ORCID Profile
0000-0002-3545-2045
Current Organisations
Universita degli Studi Di Cagliari
,
Radboud University Nijmegen
,
Universidade de São Paulo
,
Università degli Studi di Cagliari Cittadella Universitaria
,
University of Melbourne
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Publisher: Wiley
Date: 16-09-2019
DOI: 10.1111/NMO.13708
Abstract: The prokinetic effects of 5-HT
Publisher: American Physiological Society
Date: 06-2007
Abstract: The motility of the gut depends on the chemicals contained in the lumen, but the stimuli that modify motility and their relationship to enteric neural pathways are unclear. This study examined local inhibitory reflexes activated by various chemical stimulants applied to the mucosa to characterize effective physiological stimuli and the pathways they excite. Segments of the jejunum were dissected to allow access to the circular muscle on one-half of the preparation while leaving the mucosa intact on the circumferentially adjacent half. Chemicals were transiently applied to the mucosa, and responses were recorded intracellularly in nearby circular muscle cells. The amino acids l-phenylalanine, l-alanine, or l-tryptophan (all 1 mM) evoked inhibitory junction potentials (IJPs latency 150–300 ms, litude 3–8 mV, each n 6) that were blocked by TTX and partially blocked by antagonists of P2X receptors and/or a combination of antagonists at 5-HT 3 and 5-HT 4 receptors. The putative mediators 5-HT (10 μM), ATP (1 mM), and CCK-8 (1–10 μM) elicited IJPs mediated via 5-HT 3 , P2X, and CCK-B receptors, respectively. Responses were only partially reduced by the effective antagonists. IJPs evoked by electrically stimulating the mucosa were unaffected by antagonists that reduced chemically evoked responses. Both chemically and electrically evoked IJPs were resistant to nicotinic, NK 1 , NK 3 , α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid, N-methyl-d-aspartate, or CGRP receptor blockade. We conclude that mucosal stimulation by amino acids activates local neural pathways whose pharmacology depends on the nature of the stimulus. Transmitters involved at some synapses in these pathways remain to be identified.
Publisher: Elsevier BV
Date: 2009
DOI: 10.1053/J.GASTRO.2008.09.071
Abstract: Neural mechanisms underlying cholera toxin (CT)-induced intestinal hypersecretion remain unclear. We investigated long-term excitability changes in vasoactive intestinal peptide (VIP) and neuropeptide Y (NPY) secretomotor neurons after prolonged luminal exposure to CT. Isolated segments of guinea pig jejunum were incubated with saline or CT +/- neurotransmitter antagonist in the lumen the submucosal plexus was then dissected clear, circumferentially adjacent to intact mucosa. Synaptic inputs and firing properties of S neurons in ganglia next to the mucosa in control saline were studied using intracellular recording. Neurons were processed for VIP and NPY immunoreactivity. Thirty S neurons (20 VIP(+), 7 NPY(+), 3 VIP(-)/NPY(-)) from CT-treated preparations and 27 control S neurons (19 VIP(+), 4 NPY(+), 4 VIP(-)/NPY(-)) in ganglia adjacent to intact mucosa were analyzed. VIP(+) and NPY(+) neurons in CT-treated preparations fired significantly more action potentials and for longer periods during injected depolarizing current pulses (50-350 pA) than control neurons. Addition of tetrodotoxin, hexamethonium, granisetron, or the neurokinin-1 (NK1) antagonist SR140333 during the CT incubation blocked CT-induced effects in both neuron types. The NK3 antagonist SR142801 blocked CT-induced effects in NPY(+) neurons and reduced the number of action potentials in VIP(+) neurons. Synaptic activity was unaffected by CT. CT induces specific and sustained hyperexcitability of secretomotor neurons in enteric pathways. CT acts in the mucosa. Its effect is neurally mediated and depends on 5-hydroxytryptamine-3, nicotinic, and NK1 receptors. This system represents a unique model to understand the neural mechanisms of action of CT and to identify therapeutic targets.
