ORCID Profile
0000-0002-0009-2094
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Autonomic Nervous System | Foetal Development and Medicine | Cell Neurochemistry | Neurosciences
Publisher: American Physiological Society
Date: 04-2004
Abstract: Enteric neurons controlling various gut functions are prone to oxidative insults that might damage mitochondria (e.g., intestinal inflammation). To resume local energy supply, mitochondria need to be transported. We used MitoTracker dyes and confocal microscopy to investigate basic characteristics of mitochondrial transport in guinea pig myenteric neurites. During a 10-s observation of 1 mm nerve fiber, on average, three mitochondria were transported at an average speed of 0.41 ± 0.02 μm/s. Movement patterns were clearly erratic, and velocities were independent of mitochondrial size. The velocity oscillated periodically (∼6 s) but was not consistently affected by structures such as en route boutons, bifurcations, or stationary mitochondria. Also, mitochondria transported in opposite directions did not necessarily affect each others' mobility. Transport was blocked by microtubule disruption (100 μM colchicine), and destabilization (1 μM cytochalasin-D) or stabilization (10 μM phalloidin) of actin filaments, respectively, decreased (0.22 ± 0.02 μm/s, P 0.05) or increased (0.53 ± 0.02 μm/s, P 0.05) transport speed. Transport was inhibited by TTX (1 μM), and removal of extracellular Ca 2+ (plus 2 mM EGTA) had no effect. However, depletion of intracellular stores (thapsigargin) reduced (to 33%) and slowed the transport significantly (0.18 ± 0.02 μm/s, P 0.05), suggesting an important role for stored Ca 2+ in mitochondrial transport. Transport was also reduced (to 21%) by the mitochondrial uncoupler FCCP (1 μM) in a time-dependent fashion and slowed by oligomycin (10 μM). We conclude that mitochondrial transport is remarkably independent of structural nerve fiber properties. We also show that mitochondrial transport is TTX sensitive and speeds up by stabilizing actin and that functional Ca 2+ stores are required for efficient transport.
Publisher: Wiley
Date: 07-07-2003
Publisher: Elsevier BV
Date: 09-2016
DOI: 10.1016/J.YDBIO.2016.05.030
Abstract: Co-ordinated gastrointestinal function is the result of integrated communication between the enteric nervous system (ENS) and "effector" cells in the gastrointestinal tract. Unlike smooth muscle cells, interstitial cells, and the vast majority of cell types residing in the mucosa, enteric neurons and glia are not generated within the gut. Instead, they arise from neural crest cells that migrate into and colonise the developing gastrointestinal tract. Although they are "later" arrivals into the developing gut, enteric neural crest-derived cells (ENCCs) respond to many of the same secreted signalling molecules as the "resident" epithelial and mesenchymal cells, and several factors that control the development of smooth muscle cells, interstitial cells and epithelial cells also regulate ENCCs. Much progress has been made towards understanding the migration of ENCCs along the gastrointestinal tract and their differentiation into neurons and glia. However, our understanding of how enteric neurons begin to communicate with each other and extend their neurites out of the developing plexus layers to innervate the various cell types lining the concentric layers of the gastrointestinal tract is only beginning. It is critical for postpartum survival that the gastrointestinal tract and its enteric circuitry are sufficiently mature to cope with the influx of nutrients and their absorption that occurs shortly after birth. Subsequently, colonisation of the gut by immune cells and microbiota during postnatal development has an important impact that determines the ultimate outline of the intrinsic neural networks of the gut. In this review, we describe the integrated development of the ENS and its target cells.
