Anatomy and Neuroscience - Research Publications
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ItemPurinergic mechanisms in the control of gastrointestinal motility(SPRINGER, 2008-09)For many years, ATP and adenosine have been implicated in movement regulation of the gastrointestinal tract. They act through three major receptor subtypes: adenosine or P1 receptors, P2X receptors and P2Y receptors. Each of these major receptor types can be subdivided into several different classes and is widely distributed amongst various neurons, muscle types, glia and interstitial cells that regulate intestinal functions. Several key roles for the different receptors and their endogenous ligands have been identified in physiological and pharmacological studies. For example, adenosine acting at A(1) receptors appears to inhibit intestinal motility in various pathological conditions. Similarly, ATP acting at P2Y receptors is an important component of inhibitory neuromuscular transmission, acting as a cotransmitter with nitric oxide. ATP acting at P2X and P2Y(1) receptors is important for synaptic transmission in simple descending excitatory and inhibitory reflex pathways. Some P2Y receptor subtypes prefer uridine nucleotides over purine nucleotides. Thus, roles for UTP and UDP as enteric transmitters in place of ATP cannot be excluded. ATP also appears to be important for sensory transduction, especially in chemosensitive pathways that initiate local inhibitory reflexes. Despite this evidence, data are lacking about the roles of either adenosine or ATP in more complex motility patterns such as segmentation or the interdigestive migrating motor complex. Clarification of roles for purinergic transmission in these common, but understudied, motility patterns will depend on the use of subtype-specific antagonists that in some cases have not yet been developed.
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ItemExpression of muscarinic receptor subtypes in tree shrew ocular tissues and their regulation during the development of myopia(MOLECULAR VISION, 2009-03-02)PURPOSE: Muscarinic receptors are known to regulate several important physiologic processes in the eye. Antagonists to these receptors such as atropine and pirenzepine are effective at stopping the excessive ocular growth that results in myopia. However, their site of action is unknown. This study details ocular muscarinic subtype expression within a well documented model of eye growth and investigates their expression during early stages of myopia induction. METHODS: Total RNA was isolated from tree shrew corneal, iris/ciliary body, retinal, choroidal, and scleral tissue samples and was reverse transcribed. Using tree shrew-specific primers to the five muscarinic acetylcholine receptor subtypes (CHRM1-CHRM5), products were amplified using polymerase chain reaction (PCR) and their identity confirmed using automated sequencing. The expression of the receptor proteins (M1-M5) were also explored in the retina, choroid, and sclera using immunohistochemistry. Myopia was induced in the tree shrew for one or five days using monocular deprivation of pattern vision, and the expression of the receptor subtypes was assessed in the retina, choroid, and sclera using real-time PCR. RESULTS: All five muscarinic receptor subtypes were expressed in the iris/ciliary body, retina, choroid, and sclera while gene products corresponding to CHRM1, CHRM3, CHRM4, and CHRM5 were present in the corneal samples. The gene expression data were confirmed by immunohistochemistry with the M1-M5 proteins detected in the retina, choroid, and sclera. After one or five days of myopia development, muscarinic receptor gene expression remained unaltered in the retinal, choroidal, and scleral tissue samples. CONCLUSIONS: This study provides a comprehensive profile of muscarinic receptor gene and protein expression in tree shrew ocular tissues with all receptor subtypes found in tissues implicated in the control of eye growth. Despite the efficacy of muscarinic antagonists at inhibiting myopia development, the genes of the muscarinic receptor subtypes are neither regulated early in myopia (before measurable axial elongation) nor after significant structural change.
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ItemBMP receptor signaling is required for postnatal maintenance of articular cartilage(PUBLIC LIBRARY SCIENCE, 2004-11)Articular cartilage plays an essential role in health and mobility, but is frequently damaged or lost in millions of people that develop arthritis. The molecular mechanisms that create and maintain this thin layer of cartilage that covers the surface of bones in joint regions are poorly understood, in part because tools to manipulate gene expression specifically in this tissue have not been available. Here we use regulatory information from the mouse Gdf5 gene (a bone morphogenetic protein [BMP] family member) to develop new mouse lines that can be used to either activate or inactivate genes specifically in developing joints. Expression of Cre recombinase from Gdf5 bacterial artificial chromosome clones leads to specific activation or inactivation of floxed target genes in developing joints, including early joint interzones, adult articular cartilage, and the joint capsule. We have used this system to test the role of BMP receptor signaling in joint development. Mice with null mutations in Bmpr1a are known to die early in embryogenesis with multiple defects. However, combining a floxed Bmpr1a allele with the Gdf5-Cre driver bypasses this embryonic lethality, and leads to birth and postnatal development of mice missing the Bmpr1a gene in articular regions. Most joints in the body form normally in the absence of Bmpr1a receptor function. However, articular cartilage within the joints gradually wears away in receptor-deficient mice after birth in a process resembling human osteoarthritis. Gdf5-Cre mice provide a general system that can be used to test the role of genes in articular regions. BMP receptor signaling is required not only for early development and creation of multiple tissues, but also for ongoing maintenance of articular cartilage after birth. Genetic variation in the strength of BMP receptor signaling may be an important risk factor in human osteoarthritis, and treatments that mimic or augment BMP receptor signaling should be investigated as a possible therapeutic strategy for maintaining the health of joint linings.
