Content uploaded by Winfried Neuhuber
Author content
All content in this area was uploaded by Winfried Neuhuber on Oct 11, 2017
Content may be subject to copyright.
A preview of the PDF is not available
Sensory vagal innervation of the rat esophagus and cardia: a light and electron microscopic anterograde tracing study
Abstract
Wheat germ agglutinin-horseradish peroxidase conjugate (WGA-HRP) was injected into nodose ganglia of rats. In the esophagus and cardia, dense networks of anterogradely labeled fibers and beaded terminal-like arborisations were observed around myenteric ganglia after combined histochemistry for HRP and acetylcholinesterase. The muscularis externa and interna proper were free of label except for a few traversing fibers. Submucosal and mucosal labeling was rather sparse except for the most oral part of the esophagus, where a dense mucosal innervation was found. Control experiments including WGA-HRP injections into the cervical vagus nerve, nodose ganglion injections after supranodose vagotomy, and anterograde [3H]leucine tracing from the nodose ganglion indicated that all labeled fibers in the esophagus and cardia originated from sensory neurons in the nodose ganglion. Electron microscopy revealed that labeled vagal sensory terminals related to myenteric ganglia were mostly large, mitochondria-rich profiles located predominantly on the surface of the ganglia. Specialized membrane contacts connected sensory terminals with other unlabeled profiles possibly derived from intrinsic neurons. The polarity of these contacts suggested the vagal sensory terminals to be presynaptic to intrinsic neurons of the myenteric ganglia. A hypothesis is formulated postulating a mechanoreceptive role for 'myenteric' vagal sensory terminals, providing both the brainstem (via the vagus nerve) and, by synaptic action upon intrinsic neurons, the myenteric plexus with information on tension and motility of the esophagus and cardia.
... Based on indirect evidence obtained from guinea pig stomach (30), they are thought to sense the level of tension, whether generated by passive tissue stretch or generated by active muscle contraction. Ultrastructural observations also support a mechanosensory function (31). Combined with recent immunohistochemical data, ultrastructural observations suggest additional chemosensory functions and complex interactions of IGLEs with myenteric neurons and calcitonin gene-related peptide-positive spinal afferents passing through myenteric ganglia (31)(32)(33), suggesting additional chemosensory functions. ...
... Ultrastructural observations also support a mechanosensory function (31). Combined with recent immunohistochemical data, ultrastructural observations suggest additional chemosensory functions and complex interactions of IGLEs with myenteric neurons and calcitonin gene-related peptide-positive spinal afferents passing through myenteric ganglia (31)(32)(33), suggesting additional chemosensory functions. Finally, mucosal endings have been traced to the entire gastrointestinal tract, with the highest density in the villi and crypts of the proximal small intestine (34,35). ...
Given the crucial role of the gastrointestinal tract and associated organs in handling nutrient assimilation and metabolism, it has long been known that its communication with the brain is important for the control of ingestive behavior and body weight regulation. It is also clear that gut-brain communication is bidirectional and utilizes both rapid neural and slower humoral mechanisms and pathways. However, progress in understanding these mechanisms and leveraging them for the treatment of obesity and metabolic disease has been hindered by the enormous dimension of the gut mucosa, the complexity of the signaling systems, and lack of specific tools. With the ascent of modern neurobiological technology, our understanding of the role of vagal afferents in gut-brain communication has begun to change. The first function-specific populations of vagal afferents providing nutritional feedback as well as feed-forward signals have been identified with genetics-guided methodology, and it is hoped that extension of the methodology to other neural communication pathways will follow soon. Currently, efficient clinical leveraging of gut-brain communication to treat obesity and metabolic disease is limited to a few gut hormones, but a more complete understanding of function-specific and projection-specific neuronal populations should make it possible to develop selective and more effective neuromodulation approaches.
... In fact, IGLEs are also abundant in the stomach and the small and large intestines , indicating that they play an important role throughout the gastrointestinal tract. Their location, exclusively in myenteric ganglia, led to suggestions that they may be the efferent collaterals of extrinsic afferents (Berthoud and Powley, 1992) or that they may function as mixed afferent and efferent endings (Neuhuber, 1987). Whereas the present study showed that IGLEs are the transduction sites of tension-sensitive mechanoreceptors , it does not exclude the possibility that they may also play an efferent role, because they appear to make close contacts with enteric neurons (Rodrigo et al., 1975;Neuhuber, 1987;Berthoud, 1995). ...