Publisher: American Physiological Society
Date: 04-2007
Abstract: Mechanisms underlying nutrient-induced segmentation within the gut are not well understood. We have shown that decanoic acid and some amino acids induce neurally dependent segmentation in guinea pig small intestine in vitro. This study examined the neural mechanisms underlying segmentation in the circular muscle and whether the timing of segmentation contractions also depends on slow waves. Decanoic acid (1 mM) was infused into the lumen of guinea pig duodenum and jejunum. Video imaging was used to monitor intestinal diameter as a function of both longitudinal position and time. Circular muscle electrical activity was recorded by using suction electrodes. Recordings from sites of segmenting contractions showed they are always associated with excitatory junction potentials leading to action potentials. Recordings from sites oral and anal to segmenting contractions revealed inhibitory junction potentials that were time locked to those contractions. Slow waves were never observed underlying segmenting contractions. In paralyzed preparations, intracellular recording revealed that slow-wave frequency was highly consistent at 19.5 (SD 1.4) cycles per minute (c/min) in duodenum and 16.6 (SD 1.1) c/min in jejunum. By contrast, the frequencies of segmenting contractions varied widely (duodenum: 3.6–28.8 c/min, median 10.8 c/min jejunum: 3.0–27.0 c/min, median 7.8 c/min) and sometimes exceeded slow-wave frequencies for that region. Thus nutrient-induced segmentation contractions in guinea pig small intestine do not depend on slow-wave activity. Rather they result from a neural circuit producing rhythmic localized activity in excitatory motor neurons, while simultaneously activating surrounding inhibitory motor neurons.
Publisher: American Physiological Society
Date: 11-2004
Abstract: We examined specific receptor/transmitter combinations used at functionally identified synapses in ascending and descending reflex pathways of guinea pig distal colon. Excitatory (EJPs) or inhibitory junction potentials (IJPs) were recorded intracellularly from nicardipine-paralyzed circular smooth muscle in either the oral or anal recording chamber of a three-chambered organ bath, respectively. Blockade of synaptic transmission in the central chamber with a 0.25 mM Ca 2+ /12 mM Mg 2+ solution abolished EJPs evoked by distension applied either in the central or the far (anal) chamber. IJPs evoked by distension in the central or the far (oral) chamber were depressed to ∼50% of control. Hexamethonium (nicotinic receptor antagonist, 200 μM) in the central chamber reduced IJPs evoked by far or central distension to 50%, whereas EJPs evoked by far distension were abolished and EJPs evoked by central distension were reduced to 70% of control. Hexamethonium in the recording chambers reduced both IJPs and EJPs evoked by central distension to ∼50%. EJPs in the ascending pathway were unaffected by blockade of muscarinic receptors in the central chamber or blockade of neurokinin 3 tachykinin receptors in this or the recording chamber. In the descending pathway, blockade of P 2 receptors in the same chambers had only a minor effect on distension-evoked IJPs. Thus some intrinsic sensory neurons of guinea pig colon have long descending projections ( mm), but ascending projections of mm. In contrast to the ileum, transmission between ascending or descending interneurons and from sensory neurons to descending interneurons is predominantly via nicotinic receptors but transmission to inhibitory or excitatory motoneurons and from sensory neurons to ascending interneurons involves nicotinic and other unidentified receptors.