Publisher: The Korean Society of Neurogastroenterology and Motility
Date: 07-2015
DOI: 10.5056/JNM15096
Publisher: Cold Spring Harbor Laboratory
Date: 20-01-2021
DOI: 10.1101/2021.01.19.427232
Abstract: Nutrient signals sensed by enteroendocrine cells are conveyed to the enteric nervous system (ENS) to initiate intestinal reflexes. We addressed whether there are specific enteric pathways dedicated to detecting different luminal nutrients. Calcium imaging was performed on intact jejunal preparations from Wnt1-cre R26R-GCaMP3 and Villin-cre R26R-GCaMP3 mice which express a fluorescent calcium indicator in their ENS or intestinal epithelium, respectively. Glucose, acetate, and L-phenylalanine were perfused onto the mucosa whilst imaging underlying enteric neurons. Nutrient transport or diffusion across the mucosa was mimicked by applying nutrients onto sensory nerve endings in a villus, or onto myenteric ganglia. The nutrients perfused onto the mucosa each elicited Ca 2+ transients in submucosal neurons and in distinct patterns of myenteric neurons. Notably, the neurochemical subtypes of myenteric neurons that responded differed between the nutrients, while submucosal responders were predominantly cholinergic. Nutrients applied into villi or onto ganglia did not elicit specific neuronal responses but did stimulate Ca 2+ signaling in the mucosal epithelium. These data suggest that nutrients are first detected at the level of the epithelium and that the ENS is capable of discriminating between different compositions of luminal content. Furthermore, our data show that responses to mucosal stimulation are primarily in the myenteric plexus and submucosal neurons respond secondarily.
Publisher: Elsevier BV
Date: 09-2016
Publisher: American Physiological Society
Date: 04-2003
DOI: 10.1152/AJPCELL.00437.2002
Abstract: Whole cell patch-cl recordings were made from cultured myenteric neurons taken from murine proximal colon. The micropipette contained Cs + to remove K + currents. Depolarization elicited a slowly activating time-dependent outward current ( I tdo ), whereas repolarization was followed by a slowly deactivating tail current ( I tail ). I tdo and I tail were present in ∼70% of neurons. We identified these currents as Cl − currents ( I Cl ), because changing the transmembrane Cl − gradient altered the measured reversal potential ( E rev ) of both I tdo and I tail with that for I tail shifted close to the calculated Cl − equilibrium potential ( E Cl ). I Cl are Ca 2+ -activated Cl − current [ I Cl(Ca) ] because they were Ca 2+ dependent. E Cl , which was measured from the E rev of I Cl(Ca) using a gramicidin perforated patch, was −33 mV. This value is more positive than the resting membrane potential (−56.3 ± 2.7 mV), suggesting myenteric neurons accumulate intracellular Cl − . ω-Conotoxin GIVA [0.3 μM N-type Ca 2+ channel blocker] and niflumic acid [10 μM known I Cl(Ca) blocker], decreased the I Cl(Ca) . In conclusion, these neurons have I Cl(Ca) that are activated by Ca 2+ entry through N-type Ca 2+ channels. These currents likely regulate postspike frequency adaptation.
Publisher: Frontiers Media SA
Date: 25-04-2017
Publisher: Elsevier BV
Date: 12-2003
DOI: 10.1016/J.COPH.2003.10.001
Abstract: The enteric nervous system consists of two ganglionated neural networks within the gut wall that contain as many neurons as the spinal cord. Connections exist between the neurons in these two networks, enabling motility and secretion to be coordinated. It is becoming increasingly apparent that Ca(2+) movements across the cell membrane and between various intracellular compartments play a major role in the regulation of neuronal excitability and neurotransmitter release.
Publisher: Springer Science and Business Media LLC
Date: 05-02-2020
DOI: 10.1038/S41586-020-1975-8
Abstract: Neural control of the function of visceral organs is essential for homeostasis and health. Intestinal peristalsis is critical for digestive physiology and host defence, and is often dysregulated in gastrointestinal disorders
Publisher: Springer Science and Business Media LLC
Date: 12-07-2023
DOI: 10.1038/S41586-023-06188-0
Abstract: The physiological functions of mast cells remain largely an enigma. In the context of barrier damage, mast cells are integrated in type 2 immunity and, together with immunoglobulin E (IgE), promote allergic diseases. Allergic symptoms may, however, facilitate expulsion of allergens, toxins and parasites and trigger future antigen avoidance 1–3 . Here, we show that antigen-specific avoidance behaviour in inbred mice 4,5 is critically dependent on mast cells hence, we identify the immunological sensor cell linking antigen recognition to avoidance behaviour. Avoidance prevented antigen-driven adaptive, innate and mucosal immune activation and inflammation in the stomach and small intestine. Avoidance was IgE dependent, promoted by Th2 cytokines in the immunization phase and by IgE in the execution phase. Mucosal mast cells lining the stomach and small intestine rapidly sensed antigen ingestion. We interrogated potential signalling routes between mast cells and the brain using mutant mice, pharmacological inhibition, neural activity recordings and vagotomy. Inhibition of leukotriene synthesis impaired avoidance, but overall no single pathway interruption completely abrogated avoidance, indicating complex regulation. Collectively, the stage for antigen avoidance is set when adaptive immunity equips mast cells with IgE as a telltale of past immune responses. On subsequent antigen ingestion, mast cells signal termination of antigen intake. Prevention of immunopathology-causing, continuous and futile responses against per se innocuous antigens or of repeated ingestion of toxins through mast-cell-mediated antigen-avoidance behaviour may be an important arm of immunity.
