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Sympathetic neuron firing and motor complexes. A Colonic EMG and lumbar colonic nerve recordings (central efferent side) showing ongoing motor complexes over ~10 minutes. Sympathetic firing increased during each motor complex. B A single motor complex showing sympathetic burst firing at close to 2Hz and single unit spikes.
Source publication
Enteric viscerofugal neurons provide a pathway by which the enteric nervous system (ENS), otherwise confined to the gut wall, can activate sympathetic neurons in prevertebral ganglia. Firing transmitted through these pathways is currently considered fundamentally mechanosensory. The mouse colon generates a cyclical pattern of neurogenic contractile...
Similar publications
Parkinson’s disease (PD) is associated with neuronal damage in the brain and gut. This work compares changes in the enteric nervous system (ENS) of commonly used mouse models of PD that exhibit central neuropathy and a gut phenotype. Enteric neuropathy was assessed in five mouse models: peripheral injection of MPTP; intracerebral injection of 6-OHD...
Citations
... In the mouse, spontaneous colonic motor complexes display 2 Hz rhythmic contractions driven by synchronized firing of cholinergic enteric excitatory motor neurons (Spencer et al., 2005(Spencer et al., , 2018. Colonic VFNs in mice fire bursts of action potentials phase-linked with this 2 Hz rhythmicity (Hibberd et al., 2020) consistent with VFNs and excitatory motor neurons sharing a common drive. VFN firing during colonic motor complexes continues when the muscle is pharmacologically paralyzed, indicating that synaptic drive from enteric neurons (rather than mechanosensitivity) predominates (Hibberd et al., 2020). ...
... Colonic VFNs in mice fire bursts of action potentials phase-linked with this 2 Hz rhythmicity (Hibberd et al., 2020) consistent with VFNs and excitatory motor neurons sharing a common drive. VFN firing during colonic motor complexes continues when the muscle is pharmacologically paralyzed, indicating that synaptic drive from enteric neurons (rather than mechanosensitivity) predominates (Hibberd et al., 2020). ...
... Viscerofugal neurons synaptically activate sympathetic postganglionic efferents, which project back to the gut (Hibberd et al., 2020) to inhibit motility, mostly via presynaptic inhibition in the myenteric plexus (Hirst and McKirdy, 1974) although direct effects on muscle also occur (Spencer et al., 1999), which may be relevant in post-operative ileus . Thus, the VFN-mediated reflex pathway, activated in concert with motility circuits, may provide negative feedback that limits excitatory drive to smooth muscle during CMCs. ...
Background and Aims
Viscerofugal neurons (VFNs) have cell bodies in the myenteric plexus and axons that project to sympathetic prevertebral ganglia. In animals they activate sympathetic motility reflexes and may modulate glucose metabolism and feeding. We used rapid retrograde tracing from colonic nerves to identify VFNs in human colon for the first time, using ex vivo preparations with multi-layer immunohistochemistry.
Methods
Colonic nerves were identified in isolated preparations of human colon and set up for axonal tracing with biotinamide. After fixation, labeled VFN cell bodies were subjected to multiplexed immunohistochemistry for 12 established nerve cell body markers.
Results
Biotinamide tracing filled 903 viscerofugal nerve cell bodies (n = 23), most of which (85%) had axons projecting orally before entering colonic nerves. Morphologically, 97% of VFNs were uni-axonal. Of 215 VFNs studied in detail, 89% expressed ChAT, 13% NOS, 13% calbindin, 9% enkephalin, 7% substance P and 0 of 123 VFNs expressed CART. Few VFNs contained calretinin, VIP, 5HT, CGRP, or NPY. VFNs were often surrounded by dense baskets of axonal varicosities, probably reflecting patterns of connectivity; VAChT+ (cholinergic), SP+ and ENK+ varicosities were most abundant around them. Human VFNs were diverse; showing 27 combinations of immunohistochemical markers, 4 morphological types and a wide range of cell body sizes. However, 69% showed chemical coding, axonal projections, soma-dendritic morphology and connectivity similar to enteric excitatory motor neurons.
Conclusion
Viscerofugal neurons are present in human colon and show very diverse combinations of features. High proportions express ChAT, consistent with cholinergic synaptic outputs onto postganglionic sympathetic neurons in prevertebral ganglia.
... called the second brain), autonomic nervous system, and neuroendocrine and immune pathways [14]. A recent study proposed another plausible pathway of visceral-fugal neurons, which can sense the happenings inside the gut wall and communicate this sensory information to other organs, such as the brain and spinal cord, which subsequently impacts cognition, mood, and general well-being [15]. Most neurotransmitters are also produced in the gut [16]. ...
