Abstract:Background: The enteric nervous system contains multiple classes of neurons, distinguishable by morphology, immunohistochemical markers, and projections; however, specific combinations differ between species. Here, types of enteric neurons in human colon were characterized immunohistochemically, using retrograde tracing combined with multiple labeling immunohistochemistry, focussing on non-motor neurons. Methods: The fluorescent carbocyanine tracer, DiI, was applied to the myenteric plexus in ex vivo preparati… Show more
“…Immunohistochemically, they contain choline acetyltransferase (ChAT), leu-enkephalin (ENK) and, partly, SP (Brehmer et al 2005 ; Beck et al 2009 ). These chemical characteristics correspond to ascending motor and interneurons identified by Porter et al ( 1997 ) and Humenick et al ( 2021 ). Fig.…”
Section: Structure Of Human Myenteric Neuronssupporting
confidence: 78%
“…The other method deciphered target tissues of axonal projections by tracing techniques (most successful with the carbocyanine tracer DiI; Wattchow et al 1995 , 1997 ; Porter et al 1997 , 2002 ; Humenick et al 2019 , 2021 ). These studies demonstrated projection distances for motoneurons of about 1 to 2 cm (for ascending and descending pathways to circular and longitudinal muscle, respectively) as well as for interneurons of about 4 to 7 cm (for ascending and descending interneurons, respectively).…”
Section: Structure Of Human Myenteric Neuronsmentioning
confidence: 99%
“…for nNOS and ChAT (Beck et al 2009 ). This corresponds to the chemical codes of circular muscle motor neurons (Wattchow et al 1997 ; Porter et al 1997 ) and descending interneurons (Porter et al 2002 ; Humenick et al 2021 ), respectively.…”
Section: Structure Of Human Myenteric Neuronsmentioning
confidence: 99%
“…Human type III neurons display immunoreactivity for CALB (Zetzmann et al 2018 ), and CALR reactivity was demonstrated in some of them (Brehmer et al 2004b ). Tracing studies in the human colon have assigned neurons with ChAT+/CALB+ and ChAT+/CALR+ immunoreactivity to ascending and descending interneurons, respectively (Humenick et al 2021 ). However, on the one hand, long-dendritic neurons in the human colon have not yet been successfully demonstrated by NF-staining (apart from single exceptions; Beck et al 2009 ), and on the other hand, a specific chemical code of type III neurons in the human small intestine is not yet defined (Zetzmann et al 2018 ).…”
Section: Structure Of Human Myenteric Neuronsmentioning
Major advances in our understanding of the functional heterogeneity of enteric neurons are driven by the application of newly developed, innovative methods. In contrast to this progress, both animal and human enteric neurons are usually divided into only two morphological subpopulations, “Dogiel type II” neurons (with several long processes) and “Dogiel type I” neurons (with several short processes). This implies no more than the distinction of intrinsic primary afferent from all other enteric neurons. The well-known chemical and functional diversity of enteric neurons is not reflected by this restrictive dichotomy of morphological data. Recent structural investigations of human enteric neurons were performed by different groups which mainly used two methodical approaches, namely detecting the architecture of their processes and target-specific tracing of their axonal courses. Both methods were combined with multiple immunohistochemistry in order to decipher neurochemical codes. This review integrates these morphological and immunohistological data and presents a classification of human enteric neurons which we believe is not yet complete but provides an essential foundation for the further development of human gastrointestinal neuropathology.