Publisher: eLife Sciences Publications, Ltd
Date: 04-02-2019
Publisher: Frontiers Media SA
Date: 2013
Publisher: Wiley
Date: 07-02-2019
DOI: 10.1002/GLIA.23596
Publisher: Springer Science and Business Media LLC
Date: 29-11-2017
DOI: 10.1038/NRGASTRO.2017.151
Abstract: Optogenetics and chemogenetics comprise a wide variety of applications in which genetically encoded actuators and indicators are used to modulate and monitor activity with high cellular specificity. Over the past 10 years, development of these genetically encoded tools has contributed tremendously to our understanding of integrated physiology. In concert with the continued refinement of probes, strategies to target transgene expression to specific cell types have also made much progress in the past 20 years. In addition, the successful implementation of optogenetic and chemogenetic techniques thrives thanks to ongoing advances in live imaging microscopy and optical technology. Although innovation of optogenetic and chemogenetic methods has been primarily driven by researchers studying the central nervous system, these techniques also hold great promise to boost research in neurogastroenterology. In this Review, we describe the different classes of tools that are currently available and give an overview of the strategies to target them to specific cell types in the gut wall. We discuss the possibilities and limitations of optogenetic and chemogenetic technology in the gut and provide an overview of their current use, with a focus on the enteric nervous system. Furthermore, we suggest some experiments that can advance our understanding of how the intrinsic and extrinsic neural networks of the gut control gastrointestinal function.
Publisher: eLife Sciences Publications, Ltd
Date: 12-02-2019
DOI: 10.7554/ELIFE.42914
Abstract: The enteric nervous system controls a variety of gastrointestinal functions including intestinal motility. The minimal neuronal circuit necessary to direct peristalsis is well-characterized but several intestinal regions display also other motility patterns for which the underlying circuits and connectivity schemes that coordinate the transition between those patterns are poorly understood. We investigated whether in regions with a richer palette of motility patterns, the underlying nerve circuits reflect this complexity. Using Ca2+ imaging, we determined the location and response fingerprint of large populations of enteric neurons upon focal network stimulation. Complemented by neuronal tracing and volumetric reconstructions of synaptic contacts, this shows that the multifunctional proximal colon requires specific additional circuit components as compared to the distal colon, where peristalsis is the predominant motility pattern. Our study reveals that motility control is hard-wired in the enteric neural networks and that circuit complexity matches the motor pattern portfolio of specific intestinal regions.
Publisher: Frontiers Media SA
Date: 23-02-2017
Publisher: Springer Science and Business Media LLC
Date: 18-05-2020
DOI: 10.1007/S00018-020-03543-6
Abstract: The enteric nervous system (ENS) is an extensive network comprising millions of neurons and glial cells contained within the wall of the gastrointestinal tract. The major functions of the ENS that have been most studied include the regulation of local gut motility, secretion, and blood flow. Other areas that have been gaining increased attention include its interaction with the immune system, with the gut microbiota and its involvement in the gut–brain axis, and neuro-epithelial interactions. Thus, the enteric circuitry plays a central role in intestinal homeostasis, and this becomes particularly evident when there are faults in its wiring such as in neurodevelopmental or neurodegenerative disorders. In this review, we first focus on the current knowledge on the cellular composition of enteric circuits. We then further discuss how enteric circuits detect and process external information, how these signals may be modulated by physiological and pathophysiological factors, and finally, how outputs are generated for integrated gut function.