Mental health conditions have been linked closely to an imbalance of microbiota in the gut, leading to disruption of the microbiome (dysbiosis). Several neurotransmitters, such as GABA (gamma-aminobutyric acid), serotonin, and glutamate, are produced in the gut, which are associated with anxiety and depressive symptoms. Mental health and the gut have been linked closely, and many mental illnesses have been associated with gut dysbiosis. Probiotics are marketed to improve gut health, act as mood enhancers, and be effective in reducing stress as unregulated over-the-counter supplements. Given healthcare disparities and patient-doctor gaps across the globe, this review aims to appraise the literature on probiotics for the prevention and treatment of mental disorders. PubMed and Google Scholar databases were searched till March 2023 using the MeSH words "prebiotics," "probiotics," "synbiotics," and "psychobiotics." Out of 207 studies, 26 studies met the inclusion criteria and were included in the review. Studies suggest probiotics could be an effective and economical adjunct therapy; however, due to weak study design and low power, the results are inconclusive. Their use is not without risks, and healthcare providers need close supervision until more robust longitudinal studies are conducted to appraise their efficacy and safety profiles.
... The physiological role of this peripheral reflex pathway remains unclear. Recent experiments revealed synaptic activation of viscerofugal neurons during CMCs activates the peripheral reflex pathway, co-activating postganglionic sympathetic neurons to the same colonic region (Hibberd et al., 2020). ...
... Recordings from guinea pig viscerofugal neurons suggested they could be strongly driven by motor circuits (Hibberd et al., 2012b). In mice, the firing pattern of the myenteric plexus underlying CMCs (Spencer et al., 2018) also drives viscerofugal neurons and, in turn, sympathetic postganglionic neurons (Hibberd et al., 2020). Viscerofugal nerve terminals synapse on visceromotor and secretomotor sympathetic nerve cell bodies rather than vasoconstrictor neurons. ...
... The results of the present study suggest that the efferent output of the circuit (and of sympathetic activation more generally), is more likely to affect pellets propulsion than the CMCs that can activate the circuit. Indeed, recordings from the afferent and efferent arms of the circuit in mouse revealed potent activation by CMCs that did not interfere with their ongoing occurrence (Hibberd et al., 2020). That is, CMCs were not self-extinguishing, consistent with the present study and with mechanical recordings comparing CMCs in mouse colon with and without intact peripheral sympathetic circuits (Smith-Edwards et al., 2020). ...
The speed of pellet propulsion through the isolated guinea pig distal colon in vitro significantly exceeds in vivo measurements, suggesting a role for inhibitory mechanisms from sources outside the gut. The aim of this study was to investigate the effects of sympathetic nerve stimulation on three different neurogenic motor behaviors of the distal colon: transient neural events (TNEs), colonic motor complexes (CMCs), and pellet propulsion. To do this, segments of guinea pig distal colon with intact connections to the inferior mesenteric ganglion (IMG) were set up in organ baths allowing for simultaneous extracellular suction electrode recordings from smooth muscle, video recordings for diameter mapping, and intraluminal manometry. Electrical stimulation (1-20 Hz) of colonic nerves surrounding the inferior mesenteric artery caused a statistically significant, frequency-dependent inhibition of TNEs, as well as single pellet propulsion, from frequencies of 5 Hz and greater. Significant inhibition of CMCs required stimulation frequencies of 10 Hz and greater. Phentolamine (3.6 μM) abolished effects of colonic nerve stimulation, consistent with a sympathetic noradrenergic mechanism. Sympathetic inhibition was constrained to regions with intact extrinsic nerve pathways, allowing normal motor behaviors to continue without modulation in adjacent extrinsically denervated regions of the same colonic segments. The results demonstrate differential sensitivities to sympathetic input among distinct neurogenic motor behaviors of the colon. Together with findings indicating CMCs activate colo-colonic sympathetic reflexes through the IMG, these results raise the possibility that CMCs may paradoxically facilitate suppression of pellet movement in vivo, through peripheral sympathetic reflex circuits.
... The independent nature of the ENS led Langley, in his classical definition of the autonomic nervous system (9), to include the ENS as a separate autonomic division. Not only is the ENS independent, it can also communicate via intestinofugal nerves with the prevertebral sympathetic ganglia that innervate it (10)(11)(12) and directly with the CNS (13). Intestinofugal neurons may be mechanosensitive, but they appear to be mainly driven by other intrinsic neurons through cholinergic synapses and, in the colon, provide a rhythmic output to sympathetic ganglia during an intestinal behavior called the colonic motor complex (11). ...
