Anatomy and Neuroscience - Research Publications

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    Developing a spinal cord injury research strategy using a structured process of evidence review and stakeholder dialogue. Part III: outcomes
    Middleton, JW ; Piccenna, L ; Gruen, RL ; Williams, S ; Creasey, G ; Dunlop, S ; Brown, D ; Batchelor, PE ; Berlowitz, DJ ; Coates, S ; Dunn, JA ; Furness, JB ; Galea, MP ; Geraghty, T ; Kwon, BK ; Urquhart, S ; Yates, D ; Bragge, P (NATURE PUBLISHING GROUP, 2015-10)
    STUDY DESIGN: Focus Group. OBJECTIVES: To develop a unified, regional spinal cord injury (SCI) research strategy for Australia and New Zealand. SETTING: Australia. METHODS: A 1-day structured stakeholder dialogue was convened in 2013 in Melbourne, Australia, by the National Trauma Research Institute in collaboration with the SCI Network of Australia and New Zealand. Twenty-three experts participated, representing local and international research, clinical, consumer, advocacy, government policy and funding perspectives. Preparatory work synthesised evidence and articulated draft principles and options as a starting point for discussion. RESULTS: A regional SCI research strategy was proposed, whose objectives can be summarised under four themes. (1) Collaborative networks and strategic partnerships to increase efficiency, reduce duplication, build capacity and optimise research funding. (2) Research priority setting and coordination to manage competing studies. (3) Mechanisms for greater consumer engagement in research. (4) Resources and infrastructure to further develop SCI data registries, evaluate research translation and assess alignment of research strategy with stakeholder interests. These are consistent with contemporary international SCI research strategy development activities. CONCLUSION: This first step in a regional SCI research strategy has articulated objectives for further development by the wider SCI research community. The initiative has also reinforced the importance of coordinated, collective action in optimising outcomes following SCI.
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    The first brain: Species comparisons and evolutionary implications for the enteric and central nervous systems
    Furness, JB ; Stebbing, MJ (WILEY, 2018-02)
    BACKGROUND: The enteric nervous system (ENS) and the central nervous system (CNS) of mammals both contain integrative neural circuitry and similarities between them have led to the ENS being described as the brain in the gut. PURPOSE: To explore relationships between the ENS and CNS across the animal kingdom. We found that an ENS occurs in all animals investigated, including hydra, echinoderms and hemichordates that do not have a CNS. The general form of the ENS, which consists of plexuses of neurons intrinsic to the gut wall and an innervation that controls muscle movements, is similar in species as varied and as far apart as hydra, sea cucumbers, annelid worms, octopus and humans. Moreover, neurochemical similarities across phyla imply a common origin of the ENS. Investigation of extant species suggests that the ENS developed in animals that preceded the division that led to cnidaria (exemplified by hydra) and bilateria, which includes the vertebrates. The CNS is deduced to be a bilaterian development, later than the divergence from cnidaria. Consistent with the ENS having developed independent of the CNS, reciprocal connections between ENS and CNS occur in mammals, and separate neurons of ENS and CNS origin converge on visceral organs and prevertebral ganglia. We conclude that an ENS arose before and independently of the CNS. Thus the ENS can be regarded as the first brain.
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    Heterogeneity of enterochromaffin cells within the gastrointestinal tract
    Diwakarla, S ; Fothergill, LJ ; Fakhry, J ; Callaghan, B ; Furness, JB (WILEY, 2017-06)
    Enterochromaffin cells were the first endocrine cells of the gastrointestinal tract to be chemically distinguished, almost 150 years ago. It is now known that the chromaffin reaction of these cells was due to their content of the reactive aromatic amine, 5-hydroxytryptamine (5-HT, also known as serotonin). They have commonly been thought to be a special class of gut endocrine cells (enteroendocrine cells) that are distinct from the enteroendocrine cells that contain peptide hormones. The study by Martin et al. in the current issue of this journal reveals that the patterns of expression of nutrient receptors and transporters differ considerably between chromaffin cells of the mouse duodenum and colon. However, even within regions, chromaffin cells differ; in the duodenum there are chromaffin cells that contain both secretin and 5-HT, cholecystokinin and 5-HT, and all three of secretin, cholecystokinin, and 5-HT. Moreover, the ratios of these different cell types differ substantially between species. And, in terms of function, 5-HT has many roles, including in appetite, motility, fluid secretion, release of digestive enzymes and bone metabolism. The paper thus emphasizes the need to define the many different classes of enterochromaffin cells and relate this to their roles.