... Their location, exclusively in myenteric ganglia, led to suggestions that they may be the efferent collaterals of extrinsic afferents (Berthoud and Powley, 1992) or that they may function as mixed afferent and efferent endings (Neuhuber, 1987). Whereas the present study showed that IGLEs are the transduction sites of tension-sensitive mechanoreceptors , it does not exclude the possibility that they may also play an efferent role, because they appear to make close contacts with enteric neurons (Rodrigo et al., 1975;Neuhuber, 1987;Berthoud, 1995). However, a recent study examining fos expression after electrical stimulation of the vagus nerve suggested that such an efferent role for IGLEs or other vagal afferents is likely to be rather limited (Zheng et al., 1997). ...
... Vagal afferent structures in the gastrointestinal tract can be grouped into muscular and mucosal sensors. IGLEs which wrap around myenteric ganglia sandwiched between outer and inner layers of the tunica muscularis function as low-threshold mechanosensors ( Fig. 3d; Neuhuber, 1987;Berthoud and Powley, 1992;Zagorodnyuk and Brookes, 2000;Zagorodnyuk et al., 2001). They extend throughout the vagal innervation territory from the esophagus to the distal colon (Wang and Powley, 2000) and mediate essential satiety signals (Bai et al., 2019). ...
Due to its pivotal role in autonomic networks, the vagus attracts continuous interest from both basic scientists and clinicians. In particular, recent advances in vagus nerve stimulation strategies and their application to pathological conditions beyond epilepsy provide a good opportunity to recall basic features of vagal peripheral and central anatomy. In addition to the “classical” vagal brainstem nuclei, i.e., dorsal motor nucleus, nucleus ambiguus and nucleus tractus solitarii, the spinal trigeminal and paratrigeminal nuclei come into play as targets of vagal afferents. On the other hand, the nucleus of the solitary tract receives and integrates not only visceral but also somatic afferents. Thus, the vagus system participates significantly in what may be defined as “somato-visceral interface”.
... As the third type of nerve fibers investigated in the myenteric plexus of the esophagus lacked ChAT but showed a myelin sheath, we came to the conclusion that they can be classified as afferent nerve fibers. Possible origins for these afferents are intraganglionic laminar endings (IGLEs) and intramuscular arrays (IMAs) [47][48][49], playing a crucial role in the sensory physiology of the esophagus: As far as is known, primary afferent fibers serve as receptors for (1) muscle tension, (2) mucosal mechanical and chemical stimuli, and (3) mucosal tension, and therefore are significant for swallowing. In this regard, several studies could confirm the correlation of sensory nerve impairment and functional disorders of the esophagus such as functional globus, noncardiac chest pain, and dysphagia [50][51][52]. ...
Multiple sclerosis (MS) has been considered to specifically affect the central nervous system (CNS) for a long time. As autonomic dysfunction including dysphagia can occur as accompanying phenomena in patients, the enteric nervous system has been attracting increasing attention over the past years. The aim of this study was to identify glial and myelin markers as potential target structures for autoimmune processes in the esophagus. RT-PCR analysis revealed glial fibrillary acidic protein (GFAP), proteolipid protein (PLP), and myelin basic protein (MBP) expression, but an absence of myelin oligodendrocyte glycoprotein (MOG) in the murine esophagus. Selected immunohistochemistry for GFAP, PLP, and MBP including transgenic mice with cell-type specific expression of PLP and GFAP supported these results by detection of (1) GFAP, PLP, and MBP in Schwann cells in skeletal muscle and esophagus; (2) GFAP, PLP, but no MBP in perisynaptic Schwann cells of skeletal and esophageal motor endplates; (3) GFAP and PLP, but no MBP in glial cells surrounding esophageal myenteric neurons; and (4) PLP, but no GFAP and MBP in enteric glial cells forming a network in the esophagus. Our results pave the way for further investigations regarding the involvement of esophageal glial cells in the pathogenesis of dysphagia in MS.
... Parasympathetic input to both plexi is carried by efferent vagal fibres and fibres from the pelvic plexus . The rat vagus nerve emerging from the cranial cavity contains many thousands of fibres (Prechtl and Powley, 1990) and projects to the stomach and proximal small intestine (and possibly as far as the mid colon in some species) (Gabella, 1976); the great proportion are afferent axons terminating in various different areas of the tract (oesophagus, Neuhuber, 1987;stomach, Berthoud and Powley, 1992) but also a small percentage are parasympathetic efferent fibres (stomach and small intestine, Connors et al, 1983;Berthoud et al., 1991). The sympathetic input is carried in the mesenteric nerves issued by the prevertebral ganglia (outlined above). ...