... Not only is the ENS independent, it can also communicate via intestinofugal nerves with the prevertebral sympathetic ganglia that innervate it (10)(11)(12) and directly with the CNS (13). Intestinofugal neurons may be mechanosensitive, but they appear to be mainly driven by other intrinsic neurons through cholinergic synapses and, in the colon, provide a rhythmic output to sympathetic ganglia during an intestinal behavior called the colonic motor complex (11). Intestinofugal neurons and sympathetic ganglia also provide a potential pathway for long, entirely peripheral intestino-intestinal reflexes (11). ...
... Intestinofugal neurons may be mechanosensitive, but they appear to be mainly driven by other intrinsic neurons through cholinergic synapses and, in the colon, provide a rhythmic output to sympathetic ganglia during an intestinal behavior called the colonic motor complex (11). Intestinofugal neurons and sympathetic ganglia also provide a potential pathway for long, entirely peripheral intestino-intestinal reflexes (11). ...
... The independent nature of the ENS led Langley, in his classical definition of the autonomic nervous system (9), to include the ENS as a separate autonomic division. Not only is the ENS independent, it can also communicate via intestinofugal nerves with the prevertebral sympathetic ganglia that innervate it (10)(11)(12) and directly with the CNS (13). Intestinofugal neurons may be mechanosensitive, but they appear to be mainly driven by other intrinsic neurons through cholinergic synapses and, in the colon, provide a rhythmic output to sympathetic ganglia during an intestinal behavior called the colonic motor complex (11). ...
... Not only is the ENS independent, it can also communicate via intestinofugal nerves with the prevertebral sympathetic ganglia that innervate it (10)(11)(12) and directly with the CNS (13). Intestinofugal neurons may be mechanosensitive, but they appear to be mainly driven by other intrinsic neurons through cholinergic synapses and, in the colon, provide a rhythmic output to sympathetic ganglia during an intestinal behavior called the colonic motor complex (11). Intestinofugal neurons and sympathetic ganglia also provide a potential pathway for long, entirely peripheral intestino-intestinal reflexes (11). ...
... Intestinofugal neurons may be mechanosensitive, but they appear to be mainly driven by other intrinsic neurons through cholinergic synapses and, in the colon, provide a rhythmic output to sympathetic ganglia during an intestinal behavior called the colonic motor complex (11). Intestinofugal neurons and sympathetic ganglia also provide a potential pathway for long, entirely peripheral intestino-intestinal reflexes (11). ...
Modern research on gastrointestinal behavior has revealed it to be a highly complex bidirectional process in which the gut sends signals to the brain, via spinal and vagal visceral afferent pathways, and receives sympathetic and parasympathetic inputs. Concomitantly, the enteric nervous system within the bowel, which contains intrinsic primary afferent neurons, interneurons, and motor neurons, also senses the enteric environment and controls the detailed patterns of intestinal motility and secretion. The vast microbiome that is resident within the enteric lumen is yet another contributor, not only to gut behavior, but to the bidirectional signaling process, so that the existence of a microbiota-gut-brain "connectome" has become apparent. The interaction between the microbiota, the bowel, and the brain now appears to be neither a top-down nor a bottom-up process. Instead, it is an ongoing, tripartite conversation, the outline of which is beginning to emerge and is the subject of this Review. We emphasize aspects of the exponentially increasing knowledge of the microbiota-gut-brain "connectome" and focus attention on the roles that serotonin, Toll-like receptors, and macrophages play in signaling as exemplars of potentially generalizable mechanisms.
... teric intestinofugal neurons (IFNs) which have cell bodies in the myenteric plexus and project to prevertebral ganglia where they excite sympathetic neurons.56,57 A recent study in the mouse colon showed that IFNs are activated during motor patterns mediated by enteric neuronal circuitry, driving parallel firing in prevertebral sympathetic neurons.58 This suggests that enteric nervous system activity can modulate the sympathetic nervous system. ...
Background
Postoperative ileus is common and is a major clinical problem. It has been widely studied in patients and in experimental models in laboratory animals. A wide variety of treatments have been tested to prevent or modify the course of this disorder.