Publisher: Springer International Publishing
Date: 2022
Publisher: American Physiological Society
Date: 10-2022
Abstract: Live calcium imaging is often used as a proxy for electrophysiological measurements and has been a valuable tool that allows simultaneous analysis of neuronal activity in multiple cells at the population level. In the enteric nervous system, there are two main electrophysiological classes of neurons, after-hyperpolarizing (AH)- and synaptic (S)-neurons, which have been shown to have different calcium handling mechanisms. However, they are rarely considered separately in calcium imaging experiments. A handful of studies have shown that in guinea pig, a calcium transient will accompany a single action potential in AH-neurons, but multiple action potentials are required to generate a calcium transient in S-neurons. How this translates to different modes of cellular depolarization and whether this is consistent across species is unknown. In this study, we used simultaneous whole-cell patch-cl electrophysiology together with calcium imaging to investigate how enteric neurons respond to different modes of depolarization. Using both traditional (4 Hz) and also high-speed (1,000 Hz) imaging techniques, we found that single action potentials elicit calcium transients in both AH-neurons and S-neurons. Subthreshold membrane depolarizations were also able to elicit calcium transients, although calcium responses were generally lified if an action potential was present. Furthermore, we identified that responses to nicotinic acetylcholine receptor stimulation can be used to distinguish between AH- and S-neurons in calcium imaging. NEW & NOTEWORTHY Live calcium imaging is an important tool for investigating enteric nervous system (ENS) function. Previous studies have shown that multiple action potentials are needed to generate a calcium response in S-neurons, which has important implications for the interpretation of calcium imaging data. Here, we show that in mouse myenteric neurons, calcium transients are elicited by single action potentials in both AH- and S-neurons. In addition, nicotinic acetylcholine receptor stimulation can be used to distinguish between these two classes.
Publisher: Wiley
Date: 14-06-2021
DOI: 10.1111/NMO.14186
Abstract: Gastrointestinal (GI) function is critically dependent on the control of the enteric nervous system (ENS), which is situated within the gut wall and organized into two ganglionated nerve plexuses: the submucosal and myenteric plexus. The ENS is optimally positioned and together with the intestinal epithelium, is well-equipped to monitor the luminal contents such as microbial metabolites and to coordinate appropriate responses accordingly. Despite the heightened interest in the gut microbiota and its influence on intestinal physiology and pathophysiology, how they interact with the host ENS remains unclear. Using full-thickness proximal colon preparations from transgenic Villin-CreERT2 R26R-GCaMP3 and Wnt1-Cre R26R-GCaMP3 mice, which express a fluorescent Ca We show that the SCFAs acetate, propionate, and butyrate, as well as 5-HT can, to varying extents, acutely elicit epithelial and neuronal Ca Taken together, our study demonstrates that different microbial metabolites, including SCFAs and 5-HT, can acutely stimulate Ca
Publisher: Elsevier BV
Date: 2006
DOI: 10.1016/J.NEUROSCIENCE.2005.12.023
Abstract: GABA is an important inhibitory transmitter in the CNS. In the enteric nervous system, however, both excitatory and inhibitory actions have been reported. Here, we investigated the effects of GABA on the intracellular Ca2+ concentration of guinea-pig myenteric neurons (at 35 degrees C) using Fura-2-AM. Neurons were identified by 75 mM K+ depolarization (5 s), which evoked a transient intracellular Ca2+ concentration increase. GABA (10 s) induced a dose dependent (5 nM-1 microM) transient intracellular Ca2+ concentration rise in the majority of neurons (500 nM GABA: 251+/-17 nM, n=232/289). Interestingly, the response to 5 microM GABA (n=18) lasted several minutes and did not fully recover. GABA response litudes were significantly (P<0.001) reduced by GABAA and GABAB receptor antagonists (10 microM) bicuculline and phaclofen. The GABAA agonist isoguvacine (10 microM) and GABAB agonist baclofen (10 microM) induced similar responses as 50 nM GABA, while the GABAC agonist cis-4-aminocrotonic acid (CACA) (10 microM) only elicited small responses in a minority of neurons. Removal of extracellular Ca2+ abolished all responses while depletion of intracellular Ca2+ stores by thapsigargin (5 microM) did not alter the responses to 500 nM GABA (n=13), but reduction of Ca2+ influx through voltage-dependent Ca2+ channels did. The nicotinic antagonist hexamethonium (100 microM) also reduced GABA responses by almost 70% suggesting that GABA stimulates cholinergic pathways, while the purinergic receptor blocker pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS) and the 5-HT3 receptor blocker ondansetron only had minor effects. GABA elicits transient intracellular Ca2+ concentration responses in the majority of myenteric neurons through activation of GABAA and GABAB receptors and much of the response can be attributed to facilitation of ACh release. Thus GABA may act mainly as a modulator that sets the state of excitability of the enteric nerve network. A concentration of 5 microM GABA, although frequently used in pharmacological experiments, seems to cause a detrimental response reminiscent of the neurotoxic effects glutamate has in the CNS.