The development and comparison of structural features of the pelvic ganglion in male and female rats was investigated with morphometric and histochemical techniques in light and electron microscopes. Pelvic ganglia from adult rats were sexually dimorphic in volume (approximately 0.3mm³ in the male and 0.18mm³ in the female), neuron number (12,506 ± 668 neurons in the male and 6,845 ± 717 in the female) and average neuron size. At three weeks of age ganglion volume and neuron number were similar to the adult and were, therefore, already distinctly sexually dimorphic, although the smaller average neuron size showed no gender difference. In contrast, at birth pelvic ganglia revealed no gender-related differences in either volume, neuron number or size. Whereas ganglion volume and neuronal size were less than in the older animal groups, neuron numbers in newborn ganglia from both sexes were similar to those in adult male rats. Ganglia from adult males that had been castrated before puberty, were similar in volume and neuron number to unoperated animals, although neuronal size was significantly reduced. Neuronal death was observed in ganglia from newborn rats at similar extents in both sexes. Apoptotic neurons were also present in ganglia from 7-day old rats, when the extent of cell loss appeared greater in the female than in the male. It is concluded that the main features of the sexual dimorphism in the pelvic ganglion become established after birth and before puberty. Increasing testosterone levels in the early post-natal period probably influence the ontogeny of the pelvic ganglion, acting either directly on the neurons, or indirectly via trophic factors released from developing pelvic organs. Evidence suggests that target-derived factors, effected by hormone or not, play a role in neuronal survival and neuronal growth in the pelvic ganglion.
... The vagal afferent innervation of the esophageal mucosa is less understood. The anterograde tracing studies and immunostaining combined with vagal neurectomies (i.e., cuts of various segments of the vagus nerve) found that the vagal afferent innervation is very dense in the uppermost portion of the esophagus, but appears relatively rare or absent in the more distal segments of the esophagus [3,8,9] (reviewed in [10,11]). In particularly it appeared that 1 3 the body of the esophagus in the rat is almost free of vagal afferent mucosal innervation [10]. ...
The vagal afferent nerves regulate swallowing and esophageal motor reflexes. However, there are still gaps in the understanding of vagal afferent innervation of the esophageal mucosa. Anatomical studies found that the vagal afferent mucosal innervation is dense in the upper esophageal sphincter area but rare in more distal segments of the esophagus. In contrast, electrophysiological studies concluded that the vagal afferent nerve fibers also densely innervate mucosa in more distal esophagus. We hypothesized that the transfection of vagal afferent neurons with adeno-associated virus vector encoding green fluorescent protein (AAV-GFP) allows to visualize vagal afferent nerve fibers in the esophageal mucosa in the mouse. AAV-GFP was injected into the vagal jugular/nodose ganglia in vivo to sparsely label vagal afferent nerve fibers. The esophageal tissue was harvested 4–6 weeks later, the GFP signal was amplified by immunostaining, and confocal optical sections of the entire esophagi were obtained. We found numerous GFP-labeled fibers in the mucosa throughout the whole body of the esophagus. The GFP-labeled mucosal fibers were located just beneath the epithelium, branched repeatedly, had mostly longitudinal orientation, and terminated abruptly without forming terminal structures. The GFP-labeled mucosal fibers were concentrated in random areas of various sizes in which many fibers could be traced to a single parental axon. We conclude that the vagus nerves provide a robust afferent innervation of the mucosa throughout the whole body of the esophagus in the mouse. Vagal mucosal fibers may contribute to the sensing of intraluminal content and regulation of swallowing and other reflexes.
Interozeptive Afferenzen vermitteln dem Gehirn den Zustand des „inneren Milieus“, das geeignete Reaktionen einleitet, um die Homöostase zu sichern bzw. ihre Störung allostatisch zu korrigieren. In diesem Artikel wird u. a. die Möglichkeit diskutiert, dass Interozeptoren auch die zwischen den Brust- und Bauchorganen wirkenden Adhäsionskräfte detektieren und deren zentralnervöse Integration wesentlich zum Bewusstsein unseres „materiellen Selbst“ beiträgt. Osteopathische viszerale Techniken greifen in dieses Kräftespiel ein und beeinflussen so die Interozeption des Patienten.
Each organism must regulate its internal state in a metabolically efficient way as it interacts in space and time with an ever-changing and only partly predictable world. Success in this endeavor is largely determined by the ongoing communication between brain and body, and the vagus nerve is a crucial structure in that dialogue. In this review, we introduce the novel hypothesis that the afferent vagus nerve is engaged in signal processing rather than just signal relay. New genetic and structural evidence of vagal afferent fiber anatomy motivates two hypotheses: (1) that sensory signals informing on the physiological state of the body compute both spatial and temporal viscerosensory features as they ascend the vagus nerve, following patterns found in other sensory architectures, such as the visual and olfactory systems; and (2) that ascending and descending signals modulate one another, calling into question the strict segregation of sensory and motor signals, respectively. Finally, we discuss several implications of our two hypotheses for understanding the role of viscerosensory signal processing in predictive energy regulation (i.e., allostasis) as well as the role of metabolic signals in memory and in disorders of prediction (e.g., mood disorders).