Purpose
This review draws together information on animal studies of ileus with studies on human patients. It summarizes some of the conceptual advances made in understanding the mechanisms that underlie paralytic ileus. The treatments that have been tested in human subjects (both pharmacological and non‐pharmacological) and their efficacy are summarized and graded consistent with current clinical guidelines. The review is not intended to provide a comprehensive overview of ileus, but rather a general understanding of the major clinical problems associated with it, how animal models have been useful to elucidate key mechanisms and, finally, some perspectives from both scientists and clinicians as to how we may move forward with this debilitating yet common condition.
Sympathetic efferent axons regulate cardiac functions. However, the topographical distribution and morphology of cardiac sympathetic efferent axons remain insufficiently characterized due to the technical challenges involved in immunohistochemical labeling of the thick walls of the whole heart. In this study, flat‐mounts of the left and right atria and ventricles of FVB mice were immunolabeled for tyrosine hydroxylase (TH), a marker of sympathetic nerves. Atrial and ventricular flat‐mounts were scanned using a confocal microscope to construct montages. We found (1) In the atria: A few large TH‐immunoreactive (IR) axon bundles entered both atria, branched into small bundles and then single axons that eventually formed very dense terminal networks in the epicardium, myocardium and inlet regions of great vessels to the atria. Varicose TH‐IR axons formed close contact with cardiomyocytes, vessels, and adipocytes. Multiple intrinsic cardiac ganglia (ICG) were identified in the epicardium of both atria, and a subpopulation of the neurons in the ICG were TH‐IR. Most TH‐IR axons in bundles traveled through ICG before forming dense varicose terminal networks in cardiomyocytes. We did not observe varicose TH‐IR terminals encircling ICG neurons. (2) In the left and right ventricles and interventricular septum: TH‐IR axons formed dense terminal networks in the epicardium, myocardium, and vasculature. Collectively, TH labeling is achievable in flat‐mounts of thick cardiac walls, enabling detailed mapping of catecholaminergic axons and terminal structures in the whole heart at single‐cell/axon/varicosity scale. This approach provides a foundation for future quantification of the topographical organization of the cardiac sympathetic innervation in different pathological conditions.
The autonomic nervous system that regulates the gut is divided into sympathetic (SNS), parasympathetic (PNS), and enteric nervous systems (ENS). They inhibit, permit, and coordinate gastrointestinal motility, respectively. A fourth pathway, “extrinsic sensory neurons,” connect gut to the central nervous system, mediating sensation. The ENS resides within the gut wall and its activities are critical for life; ENS failure to populate the gut in development is lethal without intervention. “Viscerofugal neurons” are a distinctive class of enteric neurons, being the only type that escapes the gut wall. They form a unique circuit: their axons project out of the gut wall and activate sympathetic neurons, which then project back to the gut, and inhibit gut movements. For 80 years viscerofugal/sympathetic circuits were thought to have a restricted role, mediating simple sensory-motor reflexes. New data shows viscerofugal and sympathetic neurons behaving unexpectedly, compelling a re-evaluation of these circuits: both viscerofugal and sympathetic neurons transmit higher order, synchronized firing patterns that originate within the ENS. This identifies them as driving long-range motility control between different gut regions. There is need for gut motor control over distances beyond the range of ENS circuits, yet no mechanism has been identified to date. The entero-sympathetic circuits are ideally suited to meet this need. Here we provide an overview of the structure and functions of these peripheral sympathetic circuits, including new data showing the firing patterns generated by enteric networks can transmit through sympathetic neurons.
Of all the organ systems in the body, the gastrointestinal tract is the most complicated in terms of numbers of the structures involved, each with different functions, and the numbers and types of signaling molecules utilized. The digestion of food and absorption of nutrients, electrolytes and waters occurs in a hostile luminal environment that contains a large and diverse microbiota. At the core of regulatory control of the digestive and defensive functions of the gastrointestinal tract is the enteric nervous system (ENS), a complex system of neurons and glia in the gut wall. In this review, we discuss (i) the intrinsic neural control of gut functions involved in digestion, and (ii) how the ENS interacts with the immune system, gut microbiota and epithelium to maintain mucosal defense and barrier function. We highlight developments that have revolutionized our understanding of the physiology and pathophysiology of enteric neural control. These include the molecular architecture of the ENS, the organization and function of enteric motor circuits, and the roles of enteric glia. We explore the transduction of luminal stimuli by enteroendocrine cells, the regulation of intestinal barrier function by enteric neurons and glia, local immune control by the ENS and the role of the gut microbiota in regulating the structure and function of the ENS. Multifunctional enteric neurons work together with enteric glial cells, macrophages, interstitial cells and enteroendocrine cells integrating an array of signals to initiate outputs that are precisely regulated in space and time to control digestion and intestinal homeostasis.
