I. New insights into neuronal injury: a cautionary tale

Understanding of the pathophysiology of neuronal injury has advanced remarkably in the last decade. This largely reflects the burgeoning application of molecular techniques to neuronal cell biology. Although there is certainly no consensus hypothesis that explains all aspects of neuronal injury, a number of interesting observations have been published. In this brief review, we examine mechanisms that appear to contribute to the pathophysiology of neuronal injury, including altered Ca2+ signaling, activation of the protease cascades coupled to apoptosis, and mitochondrial deenergization associated with release of cytochrome c, production of free radicals, and oxidative injury. Finally, evidence for neuroprotective mechanisms that may ameliorate cell injury and/or death are reviewed. Little information has been published regarding the mechanisms that mediate injury in the enteric nervous system, necessitating a focus on models outside the gastrointestinal (GI) tract, which may provide insights into enteric nervous system injury.

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The Baseline Structure of the Enteric Nervous System and Its Role in Parkinson’s Disease

Life ◽

10.3390/life11080732 ◽

2021 ◽

Vol 11 (8) ◽

pp. 732

Author(s):

Gianfranco Natale ◽

Larisa Ryskalin ◽

Gabriele Morucci ◽

Gloria Lazzeri ◽

Alessandro Frati ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Nervous System ◽

Enteric Nervous System ◽

Gi Tract ◽

Multiple Control ◽

Fine Control ◽

The Central Nervous System ◽

Degenerative Alterations ◽

Comprehensive Classification

The gastrointestinal (GI) tract is provided with a peculiar nervous network, known as the enteric nervous system (ENS), which is dedicated to the fine control of digestive functions. This forms a complex network, which includes several types of neurons, as well as glial cells. Despite extensive studies, a comprehensive classification of these neurons is still lacking. The complexity of ENS is magnified by a multiple control of the central nervous system, and bidirectional communication between various central nervous areas and the gut occurs. This lends substance to the complexity of the microbiota–gut–brain axis, which represents the network governing homeostasis through nervous, endocrine, immune, and metabolic pathways. The present manuscript is dedicated to identifying various neuronal cytotypes belonging to ENS in baseline conditions. The second part of the study provides evidence on how these very same neurons are altered during Parkinson’s disease. In fact, although being defined as a movement disorder, Parkinson’s disease features a number of degenerative alterations, which often anticipate motor symptoms. Among these, the GI tract is often involved, and for this reason, it is important to assess its normal and pathological structure. A deeper knowledge of the ENS is expected to improve the understanding of diagnosis and treatment of Parkinson’s disease.

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Prion Diseases and the Gastrointestinal Tract

Canadian Journal of Gastroenterology ◽

10.1155/2006/184528 ◽

2006 ◽

Vol 20 (1) ◽

pp. 18-24 ◽

Cited By ~ 21

Author(s):

Gwynivere A Davies ◽

Adam R Bryant ◽

John D Reynolds ◽

Frank R Jirik ◽

Keith A Sharkey

Keyword(s):

Nervous System ◽

Dendritic Cells ◽

Enteric Nervous System ◽

Prion Protein ◽

Cellular Prion Protein ◽

Transmissible Spongiform Encephalopathies ◽

Spongiform Encephalopathy ◽

Gi Tract ◽

Spongiform Encephalopathies ◽

The Brain

The gastrointestinal (GI) tract plays a central role in the pathogenesis of transmissible spongiform encephalopathies. These are human and animal diseases that include bovine spongiform encephalopathy, scrapie and Creutzfeldt-Jakob disease. They are uniformly fatal neurological diseases, which are characterized by ataxia and vacuolation in the central nervous system. Alhough they are known to be caused by the conversion of normal cellular prion protein to its infectious conformational isoform (PrPsc) the process by which this isoform is propagated and transported to the brain remains poorly understood. M cells, dendritic cells and possibly enteroendocrine cells are important in the movement of infectious prions across the GI epithelium. From there, PrPscpropagation requires B lymphocytes, dendritic cells and follicular dendritic cells of Peyer’s patches. The early accumulation of the disease-causing agent in the plexuses of the enteric nervous system supports the contention that the autonomic nervous system is important in disease transmission. This is further supported by the presence of PrPscin the ganglia of the parasympathetic and sympathetic nerves that innervate the GI tract. Additionally, the lymphoreticular system has been implicated as the route of transmission from the gut to the brain. Although normal cellular prion protein is found in the enteric nervous system, its role has not been characterized. Further research is required to understand how the cellular components of the gut wall interact to propagate and transmit infectious prions to develop potential therapies that may prevent the progression of transmissible spongiform encephalopathies.