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    Selenium and vitamin E together improve intestinal epithelial barrier function and alleviate oxidative stress in heat-stressed pigs
    Liu, F ; Cottrell, JJ ; Furness, JB ; Rivera, LR ; Kelly, FW ; Wijesiriwardana, U ; Pustovit, RV ; Fothergill, LJ ; Bravo, DM ; Celi, P ; Leury, BJ ; Gabler, NK ; Dunshea, FR (WILEY, 2016-07-01)
    What is the central question of this study? Oxidative stress may play a role in compromising intestinal epithelial barrier integrity in pigs subjected to heat stress, but it is unknown whether an increase of dietary antioxidants (selenium and vitamin E) could alleviate gut leakiness in heat-stressed pigs. What is the main finding and its importance? Levels of dietary selenium (1.0 p.p.m.) and vitamin E (200 IU kg(-1) ) greater than those usually recommended for pigs reduced intestinal leakiness caused by heat stress. This finding suggests that oxidative stress plays a role in compromising intestinal epithelial barrier integrity in heat-stressed pigs and also provides a nutritional strategy for mitigating these effects. Heat stress compromises the intestinal epithelial barrier integrity of mammals through mechanisms that may include oxidative stress. Our objective was to test whether dietary supplementation with antioxidants, selenium (Se) and vitamin E (VE), protects intestinal epithelial barrier integrity in heat-stressed pigs. Female growing pigs (n = 48) were randomly assigned to four diets containing from 0.2 p.p.m. Se and 17 IU kg(-1) VE (control, National Research Council recommended) to 1.0 p.p.m. Se and 200 IU kg(-1) VE for 14 days. Six pigs from each dietary treatment were then exposed to either thermoneutral (20°C) or heat-stress conditions (35°C 09.00-17.00 h and 28°C overnight) for 2 days. Transepithelial electrical resistance and fluorescein isothiocyanate-dextran (4 kDa; FD4) permeability were measured in isolated jejunum and ileum using Ussing chambers. Rectal temperature, respiratory rate and intestinal HSP70 mRNA abundance increased (all P < 0.001), and respiratory alkalosis occurred, suggesting that pigs were heat stressed. Heat stress also increased FD4 permeability and decreased transepithelial electrical resistance (both P < 0.01). These changes were associated with changes indicative of oxidative stress, a decreased glutathione peroxidase (GPX) activity and an increased glutathione disulfide (GSSG)-to-glutathione (GSH) ratio (both P < 0.05). With increasing dosage of Se and VE, GPX-2 mRNA (P = 0.003) and GPX activity (P = 0.049) increased linearly, the GSSG:GSH ratio decreased linearly (P = 0.037), and the impacts of heat stress on intestinal barrier function were reduced (P < 0.05 for both transepithelial electrical resistance and FD4 permeability). In conclusion, in pigs an increase of dietary Se and VE mitigated the impacts of heat stress on intestinal barrier integrity, associated with a reduction in oxidative stress.