The vagus nerve is an indispensable body-brain connection that controls vital aspects of autonomic physiology like breathing, heart rate, blood pressure, and gut motility, reflexes like coughing and swallowing, and survival behaviors like feeding, drinking, and sickness responses. Classical physiological studies and recent molecular/genetic approaches have revealed a tremendous diversity of vagal sensory neuron types that innervate different internal organs, with many cell types remaining poorly understood. Here, we review the state of knowledge related to vagal sensory neurons that innervate the respiratory, cardiovascular, and digestive systems. We focus on cell types and their response properties, physiological/behavioral roles, engaged neural circuits and, when possible, sensory receptors. We are only beginning to understand the signal transduction mechanisms used by vagal sensory neurons and upstream sentinel cells, and future studies are needed to advance the field of interoception to the level of mechanistic understanding previously achieved for our external senses.
This and the following three chapters will deal with the morphological and physiological characteristics of cutaneous, joint and tendon receptors that have been identified in vertebrates. A recent historical review of the morphology of cutaneous receptors was given by Munger (1971) in Chapter 17, Volume I of this Handbook and the present morphological account is largely restricted to those receptors which have been studied in detail both electrophysiologically and electron microscopically. This recent work has brought together single unit electrophysiological analysis of cutaneous receptors, which in several instances have been marked and identified during the physiological experiments, and detailed electron microscopical of these same receptors (in some instances those actually identified in the physiological experiments). This very detailed morphological investigation has allowed such accurate detail to be established, that some functions can be postulated on the basis of morphological structure. It is still not possible, however, to account for the transducer function of the receptors in molecular terms, and further technological developments, for example in histochemical technique, may be necessary before it is possible to account for diverse physiological responses from morphologically indistinguishable structures.
The enteric nervous system (ENS) is an independent integrative nervous system with most of the neurophysiological complexities found in the central nervous system. It is a third division of the autonomic nervous system, which functions as a brain in the gut placed in close apposition to the effector systems it controls. The ENS controls the musculature, secretory glands, and blood vasculature of the gastrointestinal tract and organizes the moment-to-moment activity of each effector into coordinated behavior that is adapted to the digestive state at the level of the whole gut and adaptive for homeostasis at the level of the functioning individual.
In the normal state one is largely unaware of prevailing conditions in the abdominal viscera apart from the rather vague sensations which signal the fullness of the stomach, of the distal colon and of the bladder. This is all the more surprising, because the visceral nerves contain a preponderance of afferent (sensory) fibres. In the vagus nerves (Fig. 1) the proportion of afferent axons is 80–90% (Daly and Evans, 1953; Agostini
et al., 1957), in the splanchnic nerves it is >50% (Foley, 1948) and in the pelvic nerves it is 30% (Ranson, 1921). Even these figures are probably too low, as Daly and Evans (1953) and Agostini
et al. (1957) have demonstrated that many visceral afferent fibres are nonmyelinated and exist in larger numbers than hitherto suspected. On the purely numerical basis of their afferent: efferent axons ratio, the visceral nerves should be regarded, therefore, principally as sensory nerves and only secondarily as motor nerves. This is in contrast to the classical attitude derived from studies on the autonomic nervous system, which has unduly emphasized visceral motor pathways.
For a long time, particularly following Langley’s work (see Gabella 1976), it was believed that the autonomic nervous system (vegetative or visceral) represented mainly or solely an efferent pathway. This view persisted even though early electrophysiological studies pointed out that visceral nerves contained a variety of afferent fibers. For instance, Adrian (1933), the pioneer in the single-fiber recording technique, described several different kinds of vagal afferent activity related to the cardiac and respiratory cycles. A few years later, Heymans and Neil (1937) discovered the carotid sinus baroreceptors whose discharge is related to the cardiac cycles. However, it took systematic histological analyses to provide quantitative information on the relative importance of the afferent side of visceral innervation. The work of Agostoni et al. (1957) in the cat and Evans and Murray (1954) in the rabbit represented principal contributions in this regard by showing that afferent fibers made up 80% of the vagal nerve. These observations were based upon light-microscopic comparison of the number of fibers in intact nerves with those in which efferent fibers had been eliminated by a bilateral transection central to the nodose ganglia. Even these light-microscopic histological studies indicated that a large proportion of unmyelinated fibers (approximately four-fifths) comprised the afferent vagal component. Light microscopy is only marginally useful for identifying unmyelinated fibers because of their very small size; recent data, in part electron-microscopic analyses, have confirmed the preponderance of afferent fibers in the vagal nerves, and showed that the unmylinated afferent component is even larger than earlier light-microscopic studies had suggested (Mei et al. 1980). Although the vagi do contain an exceptional number of afferent fibers, other visceral nerves similarly studied also proved to have a large afferent population.