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Adult enteric nervous system in health is maintained by a dynamic balance between neuronal apoptosis and neurogenesis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1619406114 ◽

2017 ◽

Vol 114 (18) ◽

pp. E3709-E3718 ◽

Cited By ~ 79

Author(s):

Subhash Kulkarni ◽

Maria-Adelaide Micci ◽

Jenna Leser ◽

Changsik Shin ◽

Shiue-Cheng Tang ◽

...

Keyword(s):

Nervous System ◽

Enteric Nervous System ◽

Dynamic Balance ◽

Neuronal Cell ◽

Cell Loss ◽

Enteric Neurons ◽

Phosphatase And Tensin Homolog ◽

Tensin Homolog ◽

Myenteric Ganglia

According to current dogma, there is little or no ongoing neurogenesis in the fully developed adult enteric nervous system. This lack of neurogenesis leaves unanswered the question of how enteric neuronal populations are maintained in adult guts, given previous reports of ongoing neuronal death. Here, we confirm that despite ongoing neuronal cell loss because of apoptosis in the myenteric ganglia of the adult small intestine, total myenteric neuronal numbers remain constant. This observed neuronal homeostasis is maintained by new neurons formed in vivo from dividing precursor cells that are located within myenteric ganglia and express both Nestin and p75NTR, but not the pan-glial marker Sox10. Mutation of the phosphatase and tensin homolog gene in this pool of adult precursors leads to an increase in enteric neuronal number, resulting in ganglioneuromatosis, modeling the corresponding disorder in humans. Taken together, our results show significant turnover and neurogenesis of adult enteric neurons and provide a paradigm for understanding the enteric nervous system in health and disease.

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Regional cytoarchitecture of the adult and developing mouse enteric nervous system

10.1101/2021.07.16.452735 ◽

2021 ◽

Author(s):

Ryan Hamnett ◽

Lori Bowe Dershowitz ◽

Vandana Sampathkumar ◽

Ziyue Wang ◽

Vincent De Andrade ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Enteric Nervous System ◽

Gi Tract ◽

The Central Nervous System

The enteric nervous system (ENS) populates the gastrointestinal (GI) tract and controls GI function. In contrast to the central nervous system, macrostructure of the ENS has been largely overlooked. Here, we visually and computationally demonstrate that the ENS is organized in circumferential stripes that regionally differ in development and neuronal composition. This characterization provides a blueprint for future understanding of region-specific GI function and identifying ENS structural correlates of GI disorders.

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V. Genes, lineages, and tissue interactions in the development of the enteric nervous system

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1998.275.5.g869 ◽

1998 ◽

Vol 275 (5) ◽

pp. G869-G873

Author(s):

Michael D. Gershon

Keyword(s):

Nervous System ◽

Enteric Nervous System ◽

Neurotrophic Factor ◽

Protein A ◽

Growth Factor Receptor ◽

Enteric Neurons ◽

Gi Tract ◽

Tissue Interactions ◽

Multipotent Cells ◽

V Genes

The enteric nervous system is derived from the vagal, rostral-truncal, and sacral levels of the neural crest. Because the crest-derived population that colonizes the bowel contains multipotent cells, terminal differentiation occurs in the gut and is influenced by both the enteric microenvironment and the responsivity of multiple lineages of precursors. Enteric growth factor-receptor combinations, which promote the development of enteric neurons and/or glia in most of the gastrointestinal (GI) tract, include glial cell line-derived neurotrophic factor-GFRα-1-Ret, NT-3-TrkC, a still-to-be-identified neuropoietic cytokine-ciliary neurotrophic factor receptor-α, serotonin (5-HT)-5-HT2B, and LBP110, a 110-kDa laminin-1 binding protein. A qualitatively different effect is shown by the peptide-receptor combination ET-3-ETB, which inhibits neuronal differentiation and appears to prevent the premature differentiation of enteric neurons before colonization of the GI tract has been completed (resulting in aganglionosis of the terminal colon).