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    A comparison of the anatomical and gastrointestinal functional development between gilt and sow progeny around birth and weaning
    Craig, JR ; Dunshea, FR ; Cottrell, JJ ; Furness, JB ; Wijesiriwardana, UA ; Pluske, J (American Society of Animal Science, 2019-09-01)
    Gilt progeny (GP) often have restricted growth performance and health status in comparison to sow progeny (SP) from birth, with the underlying mechanisms responsible for this yet to be fully understood. The present study aimed to compare differences in growth and development between GP and SP in the first 24 h after birth and in the periweaning period. Two cohorts of pigs including 36 GP and 37 SP were euthanized at 1 of 4 time points: a birth cohort (at birth before suckling, 0 h; and 24 h after birth, 24 h; n = 33) and a weaning cohort (at approximately 29 d of age; “pre-weaning,” PrW; and 24 h after weaning; “post-weaning,” PoW; n = 40). Pigs were individually weighed at 0 h, 24 h, PrW, and PoW up until the point of euthanasia, at which time the weights of selected tissues and organs were recorded and analyzed relative to BW. The length of the small intestine (SI), femur, and body were also measured, and a serum sample was collected and analyzed for IgG concentration. Samples of jejunal and ileal mucosa were collected and analyzed for total protein and specific activity of lactase. Euthanized GP were lighter (P < 0.01) than SP at all time points. At all time points, the ratios of quadriceps weight to femur length, BW to body length, spleen to BW (all P < 0.05), and SI weight to length (P < 0.10) were lower in GP than in SP. There was no difference (P ≥ 0.05) in stomach or heart to BW ratios between GP and SP in either cohort. The brain to liver weight ratio was greater (P = 0.044) in GP than in SP in the birth cohort, and the brain to BW ratio was greater (P < 0.01) in GP in both the birth and weaning cohorts. The liver to BW ratio was similar (P = 0.35) at birth but greater (P = 0.014) in GP around weaning. Total mucosal protein content in the jejunum and ileum was lower (P = 0.007) in GP at 24 h compared with SP, and specific activity of lactase was greater (P = 0.022) in GP in the birth cohort, whereas there were no differences in the weaning cohort (P ≥ 0.10). Gilt progeny had lower (P < 0.001) serum IgG concentration compared with SP at 24 h, but there was no difference (P ≥ 0.10) in the weaning cohort. Collectively, these findings suggest that the early development of GP may be delayed compared with SP and that a number of the anatomical differences between GP and SP that exist after birth are also present at weaning.
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    Muscarinic receptor 1 allosteric modulators stimulate colorectal emptying in dog, mouse and rat and resolve constipation
    Pustovit, RV ; Itomi, Y ; Ringuet, M ; Diwakarla, S ; Chai, X-Y ; McQuade, RM ; Tsukimi, Y ; Furness, JB (WILEY, 2019-11)
    BACKGROUND: Because M1 muscarinic receptors are expressed by enteric neurons, we investigated whether positive allosteric modulators of these receptors (M1PAMs) would enhance colorectal propulsion and defecation in dogs, mice, and rats. METHODS: The potencies of the M1PAMs, T662 or T523, were investigated using M1 receptor-expressing CHO cells. Effectiveness of M1PAMs on defecation was investigated by oral administration in mice and rats, by recording propulsive contractions in anaesthetized rats and by recording high amplitude propagating contractions in dogs. KEY RESULTS: PAM EC50 values in M1 receptor-expressing CHO cells were 0.7-1.8 nmol/L for T662 and 8-10 nmol/L for T523. The compounds had 1000-fold lower potencies as agonists. In anesthetized rats, both compounds elicited propulsive colorectal contractions, and in dogs, mice, and rats, oral administration increased fecal output. No adverse effects were observed in conscious animals. M1PAMs triggered propagated high amplitude contractions and caused defecation in dogs. Nerve-mediated contractions were enhanced in the isolated mouse colon. M1PAMs were equi-effective in rats with or without the pelvic nerves being severed. In two models of constipation in mice, opiate-induced constipation and constipation of aging, defecation was induced and constipation was reversed. CONCLUSION AND INFERENCES: M1PAMs act at targets sites in the colorectum to enhance colorectal propulsion. They are effective across species, and they reverse experimentally induced constipation. Previous studies have shown that they are safe in human. Because they provide an enhancement of physiological control rather than being direct agonists, they are predicted to provide effective treatment for constipation.
