Tissue-Specific Mathematical Models of Slow Wave Entrainment in Wild-Type and 5-HT2B Knockout Mice with Altered Interstitial Cells of Cajal Networks

Du, Peng; O’Grady, Greg; Gibbons, Simon J.; Yassi, Rita; Lees-Green, Rachel; Farrugia, Gianrico; Cheng, Leo K.; Pullan, Andrew J.

doi:10.1016/j.bpj.2010.01.009

Cited by 56 publications

(107 citation statements)

References 32 publications

(63 reference statements)

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“…5-HT promotes the survival of ICC cells in culture via actions on 5-HT 2B receptors 130 , and the density of ICC is decreased in 5-HT 2B receptor deficient mice. Modeling of these changes suggests that alterations of the ICC network would impair slow wave propagation and ultimately motility and transit in the intestines 131 .…”

Section: Functions Of 5-ht In the Gastrointestinal Tractmentioning

confidence: 99%

Serotonin signalling in the gut—functions, dysfunctions and therapeutic targets

Mawe

Hoffman

2013

Nat Rev Gastroenterol Hepatol

871

783

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Serotonin (5-HT) has been recognized for decades as an important signaling molecule in the gut, but it is still revealing its secrets. We continue to discover novel gastrointestinal (GI) functions of 5-HT, as well as actions of gut-derived 5-HT outside of the gut, and we are learning how 5-HT signaling is altered in GI disorders. Furthermore, new therapeutic targets related to 5-HT signaling are being identified that can hopefully be exploited to alleviate the symptoms of functional GI disorders. Conventional functions of 5-HT in the gut involving intrinsic reflexes include stimulation of propulsive and segmentation motility patterns, epithelial secretion, and vasodilation. Activation of extrinsic vagal and spinal afferent fibers results in slowed gastric emptying, pancreatic secretion, satiation, pain and discomfort, as well as nausea and vomiting. Within the gut, 5-HT also exerts non-conventional actions that include serving as a pro-inflammatory signaling molecule and as a trophic factor to promote the development and maintenance of neurons and interstitial cells of Cajal. Platelet 5-HT, which comes from the gut, can promote hemostasis, influence bone development, and contribute to allergic airway inflammation. 5-HT3 receptor antagonists and 5-HT4 receptor agonists have been used to treat functional disorders with diarrhea or constipation, respectively. More recently, the synthetic enzyme, tryptophan hydroxylase has been targeted, and there are recent findings suggesting that epithelial 5-HT4 receptors could be targeted to provide a safe and effective treatment for constipation. Here we provide an overview of these serotonergic actions and treatment strategies.

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Section: Functions Of 5-ht In the Gastrointestinal Tractmentioning

confidence: 99%

Serotonin signalling in the gut—functions, dysfunctions and therapeutic targets

Mawe

Hoffman

2013

Nat Rev Gastroenterol Hepatol

871

783

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“…Previous studies have simulated tissue-specific slow wave propagation over ICC networks by coupling imaging data with a modified biophysically-based Corrias and Buist cell model [12] embedded within a continuum modeling framework [11, 13]. However, this methodology is computationally expensive [13], mainly due to the large number of equations and parameters present in the cell model, and hence difficulties exist in up-scaling these simulations to larger multiscale simulation studies.…”

Section: Introductionmentioning

confidence: 99%

Cellular automaton model for simulating tissue-specific intestinal electrophysiological activity

Gao

O’Grady

et al. 2013

2013 35th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC)

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Depletion of interstitial cell of Cajal (ICC) networks is known to occur in various gastrointestinal (GI) motility disorders. Although techniques for quantifying the structure of ICC networks are available, the ICC network structure-function relationships are yet to be well elucidated. Existing methods of relating ICC structure to function are computationally expensive, and it is difficult to up-scale them to larger multiscale simulations. A new cellular automaton model for simulating tissue-specific slow wave propagation was developed, and in preliminary studies the automaton model was applied on jejunal ICC network structures from wild-type and 5-HT2B receptor knockout (ICC depleted) mice. Two metrics were also developed to quantify the simulated propagation patterns: 1) ICC and 2) non-ICC activation lag metrics. These metrics measured the average delay in time taken for the slow wave to propagate across the ICC and non-ICC domain throughout the entire network compared to the theoretical fastest propagation, respectively. Slow wave propagation was successfully simulated across the ICC networks with greatly reduced computational time compared to previous methods, and the propagation pattern metrics quantitatively revealed an impaired propagation during ICC depletion. In conclusion, the developed slow wave propagation model and propagation pattern metrics offer a computationally efficient framework for relating ICC structure to function. These tools can now be further applied to define ICC structure-function relationships across various spatial and temporal scales.

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“…21,22 Cholinergic regulation is also known to modulate ICC-IM frequencies, potentially inducing arrhythmias, 23 and a role for autonomic neuropathy in aberrant slow wave initiation therefore deserves further investigation. In terms of conduction abnormalities, biophysically-based modeling studies have shown that slowed haphazard conduction occurs in states of ICC loss, 24 potentially promoting arrhythmias. In addition, conduction blocks must result when ICC loss falls below a critical threshold.…”

Section: The Pathological Basis For Arrhythmias In Gastroparesismentioning

confidence: 99%

Gastric Arrhythmias in Gastroparesis

O’Grady

Abell

2015

Gastroenterology Clinics of North America

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Gastric arrhythmias occur in gastroparesis, however, their meaning and significance has been debated. Recently, an improved understanding of dysrhythmia has begun to emerge, informed by cellular, physiological, and engineering progress. This review discusses these advances and considers clinical applications. An important foundation has been defining histopathological abnormalities in gastroparesis. The finding that interstitial cells of Cajal are depleted and injured provides mechanisms for arrhythmogenesis in gastroparesis, and has reinvigorated clinical interest in electrical diagnostics. Electrogastrography (EGG) has been the dominant method to date, demonstrating consistent associations between arrhythmias and gastroparesis, however, is fundamentally limited by its summative nature, low signal quality, and incomplete sensitivity and specificity. Recently, high-resolution (HR; multi-electrode) mapping has emerged, providing superior spatial data on arrhythmic patterns and mechanisms, and enabling new insights and classifications. However, HR mapping is currently limited by invasiveness, and low-resolution approaches are being assessed as bridging techniques until this limitation is overcome.

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Tissue-Specific Mathematical Models of Slow Wave Entrainment in Wild-Type and 5-HT2B Knockout Mice with Altered Interstitial Cells of Cajal Networks

Cited by 56 publications

References 32 publications

Serotonin signalling in the gut—functions, dysfunctions and therapeutic targets

Serotonin signalling in the gut—functions, dysfunctions and therapeutic targets

Cellular automaton model for simulating tissue-specific intestinal electrophysiological activity

Gastric Arrhythmias in Gastroparesis

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