Anatomy and Neuroscience - Research Publications
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ItemThe first brain: Species comparisons and evolutionary implications for the enteric and central nervous systems(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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ItemA comparison of the anatomical and gastrointestinal functional development between gilt and sow progeny around birth and weaning(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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ItemMuscarinic receptor 1 allosteric modulators stimulate colorectal emptying in dog, mouse and rat and resolve constipation(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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ItemDiversity of enteroendocrine cells investigated at cellular and subcellular levels: the need for a new classification scheme(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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ItemAn objective in vivo diagnostic method for inflammatory bowel disease(ROYAL SOC, 2018-03)Inflammatory damage to the bowel, as occurs in inflammatory bowel disease (IBD), is debilitating to patients. In both patients and animal experimental models, histological analyses of biopsies and endoscopic examinations are used to evaluate the disease state. However, such measurements often have delays and are invasive, while endoscopy is not quantitatively objective. Therefore, a real-time quantitative method to assess compromised mucosal barrier function is advantageous. We investigated the correlation of in vivo changes in electrical transmural impedance with histological measures of inflammation. Four platinum (Pt) ball electrodes were placed in the lumen of the rat small intestine, with a return electrode under the skin. Electrodes placed within the non-inflamed intestine generated stable impedances during the 3 h testing period. Following an intraluminal injection of 2,4,6-trinitrobenzene sulfonic acid (TNBS), an established animal model of IBD, impedances in the inflamed region significantly decreased relative to a region not exposed to TNBS (p < 0.05). Changes in intestinal transmural impedance were correlated (p < 0.05) with histologically assessed damage to the mucosa and increases in neutrophil, eosinophil and T-cell populations at 3 h compared with tissue from control regions. This quantitative, real-time assay may have application in the diagnosis and clinical management of IBD.
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ItemAnti-inflammatory Effects of Abdominal Vagus Nerve Stimulation on Experimental Intestinal Inflammation(FRONTIERS MEDIA SA, 2019-05-08)Electrical stimulation of the cervical vagus nerve is an emerging treatment for inflammatory bowel disease (IBD). However, side effects from cervical vagal nerve stimulation (VNS) are often reported by patients. Here we hypothesized that stimulating the vagus nerve closer to the end organ will have fewer off-target effects and will effectively reduce intestinal inflammation. Specifically, we aimed to: (i) compare off-target effects during abdominal and cervical VNS; (ii) verify that VNS levels were suprathreshold; and (iii) determine whether abdominal VNS reduces chemically-induced intestinal inflammation in rats. An electrode array was developed in-house to stimulate and record vagal neural responses. In a non-recovery experiment, stimulation-induced off-target effects were measured by implanting the cervical and abdominal vagus nerves of anaesthetized rats (n = 5) and recording changes to heart rate, respiration and blood pressure during stimulation (10 Hz; symmetric biphasic current pulse; 320 nC per phase). In a chronic experiment, the efficacy of VNS treatment was assessed by implanting an electrode array onto the abdominal vagus nerve and recording in vivo electrically-evoked neural responses during the implantation period. After 14 days, the intestine was inflamed with TNBS (2.5% 2,4,6-trinitrobenzene sulphonic acid) and rats received therapeutic VNS (n = 7; 10 Hz; 320 nC per phase; 3 h/day) or no stimulation (n = 8) for 4.5 days. Stool quality, plasma C-reactive protein and histology of the inflamed intestine were assessed. Data show that abdominal VNS had no effect (two-way RM-ANOVA: P ≥ 0.05) on cardiac, respiratory and blood pressure parameters. However, during cervical VNS heart rate decreased by 31 ± 9 beats/minute (P ≥ 0.05), respiration was inhibited and blood pressure decreased. Data addressing efficacy of VNS treatment show that electrically-evoked neural response thresholds remained stable (one-way RM ANOVA: P ≥ 0.05) and therapeutic stimulation remained above threshold. Chronically stimulated rats, compared to unstimulated rats, had improved stool quality (two-way RM ANOVA: P < 0.0001), no blood in feces (P < 0.0001), reduced plasma C-reactive protein (two-way RM ANOVA: P < 0.05) and a reduction in resident inflammatory cell populations within the intestine (Kruskal-Wallis: P < 0.05). In conclusion, abdominal VNS did not evoke off-target effects, is an effective treatment of TNBS-induced inflammation, and may be an effective treatment of IBD in humans.
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ItemBetaine and Antioxidants Improve Growth Performance, Breast Muscle Development and Ameliorate Thermoregulatory Responses to Cyclic Heat Exposure in Broiler Chickens(MDPI, 2018-10)Heat stress (HS) is an environmental stressor challenging poultry production and requires a strategy to cope with it. A total of 288-day-old male broiler chicks were fed with one of the following diets: basal diet, basal with betaine (BET), or with selenium and vitamin E (AOX), or with a combination of BET and AOX, under thermoneutral and cyclic HS. Results showed that HS reduced average daily feed intake (ADFI) (p = 0.01) and average daily gain (ADG) (p < 0.001), and impaired feed conversion ratio (FCR) (p = 0.03) during rearing period (0⁻42 day). BET increased ADG (p = 0.001) and decreased FCR (p = 0.02), whereas AOX had no effects. Breast muscle weight was decreased by HS (p < 0.001) and increased by BET (p < 0.001). Rectal temperature was increased by HS (p < 0.001) and improved by BET overall. Respiration rate was increased by HS (p < 0.001), but BET decreased it during HS (p = 0.04). Jejunum transepithelial resistance was reduced by HS and had no effect on permeability whereas BET increased jejunum permeability (p = 0.013). Overall, the reductions in ADG of broiler chickens during HS were ameliorated by supplementation with BET, with much of the increase in ADG being breast muscle.
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ItemCalibration of thresholds for functional engagement of vagal A, B and C fiber groups in vivo.(Future Medicine Ltd, 2018-01)UNLABELLED: Vagal nerve stimulation is widely used therapeutically but the fiber groups activated are often unknown. AIM: To establish a simple protocol to define stimulus thresholds for vagal A, B and C fibers. METHODS: The intact left or right cervical vagus was stimulated with 0.1 ms pulses in spontaneously breathing anesthetized rats. Heart and respiratory rate responses to vagal stimulation were recorded. The vagus was subsequently cut distally, and mass action potentials to the same stimuli were recorded. RESULTS: Stimulating at either 50 Hz for 2 s or 2 Hz for 10 s at experimentally determined strengths revealed A, B and C fiber thresholds that were related to respiratory and heart rate changes. CONCLUSION: Our simple protocol discriminates vagal A, B and C fiber thresholds in vivo.