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The Enteric Nervous System and Its Emerging Role as a Therapeutic Target

Gastroenterology Research and Practice ◽

10.1155/2020/8024171 ◽

2020 ◽

Vol 2020 ◽

pp. 1-13

Author(s):

Mark A. Fleming ◽

Lubaina Ehsan ◽

Sean R. Moore ◽

Daniel E. Levin

Keyword(s):

Nervous System ◽

Enteric Nervous System ◽

Therapeutic Target ◽

Normal Function ◽

Gi Tract ◽

Current Therapies ◽

The Central Nervous System ◽

Local Reflex ◽

And Function ◽

Myenteric Plexuses

The gastrointestinal (GI) tract is innervated by the enteric nervous system (ENS), an extensive neuronal network that traverses along its walls. Due to local reflex circuits, the ENS is capable of functioning with and without input from the central nervous system. The functions of the ENS range from the propulsion of food to nutrient handling, blood flow regulation, and immunological defense. Records of it first being studied emerged in the early 19th century when the submucosal and myenteric plexuses were discovered. This was followed by extensive research and further delineation of its development, anatomy, and function during the next two centuries. The morbidity and mortality associated with the underdevelopment, infection, or inflammation of the ENS highlight its importance and the need for us to completely understand its normal function. This review will provide a general overview of the ENS to date and connect specific GI diseases including short bowel syndrome with neuronal pathophysiology and current therapies. Exciting opportunities in which the ENS could be used as a therapeutic target for common GI diseases will also be highlighted, as the further unlocking of such mechanisms could open the door to more therapy-related advances and ultimately change our treatment approach.

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Ret loss-of-function decreases enteric neural crest progenitor proliferation and restricts developmental fate potential during enteric nervous system development

10.1101/2021.12.28.474390 ◽

2021 ◽

Author(s):

Elizabeth Vincent ◽

Sumantra Chatterjee ◽

Gabrielle H Cannon ◽

Dallas Auer ◽

Holly Ross ◽

...

Keyword(s):

Nervous System ◽

Motor Neuron ◽

Neural Crest ◽

Enteric Nervous System ◽

Expression Patterns ◽

Critical Role ◽

Nervous System Development ◽

Developmental Trajectory ◽

Loss Of Function ◽

Gi Tract

The receptor tyrosine kinase gene RET plays a critical role in the fate specification of enteric neural crest cells (ENCCs) during enteric nervous system (ENS) development. Ret loss of function (LoF) alleles are associated with Hirschsprung disease (HSCR), which is marked by aganglionosis of the gastrointestinal (GI) tract. ENCCs invade the developing GI tract, proliferate, migrate caudally, and differentiate into all of the major ENS cell types. Although the major phenotypic consequences, and the underlying transcriptional changes from Ret LoF in the developing ENS have been described, its cell type and state-specific effects are unknown. Consequently, we performed single-cell RNA sequencing (scRNA-seq) on an enriched population of ENCCs isolated from the developing GI tract of Ret null heterozygous and homozygous mouse embryos at embryonic day (E)12.5 and E14.5. We demonstrate four significant findings: (1) Ret-expressing ENCCs are a heterogeneous population composed of ENS progenitors as well as glial and neuronal committed cells; (2) neurons committed to a predominantly inhibitory motor neuron developmental trajectory are not produced under Ret LoF, leaving behind a mostly excitatory motor neuron developmental program; (3) HSCR-associated and Ret gene regulatory network genes exhibit distinct expression patterns across Ret-expressing ENCC cells with their expression impacted by Ret LoF; and (4) Ret deficiency leads to precocious differentiation and reduction in the number of proliferating ENS precursors. Our results support a model in which Ret contributes to multiple distinct cellular phenotypes and that Ret LoF contributes to GI aganglionosis in multiple independent ways.

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A120 INFLUENCE OF THE MICROBIOTA ON THE POSTNATAL DEVELOPMENT OF THE ENTERIC NERVOUS SYSTEM IS DEPENDENT ON MOUSE STRAIN

Journal of the Canadian Association of Gastroenterology ◽

10.1093/jcag/gwz047.119 ◽

2020 ◽

Vol 3 (Supplement_1) ◽

pp. 140-141

Author(s):

J Huang ◽

J Popov ◽

F Markovic ◽

E Ratcliffe

Keyword(s):