“…Immunohistochemically, they contain choline acetyltransferase (ChAT), leu-enkephalin (ENK) and, partly, SP (Brehmer et al 2005 ; Beck et al 2009 ). These chemical characteristics correspond to ascending motor and interneurons identified by Porter et al ( 1997 ) and Humenick et al ( 2021 ). Fig.…”
Section: Structure Of Human Myenteric Neuronssupporting
confidence: 78%
“…The other method deciphered target tissues of axonal projections by tracing techniques (most successful with the carbocyanine tracer DiI; Wattchow et al 1995 , 1997 ; Porter et al 1997 , 2002 ; Humenick et al 2019 , 2021 ). These studies demonstrated projection distances for motoneurons of about 1 to 2 cm (for ascending and descending pathways to circular and longitudinal muscle, respectively) as well as for interneurons of about 4 to 7 cm (for ascending and descending interneurons, respectively).…”
Section: Structure Of Human Myenteric Neuronsmentioning
confidence: 99%
“…for nNOS and ChAT (Beck et al 2009 ). This corresponds to the chemical codes of circular muscle motor neurons (Wattchow et al 1997 ; Porter et al 1997 ) and descending interneurons (Porter et al 2002 ; Humenick et al 2021 ), respectively.…”
Section: Structure Of Human Myenteric Neuronsmentioning
confidence: 99%
“…Human type III neurons display immunoreactivity for CALB (Zetzmann et al 2018 ), and CALR reactivity was demonstrated in some of them (Brehmer et al 2004b ). Tracing studies in the human colon have assigned neurons with ChAT+/CALB+ and ChAT+/CALR+ immunoreactivity to ascending and descending interneurons, respectively (Humenick et al 2021 ). However, on the one hand, long-dendritic neurons in the human colon have not yet been successfully demonstrated by NF-staining (apart from single exceptions; Beck et al 2009 ), and on the other hand, a specific chemical code of type III neurons in the human small intestine is not yet defined (Zetzmann et al 2018 ).…”
Section: Structure Of Human Myenteric Neuronsmentioning
Major advances in our understanding of the functional heterogeneity of enteric neurons are driven by the application of newly developed, innovative methods. In contrast to this progress, both animal and human enteric neurons are usually divided into only two morphological subpopulations, “Dogiel type II” neurons (with several long processes) and “Dogiel type I” neurons (with several short processes). This implies no more than the distinction of intrinsic primary afferent from all other enteric neurons. The well-known chemical and functional diversity of enteric neurons is not reflected by this restrictive dichotomy of morphological data. Recent structural investigations of human enteric neurons were performed by different groups which mainly used two methodical approaches, namely detecting the architecture of their processes and target-specific tracing of their axonal courses. Both methods were combined with multiple immunohistochemistry in order to decipher neurochemical codes. This review integrates these morphological and immunohistological data and presents a classification of human enteric neurons which we believe is not yet complete but provides an essential foundation for the further development of human gastrointestinal neuropathology.
“…Long descending projections run for up to 70 mm down the colon, whereas long ascending neurons project for up to 43 mm. These long descending and ascending myenteric neurons would act as putative interneurons in polysynaptic polarized reflex pathways involved in propulsion and other possible intestinal functions [ 48 ].…”
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.
Quantitative data of biological systems provide valuable baseline information for understanding pathology, experimental perturbations, and computational modeling. In mouse colon, calcitonin gene‐related peptide (CGRP) is expressed by myenteric neurons with multiaxonal (Dogiel type II) morphology, characteristic of intrinsic primary afferent neurons (IPANs). Analogous neurons in other species and gut regions represent 5–35% of myenteric neurons. We aimed to quantify proportions of CGRP‐immunopositive (CGRP+) myenteric neurons. Colchicine‐treated wholemount preparations of proximal, mid, and distal colon were labeled for HuC/D, CGRP, nitric oxide synthase (NOS), and peripherin (Per). The pan‐neuronal markers (Hu+/Per+) co‐labeled 94% of neurons. Hu+/Per– neurons comprised ∼6%, but Hu‐/Per+ cells were rare. Thus, quantification was based on Hu+ myenteric neurons (8576 total; 1225 ± 239 per animal, n = 7). CGRP+ cell bodies were significantly larger than the average of all Hu+ neurons (329 ± 13 vs. 261 ± 12 μm2, p < .0001). CGRP+ neurons comprised 19% ± 3% of myenteric neurons without significant regional variation. NOS+ neurons comprised 42% ± 2% of myenteric neurons overall, representing a lower proportion in proximal colon, compared to mid and distal colon (38% ± 2%, 44% ± 2%, and 44% ± 3%, respectively). Peripherin immunolabeling revealed cell body and axonal morphology in some myenteric neurons. Whether all CGRP+ neurons were multiaxonal could not be addressed using peripherin immunolabeling. However, of 118 putatively multiaxonal neurons first identified based on peripherin immunoreactivity, all were CGRP+ (n = 4). In conclusion, CGRP+ myenteric neurons in mouse colon were comprehensively quantified, occurring within a range expected of a putative IPAN marker. All Per+ multiaxonal neurons, characteristic of Dogiel type II/IPAN morphology, were CGRP+.
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