Publisher: MyJove Corporation
Date: 03-02-2016
DOI: 10.3791/53828
Publisher: Frontiers Media SA
Date: 2010
Publisher: Oxford University Press (OUP)
Date: 19-07-2016
Publisher: Frontiers Media SA
Date: 19-09-2014
Publisher: Wiley
Date: 04-2004
Publisher: EDP Sciences
Date: 2019
DOI: 10.1051/0004-6361/201834148
Abstract: Context . The compact radio source Sagittarius A ∗ (Sgr A ∗ ) in the Galactic centre is the primary supermassive black hole candidate. General relativistic magnetohydrodynamical (GRMHD) simulations of the accretion flow around Sgr A ∗ predict the presence of sub-structure at observing wavelengths of ∼3 mm and below (frequencies of 86 GHz and above). For very long baseline interferometry (VLBI) observations of Sgr A ∗ at this frequency the blurring effect of interstellar scattering becomes sub-dominant, and arrays such as the high sensitivity array (HSA) and the global mm-VLBI array (GMVA) are now capable of resolving potential sub-structure in the source. Such investigations help to improve our understanding of the emission geometry of the mm-wave emission of Sgr A ∗ , which is crucial for constraining theoretical models and for providing a background to interpret 1 mm VLBI data from the Event Horizon Telescope (EHT). Aims . Following the closure phase analysis in our first paper, which indicates asymmetry in the 3 mm emission of Sgr A ∗ , here we have used the full visibility information to check for possible sub-structure. We extracted source size information from closure litude analysis, and investigate how this constrains a combined fit of the size-frequency relation and the scattering law for Sgr A ∗ . Methods . We performed high-sensitivity VLBI observations of Sgr A ∗ at 3 mm using the Very Long Baseline Array (VLBA) and the Large Millimeter Telescope (LMT) in Mexico on two consecutive days in May 2015, with the second epoch including the Greenbank Telescope (GBT). Results . We confirm the asymmetry for the experiment including GBT. Modelling the emission with an elliptical Gaussian results in significant residual flux of ∼10 mJy in south-eastern direction. The analysis of closure litudes allows us to precisely constrain the major and minor axis size of the main emission component. We discuss systematic effects which need to be taken into account. We consider our results in the context of the existing body of size measurements over a range of observing frequencies and investigate how well-constrained the size-frequency relation is by performing a simultaneous fit to the scattering law and the size-frequency relation. Conclusions . We find an overall source geometry that matches previous findings very closely, showing a deviation in fitted model parameters less than 3% over a time scale of weeks and suggesting a highly stable global source geometry over time. The reported sub-structure in the 3 mm emission of Sgr A ∗ is consistent with theoretical expectations of refractive noise on long baselines. However, comparing our findings with recent results from 1 mm and 7 mm VLBI observations, which also show evidence for east-west asymmetry, we cannot exclude an intrinsic origin. Confirmation of persistent intrinsic substructure will require further VLBI observations spread out over multiple epochs.
Publisher: Public Library of Science (PLoS)
Date: 07-02-2013
Publisher: Springer Science and Business Media LLC
Date: 19-07-2021
DOI: 10.1038/S41550-021-01417-W
Abstract: Very-long-baseline interferometry (VLBI) observations of active galactic nuclei at millimetre wavelengths have the power to reveal the launching and initial collimation region of extragalactic radio jets, down to 10–100 gravitational radii ( r g ≡ G M / c 2 ) scales in nearby sources 1 . Centaurus A is the closest radio-loud source to Earth 2 . It bridges the gap in mass and accretion rate between the supermassive black holes (SMBHs) in Messier 87 and our Galactic Centre. A large southern declination of −43° has, however, prevented VLBI imaging of Centaurus A below a wavelength of 1 cm thus far. Here we show the millimetre VLBI image of the source, which we obtained with the Event Horizon Telescope at 228 GHz. Compared with previous observations 3 , we image the jet of Centaurus A at a tenfold higher frequency and sixteen times sharper resolution and thereby probe sub-lightday structures. We reveal a highly collimated, asymmetrically edge-brightened jet as well as the fainter counterjet. We find that the source structure of Centaurus A resembles the jet in Messier 87 on ~500 r g scales remarkably well. Furthermore, we identify the location of Centaurus A’s SMBH with respect to its resolved jet core at a wavelength of 1.3 mm and conclude that the source’s event horizon shadow 4 should be visible at terahertz frequencies. This location further supports the universal scale invariance of black holes over a wide range of masses 5,6 .
Publisher: American Astronomical Society
Date: 29-10-2019
Publisher: Wiley
Date: 16-11-2016
DOI: 10.1111/BPH.13646
Publisher: American Astronomical Society
Date: 06-2021
Publisher: European Respiratory Society (ERS)
Date: 14-05-2008
DOI: 10.1183/09031936.00002108
Abstract: There is poor agreement on definitions of different phenotypes of preschool wheezing disorders. The present Task Force proposes to use the terms episodic (viral) wheeze to describe children who wheeze intermittently and are well between episodes, and multiple-trigger wheeze for children who wheeze both during and outside discrete episodes. Investigations are only needed when in doubt about the diagnosis. Based on the limited evidence available, inhaled short-acting beta(2)-agonists by metered-dose inhaler/spacer combination are recommended for symptomatic relief. Educating parents regarding causative factors and treatment is useful. Exposure to tobacco smoke should be avoided allergen avoidance may be considered when sensitisation has been established. Maintenance treatment with inhaled corticosteroids is recommended for multiple-trigger wheeze benefits are often small. Montelukast is recommended for the treatment of episodic (viral) wheeze and can be started when symptoms of a viral cold develop. Given the large overlap in phenotypes, and the fact that patients can move from one phenotype to another, inhaled corticosteroids and montelukast may be considered on a trial basis in almost any preschool child with recurrent wheeze, but should be discontinued if there is no clear clinical benefit. Large well-designed randomised controlled trials with clear descriptions of patients are needed to improve the present recommendations on the treatment of these common syndromes.