Publisher: Wiley
Date: 14-09-2020
DOI: 10.1113/JP280594
Publisher: The Company of Biologists
Date: 02-2021
DOI: 10.1242/DEV.182543
Abstract: During embryonic development, the gut is innervated by intrinsic (enteric) and extrinsic nerves. Focusing on mammalian ENS development, in this Review we highlight how important the different compartments of this innervation are to assure proper gut function. We specifically address the three-dimensional architecture of the innervation, paying special attention to the differences in development along the longitudinal and circumferential axes of the gut. We review recent information about the formation of both intrinsic innervation, which is fairly well-known, as well as the establishment of the extrinsic innervation, which, despite its importance in gut-brain signaling, has received much less attention. We further discuss how external microbial and nutritional cues or neuroimmune interactions may influence development of gut innervation. Finally, we provide summary tables, describing the location and function of several well-known molecules, along with some newer factors that have more recently been implicated in the development of gut innervation.
Publisher: Elsevier BV
Date: 08-2017
DOI: 10.1016/J.YDBIO.2017.05.018
Abstract: The enteric nervous system (ENS) is an extensive network of neurons in the gut wall that arises from neural crest-derived cells. Like other populations of neural crest cells, it is known that enteric neural crest-derived cells (ENCCs) influence the behaviour of each other and therefore must communicate. However, little is known about how ENCCs communicate with each other. In this study, we used Ca
Publisher: American Physiological Society
Date: 2020
Abstract: Detection of nutritional and noxious food components in the gut is a crucial component of gastrointestinal function. Contents in the gut lumen interact with enteroendocrine cells dispersed throughout the gut epithelium. Enteroendocrine cells release many different hormones, neuropeptides, and neurotransmitters that communicate either directly or indirectly with the central nervous system and the enteric nervous system, a network of neurons and glia located within the gut wall. Several populations of enteric neurons extend processes that innervate the gastrointestinal lamina propria however, how these processes develop and begin to transmit information from the mucosa is not fully understood. In this study, we found that Tuj1-immunoreactive neurites begin to project out of the myenteric plexus at embryonic day (E)13.5 in the mouse small intestine, even before the formation of villi. Using live calcium imaging, we discovered that neurites were capable of transmitting electrical information from stimulated villi to the plexus by E15.5. In unpeeled gut preparations where all layers were left intact, we also mimicked the basolateral release of 5-HT from enteroendocrine cells, which triggered responses in myenteric cell bodies at postnatal day (P)0. Altogether, our results show that enteric neurons extend neurites out of the myenteric plexus early during mouse enteric nervous system development, innervating the gastrointestinal mucosa, even before villus formation in mice of either sex. Neurites are already able to conduct electrical information at E15.5, and responses to 5-HT develop postnatally. NEW & NOTEWORTHY How enteric neurons project into the gut mucosa and begin to communicate with the epithelium during development is not known. Our study shows that enteric neurites project into the lamina propria as early as E13.5 in the mouse, before development of the submucous plexus and before formation of intestinal villi. These neurites are capable of transmitting electrical signals back to their cell bodies by E15.5 and respond to serotonin applied to neurite terminals by birth.
Start Date: 2013
End Date: 12-2016
Amount: $513,000.00
Funder: Australian Research Council
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