOR endocytosis is spatially and temporally regulated. A significant proportion of DOR is internalized in myenteric neurons during inflammation. The relative proportion of all myenteric neurons that expressed DOR and the overlap with the nNOS-positive population are increased in inflammation. DOR-specific innervation of the circular muscle is increased in inflammation, and this is consistent with enhanced responsiveness to the DOR agonist SNC80.

scholarly journals Single-cell molecular interrogation of enteric nervous system development

2017 ◽  
Vol 145 ◽  
pp. S67
Author(s):  
Khomgrit Morarach ◽  
Fatima Memic ◽  
Amit Zeisel ◽  
Hannah Hochgerner ◽  
Ulrika Marklund ◽  
...  
Keyword(s):  
Nervous System ◽  
Enteric Nervous System ◽  
Single Cell ◽  
System Development ◽  
Nervous System Development ◽  
Enteric Nervous System Development

scholarly journals Computational simulations and Ca2+ imaging reveal that slow synaptic depolarizations (slow EPSPs) inhibit fast EPSP evoked action potentials for most of their time course in enteric neurons

2021 ◽  
Author(s):  
Parvin Zarei Eskikand ◽  
Katerina Koussoulas ◽  
Rachel M. Gwynne ◽  
Joel C. Bornstein
Keyword(s):  
Nervous System ◽  
Ion Channels ◽  
Enteric Nervous System ◽  
Action Potentials ◽  
Enteric Neurons ◽  
Autonomous Nervous System ◽  
Myenteric Neurons ◽  
Synaptic Potentials ◽  
Mouse Colon ◽  
Time Courses

AbstractTransmission between neurons in the extensive enteric neural networks of the gut involves synaptic potentials with vastly different time courses and underlying conductances. Most enteric neurons exhibit fast excitatory post-synaptic potentials (EPSPs) lasting 20-50 ms, but many also exhibit slow EPSPs that last up to 100 s. When large enough, slow EPSPs excite action potentials at the start of the slow depolarization, but how they affect action potentials evoked by fast EPSPs is unknown. Furthermore, two other sources of synaptic depolarization probably occur in enteric circuits, activated via GABAA or GABAC receptors; how these interact with other synaptic depolarizations is also unclear. We built a compartmental model of enteric neurons incorporating realistic voltage-dependent ion channels, then simulated fast EPSPs, slow EPSPs and GABAA or GABAC ligand-gated Cl- channels to explore these interactions. Model predictions were tested by imaging Ca2+ transients in myenteric neurons ex vivo as an indicator of their activity during synaptic interactions. The model could mimic firing of myenteric neurons in mouse colon evoked by depolarizing current during intracellular recording and the fast and slow EPSPs in these neurons. Subthreshold fast EPSPs evoked spikes during the rising phase of a slow EPSP, but suprathreshold fast EPSPs could not evoke spikes later in a slow EPSP. This predicted inhibition was confirmed by Ca2+ imaging in which stimuli that evoke slow EPSPs suppressed activity evoked by fast EPSPs in many myenteric neurons. The model also predicted that synchronous activation of GABAA receptors and fast EPSPs potentiated firing evoked by the latter, while synchronous activation of GABAC receptors with fast EPSPs, potentiated firing and then suppressed it. The results reveal that so-called slow EPSPs have a biphasic effect being likely to suppress fast EPSP evoked firing over very long periods, perhaps accounting for prolonged quiescent periods seen in enteric motor patterns.Author SummaryThe gastrointestinal tract is the only organ with an extensive semi-autonomous nervous system that generates complex contraction patterns independently. Communication between neurons in this “enteric” nervous system is via depolarizing synaptic events with dramatically different time courses including fast synaptic potentials lasting around 20-50 ms and slow depolarizing synaptic potentials lasting for 10 – 120 s. Most neurons have both. We explored how slow synaptic depolarizations affect generation of action potentials by fast synaptic potentials using computational simulation of small networks of neurons implemented as compartmental models with realistic membrane ion channels. We found that slow synaptic depolarizations have biphasic effects; they initially make fast synaptic potentials more likely to trigger action potentials, but then actually prevent action potential generation by fast synaptic potentials with the inhibition lasting several 10s of seconds. We confirmed the inhibitory effects of the slow synaptic depolarizations using live Ca imaging of enteric neurons from mouse colon in isolated tissue. Our results identify a novel form of synaptic inhibition in the enteric nervous system of the gut, which may account for the vastly differing time courses between signalling in individual gut neurons and rhythmic contractile patterns that often repeat at more than 60 s intervals.

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