Publisher: American Physiological Society
Date: 07-2009
Abstract: Slow excitatory postsynaptic potentials (EPSPs) in enteric neurons arise from erse sources, but which neurotransmitters mediate specific types of slow EPSPs is unclear. We investigated transmitters and receptors mediating slow EPSPs in myenteric neurons evoked by electrical stimulation of the mucosa in guinea pig small intestine. Segments of ileum or jejunum were dissected to allow access to the myenteric plexus adjacent to intact mucosa, in vitro. AH and S neurons were impaled with conventional intracellular electrodes. Trains of stimuli delivered to the mucosa evoked slow EPSPs in AH neurons that were blocked or depressed by the neurokinin-1 (NK1) tachykinin antagonist SR140333 (100 nM) in 10 of 11 neurons the NK3 tachykinin receptor antagonist SR142801 (100 nM) had no effect on slow EPSPs in seven of nine AH neurons. Single pulses to the mucosa evoked fast EPSPs and slow depolarizations in S neurons. The depolarizations were ided into intermediate (durations 300–900 ms) or slow (durations 1.3–9 s) EPSPs. The slow EPSPs were blocked by pyridoxal phosphate-6-axophenyl-2–4-disulfonic acid (30 μM, N = 3) or the specific P2Y 1 antagonist MRS 2179 (10 μM, N = 6) and were predominantly in anally projecting S neurons that were immunoreactive for nitric oxide synthase (NOS). In contrast, intermediate EPSPs were predominantly evoked in NOS-negative neurons these were abolished by MRS 2179 ( N = 8). Thus activation of pathways running from the mucosa excites three different types of slow EPSP in myenteric neurons, which are mediated by either a tachykinin (NK1, AH neurons) or a purine nucleotide (P2Y 1 , S neurons).
Publisher: Elsevier BV
Date: 05-2017
DOI: 10.1053/J.GASTRO.2017.01.005
Abstract: Cell therapy offers the potential to treat gastrointestinal motility disorders caused by diseased or absent enteric neurons. We examined whether neurons generated from transplanted enteric neural cells provide a functional innervation of bowel smooth muscle in mice. Enteric neural cells expressing the light-sensitive ion channel, channelrhodopsin, were isolated from the fetal or postnatal mouse bowel and transplanted into the distal colon of 3- to 4-week-old wild-type recipient mice. Intracellular electrophysiological recordings of responses to light stimulation of the transplanted cells were made from colonic smooth muscle cells in recipient mice. Electrical stimulation of endogenous enteric neurons was used as a control. The axons of graft-derived neurons formed a plexus in the circular muscle layer. Selective stimulation of graft-derived cells by light resulted in excitatory and inhibitory junction potentials, the electrical events underlying contraction and relaxation, respectively, in colonic muscle cells. Graft-derived excitatory and inhibitory motor neurons released the same neurotransmitters as endogenous motor neurons-acetylcholine and a combination of adenosine triphosphate and nitric oxide, respectively. Graft-derived neurons also included interneurons that provided synaptic inputs to motor neurons, but the pharmacologic properties of interneurons varied with the age of the donors from which enteric neural cells were obtained. Enteric neural cells transplanted into the bowel give rise to multiple functional types of neurons that integrate and provide a functional innervation of the smooth muscle of the bowel wall. Circuits composed of both motor neurons and interneurons were established, but the age at which cells are isolated influences the neurotransmitter phenotype of interneurons that are generated.