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    Distribution and characterisation of CCK containing enteroendocrine cells of the mouse small and large intestine
    Fakhry, J ; Wang, J ; Martins, P ; Fothergill, LJ ; Hunne, B ; Prieur, P ; Shulkes, A ; Rehfeld, JF ; Callaghan, B ; Furness, JB (SPRINGER, 2017-08)
    There is general consensus that enteroendocrine cells, EEC, containing the enteric hormone cholecystokinin (CCK) are confined to the small intestine and predominate in the duodenum and jejunum. Contrary to this, EEC that express the gene for CCK have been isolated from the large intestine of the mouse and there is evidence for EEC that contain CCK-like immunoreactivity in the mouse colon. However, the human and rat colons do not contain CCK cells. In the current study, we use immunohistochemistry to investigate CCK peptide presence in endocrine cells, PCR to identify cck transcripts and chromatography to identify CCK peptide forms in the mouse small and large intestine. The colocalisation of CCK and 5-HT, hormones that have been hypothesised to derive from cells of different lineages, was also investigated. CCK immunoreactivity was found in EEC throughout the mouse small and large intestine but positive cells were rare in the rectum. Immunoreactive EEC were as common in the caecum and proximal colon as they were in the duodenum and jejunum. CCK gene transcripts were found in the mucosa throughout the intestine but mRNA for gastrin, a hormone that can bind some anti-CCK antibodies, was only found in the stomach and duodenum. Characterisation of CCK peptides of the colon by extraction, chromatographic separation and radioimmunoassay revealed bioactive amidated and sulphated forms, including CCK-8 and CCK-33. Moreover, CCK-containing EEC in the large intestine bound antibodies that target the biologically active sulfated form. Colocalisation of CCK and 5-HT occurred in a proportion of EEC throughout the small intestine and in the caecum but these hormones were not colocalised in the colon, where there was CCK and PYY colocalisation. It is concluded that authentic, biologically active, CCK occurs in EEC of the mouse large intestine.
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    Diversity of enteroendocrine cells investigated at cellular and subcellular levels: the need for a new classification scheme
    Fothergill, LJ ; Furness, JB (SPRINGER, 2018-12)
    Enteroendocrine cells were historically classified by a letter code, each linked to a single hormone, deduced to be the only hormone produced by the cell. One type, the L cell, was recognised to store and secrete two products, peptide YY (PYY) and glucagon-related peptides. Many other exceptions to the one-cell one-hormone classifications have been reported over the last 40 years or so, and yet the one-hormone dogma has persisted. In the last 6 years, a plethora of data has appeared that makes the concept unviable. Here, we describe the evidence that multiple hormone transcripts and their products reside in single cells and evidence that the hormones are often, but not always, processed into separate storage vesicles. It has become clear that most enteroendocrine cells contain multiple hormones. For example, most secretin cells contain 5-hydroxytryptamine (5-HT), and in mouse many of these also contain cholecystokinin (CCK). Furthermore, CCK cells also commonly store ghrelin, glucose-dependent insulinotropic peptide (GIP), glucagon-like peptide-1 (GLP-1), neurotensin, and PYY. Several hormones, for example, secretin and 5-HT, are in separate storage vesicles at a subcellular level. Hormone patterns can differ considerably between species. Another complication is that relative levels of expression vary substantially. This means that data are significantly influenced by the sensitivities of detection techniques. For example, a hormone that can be detected in storage vesicles by super-resolution microscopy may not be above threshold for detection by conventional fluorescence microscopy. New nomenclature for cell clusters with common attributes will need to be devised and old classifications abandoned.
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    Identification of enteroendocrine cells that express TRPA1 channels in the mouse intestine
    Cho, H-J ; Callaghan, B ; Bron, R ; Bravo, DM ; Furness, JB (SPRINGER, 2014-04)
    TRPA1 is an ion channel that detects specific chemicals in food and also transduces mechanical, cold and chemical stimulation. Its presence in sensory nerve endings is well known and recent evidence indicates that it is expressed by some gastrointestinal enteroendocrine cells (EEC). The purpose of the present work is to identify and quantify EEC that express TRPA1 in the mouse gastrointestinal tract. Combined in situ hybridisation histochemistry for TRPA1 and immunofluorescence for EEC hormones was used. TRPA1 expressing EEC were common in the duodenum and jejunum, were rare in the distal small intestine and were absent from the stomach and large intestine. In the duodenum and jejunum, TRPA1 occurred in EEC that contained both cholecystokinin (CCK) and 5-hydroxytryptamine (5HT) and in a small number of cells expressing 5HT but not CCK. TRPA1 was absent from CCK cells that did not express 5HT and from EEC containing glucagon-like insulinotropic peptide. Thus TRPA1 is contained in very specific EEC populations. It is suggested that foods such as garlic and cinnamon that contain TRPA1 stimulants may aid digestion by facilitating the release of CCK.