Nervous System ◽

Enteric Nervous System ◽

Postnatal Development ◽

Mouse Strain ◽

Host Response ◽

Inbred Mouse Strain ◽

Neuronal Cell ◽

Postnatal Life ◽

Neuronal Marker ◽

Nih Swiss

Abstract Background Gastrointestinal function depends on the normal formation of the enteric nervous system (ENS) during fetal and postnatal development. Prior research in an outbred strain of mice (NIH Swiss) has shown that the absence of the gut microbiome in germ-free (GF) mice results in morphological and functional abnormalities of the ENS compared to specific pathogen free (SPF) mice, including an alteration in proportion of nitrergic neurons. Increasing research has been suggesting that the genetic background of the host can impact the host response to the GF state. Aims We tested the hypothesis that the absence of the microbiome in an inbred mouse strain (C57BL/6) could influence the development of the ENS during early postnatal life. Methods C57BL/6 GF and SPF mice were sacrificed at postnatal day 3 (P3) and P28 (n=4–5 per group). Ileum and colon were collected at P3 and P28 and processed for whole mount preparations. The neuronal network in the myenteric plexus was visualized by immunohistochemistry using antibodies against the pan-neuronal marker PGP9.5. Neuronal cell bodies and nitrergic neurons were identified by immunolabeling with antibodies to the neuronal marker HuC/D and to neuronal nitric oxide (nNOS). Nerve fibre density was quantified by measuring the percentage of PGP9.5-positive pixels (μm2) compared to the whole field using an image analysis program (Volocity; reported as %). Proportions of nitrergic to myenteric neurons were determined by manually counting (blinded) the number of nNOS-positive neurons and dividing by the total number of HuC/D-positive cells per field (reported as %). Results We found a significant increase in nerve density at P3 in the GF compared to SPF mice in both ileum (43% vs. 37%; p=0.03) and colon (45% vs. 39%; p=0.03). No significant differences, however, were identified between GF and SPF mice at P28 in either ileum (27% vs. 25%; n.s.) or colon (31% vs. 32%; n.s.). At P3, no significant differences in proportion of nitrergic neurons were seen in the GF compared to SPF ileum (27% vs. 27%; n.s.). Conclusions In contrast to earlier observations in the NIH Swiss mice, in which GF mice had decreased nerve density and an increase in nitrergic neurons at P3, our findings reveal an opposite response in nerve density in the C57BL/6 mice and no change in nitrergic neurons. These results suggest that the genetic strain of the mouse model can influence the host response to changes in the microbiome. Further studies are needed to further elucidate potential underlying mechanisms. Funding Agencies NSERC

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Hyperglycaemia-Induced Downregulation in Expression of nNOS Intramural Neurons of the Small Intestine in the Pig

International Journal of Molecular Sciences ◽

10.3390/ijms20071681 ◽

2019 ◽

Vol 20 (7) ◽

pp. 1681 ◽

Cited By ~ 6

Author(s):

Michał Bulc ◽

Katarzyna Palus ◽

Michał Dąbrowski ◽

Jarosław Całka

Keyword(s):

Nitric Oxide ◽

Nervous System ◽

Small Intestine ◽

Enteric Nervous System ◽

Molecular Mechanisms ◽

Muscle Relaxation ◽

Biologically Active ◽

Enteric Neurons ◽

Smooth Muscle Relaxation ◽

Gi Tract

Diabetic autonomic peripheral neuropathy (PN) involves a broad spectrum of organs. One of them is the gastrointestinal (GI) tract. The molecular mechanisms underlying the pathogenesis of digestive complications are not yet fully understood. Digestion is controlled by the central nervous system (CNS) and the enteric nervous system (ENS) within the wall of the GI tract. Enteric neurons exert regulatory effects due to the many biologically active substances secreted and released by enteric nervous system (ENS) structures. These include nitric oxide (NO), produced by the neural nitric oxide synthase enzyme (nNOS). It is a very important inhibitory factor, necessary for smooth muscle relaxation. Moreover, it was noted that nitrergic innervation can undergo adaptive changes during pathological processes. Additionally, nitrergic neurons function may be regulated through the synthesis of other active neuropeptides. Therefore, in the present study, using the immunofluorescence technique, we first examined the influence of hyperglycemia on the NOS- containing neurons in the porcine small intestine and secondly the co-localization of nNOS with vasoactive intestinal polypeptide (VIP), galanin (GAL) and substance P (SP) in all plexuses studied. Following chronic hyperglycaemia, we observed a reduction in the number of the NOS-positive neurons in all intestinal segments studied, as well as an increased in investigated substances in nNOS positive neurons. This observation confirmed that diabetic hyperglycaemia can cause changes in the neurochemical characteristics of enteric neurons, which can lead to numerous disturbances in gastrointestinal tract functions. Moreover, can be the basis of an elaboration of these peptides analogues utilized as therapeutic agents in the treatment of GI complications.

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