Publisher: Frontiers Media SA
Date: 27-04-2017
Publisher: Frontiers Media SA
Date: 04-12-2017
Publisher: American Physiological Society
Date: 03-2010
Abstract: Vasoactive intestinal peptide (VIP) immunoreactive neurons are important secretomotor neurons in the submucous plexus. They are the only submucosal neurons to receive inhibitory inputs and exhibit both noradrenergic and nonadrenergic inhibitory synaptic potentials (IPSPs). The former are mediated by α 2 -adrenoceptors, but the receptors mediating the latter have not been identified. We used standard intracellular recording, RT-PCR, and confocal microscopy to test whether 5-HT 1A , SST 1 , and/or SST 2 receptors mediate nonadrenergic IPSPs in VIP submucosal neurons in guinea pig ileum in vitro. The specific 5-HT 1A receptor antagonist WAY 100135 (1 μM) reduced the litude of IPSPs, an effect that persisted in the presence of the α 2 -adrenoceptor antagonist idazoxan (2 μM), suggesting that 5-HT might mediate a component of the IPSPs. Confocal microscopy revealed that there were many 5-HT-immunoreactive varicosities in close contact with VIP neurons. The specific SSTR 2 antagonist CYN 154806 (100 nM) and a specific SSTR 1 antagonist SRA 880 (3 μM) each reduced the litude of nonadrenergic IPSPs and hyperpolarizations evoked by somatostatin. In contrast with the other antagonists, CYN 154806 also reduced the durations of nonadrenergic IPSPs. Effects of WAY 100135 and CYN 154806 were additive. RT-PCR revealed gene transcripts for 5-HT 1A , SST 1 , and SST 2 receptors in stripped submucous plexus preparations consistent with the pharmacological data. Although the involvement of other neurotransmitters or receptors cannot be excluded, we conclude that 5-HT 1A , SST 1 , and SST 2 receptors mediate nonadrenergic IPSPs in the noncholinergic (VIP) secretomotor neurons. This study thus provides the tools to identify functions of enteric neural pathways that inhibit secretomotor reflexes.
Publisher: EDP Sciences
Date: 10-2017
Publisher: American Astronomical Society
Date: 10-08-2012
Publisher: Public Library of Science (PLoS)
Date: 13-06-2022
DOI: 10.1371/JOURNAL.PCBI.1009717
Abstract: Transmission between neurons in the extensive enteric neural networks of the gut involves synaptic potentials with vastly different time courses and underlying conductances. Most enteric neurons exhibit fast excitatory post-synaptic potentials (EPSPs) lasting 20–50 ms, but many also exhibit slow EPSPs that last up to 100 s. When large enough, slow EPSPs excite action potentials at the start of the slow depolarization, but how they affect action potentials evoked by fast EPSPs is unknown. Furthermore, two other sources of synaptic depolarization probably occur in enteric circuits, activated via GABA A or GABA C receptors how these interact with other synaptic depolarizations is also unclear. We built a compartmental model of enteric neurons incorporating realistic voltage-dependent ion channels, then simulated fast EPSPs, slow EPSPs and GABA A or GABA C ligand-gated Cl - channels to explore these interactions. Model predictions were tested by imaging Ca 2+ transients in myenteric neurons ex vivo as an indicator of their activity during synaptic interactions. The model could mimic firing of myenteric neurons in mouse colon evoked by depolarizing current during intracellular recording and the fast and slow EPSPs in these neurons. Subthreshold fast EPSPs evoked spikes during the rising phase of a slow EPSP, but suprathreshold fast EPSPs could not evoke spikes later in a slow EPSP. This predicted inhibition was confirmed by Ca 2+ imaging in which stimuli that evoke slow EPSPs suppressed activity evoked by fast EPSPs in many myenteric neurons. The model also predicted that synchronous activation of GABA A receptors and fast EPSPs potentiated firing evoked by the latter, while synchronous activation of GABA C receptors with fast EPSPs, potentiated firing and then suppressed it. The results reveal that so-called slow EPSPs have a biphasic effect being likely to suppress fast EPSP evoked firing over very long periods, perhaps accounting for prolonged quiescent periods seen in enteric motor patterns.
Location: Italy
No related grants have been discovered for Rachel Gwynne.