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ItemImmunolocalization of serotonin in Onychophora argues against segmental ganglia being an ancestral feature of arthropods.(Springer Science and Business Media LLC, 2007-07-15)BACKGROUND: Onychophora (velvet worms) represent the most basal arthropod group and play a pivotal role in the current discussion on the evolution of nervous systems and segmentation in arthropods. Although there is a wealth of information on the immunolocalization of serotonin (5-hydroxytryptamine, 5-HT) in various euarthropods, as yet no comparable localization data are available for Onychophora. In order to understand how the onychophoran nervous system compares to that of other arthropods, we studied the distribution of serotonin-like immunoreactive neurons and histological characteristics of ventral nerve cords in Metaperipatus blainvillei (Onychophora, Peripatopsidae) and Epiperipatus biolleyi (Onychophora, Peripatidae). RESULTS: We demonstrate that paired leg nerves are the only segmental structures associated with the onychophoran nerve cord. Although the median commissures and peripheral nerves show a repeated pattern, their arrangement is independent from body segments characterized by the position of legs and associated structures. Moreover, the somata of serotonin-like immunoreactive neurons do not show any ordered arrangement in both species studied but are instead scattered throughout the entire length of each nerve cord. We observed neither a serially iterated nor a bilaterally symmetric pattern, which is in contrast to the strictly segmental arrangement of serotonergic neurons in other arthropods. CONCLUSION: Our histological findings and immunolocalization experiments highlight the medullary organization of the onychophoran nerve cord and argue against segmental ganglia of the typical euarthropodan type being an ancestral feature of Onychophora. These results contradict a priori assumptions of segmental ganglia being an ancestral feature of arthropods and, thus, weaken the traditional Articulata hypothesis, which proposes a sistergroup relationship of Annelida and Arthropoda.
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ItemNo Preview AvailableType 1 angiotensin receptor pharmacology: signaling beyond G proteins.(Elsevier BV, 2007-01)Drugs that inhibit the production of angiotensin II (AngII) or its access to the type 1 angiotensin receptor (AT(1)R) are prescribed to alleviate high blood pressure and its cardiovascular complications. Accordingly, much research has focused on the molecular pharmacology of AT(1)R activation and signaling. An emerging theme is that the AT(1)R generates G protein dependent as well as independent signals and that these transduction systems separately contribute to AT(1)R biology in health and disease. Regulatory molecules termed arrestins are central to this process as is the capacity of AT(1)R to crosstalk with other receptor systems, such as the widely studied transactivation of growth factor receptors. AT(1)R function can also be modulated by polymorphisms in the AGTR gene, which may significantly alter receptor expression and function; a capacity of the receptor to dimerize/oligomerize with altered pharmacology; and by the cellular environment in which the receptor resides. Together, these aspects of the AT(1)R "flavour" the response to angiotensin; they may also contribute to disease, determine the efficacy of current drugs and offer a unique opportunity to develop new therapeutics that antagonize only selective facets of AT(1)R function.
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ItemNo Preview AvailableAn Integrated Object Model and Method Framework for Subject-Centric e-Research Applications.(Frontiers Media SA, 2009)A framework that integrates an object model, research methods (workflows), the capture of experimental data sets and the provenance of those data sets for subject-centric research is presented. The design of the Framework object model draws on and extends pre-existing object models in the public domain. In particular the Framework tracks the state and life cycle of a subject during an experimental method, provides for reusable subjects, primary, derived and recursive data sets of arbitrary content types, and defines a user-friendly and practical scheme for citably identifying information in a distributed environment. The Framework is currently used to manage neuroscience Magnetic Resonance and microscopy imaging data sets in both clinical and basic neuroscience research environments. The Framework facilitates multi-disciplinary and collaborative subject-based research, and extends earlier object models used in the research imaging domain. Whilst the Framework has been explicitly validated for neuroimaging research applications, it has broader application to other fields of subject-centric research.
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ItemNo Preview AvailableGenetic control of the innate immune response.(Springer Science and Business Media LLC, 2003-06-26)BACKGROUND: Susceptibility to infectious diseases is directed, in part, by the interaction between the invading pathogen and host macrophages. This study examines the influence of genetic background on host-pathogen interactions, by assessing the transcriptional responses of macrophages from five inbred mouse strains to lipopolysaccharide (LPS), a major determinant of responses to gram-negative microorganisms. RESULTS: The mouse strains examined varied greatly in the number, amplitude and rate of induction of genes expressed in response to LPS. The response was attenuated in the C3H/HeJlpsd strain, which has a mutation in the LPS receptor Toll-like receptor 4 (TLR4). Variation between mouse strains allowed clustering into early (C57Bl/6J and DBA/2J) and delayed (BALB/c and C3H/ARC) transcriptional phenotypes. There was no clear correlation between gene induction patterns and variation at the Bcg locus (Slc11A1) or propensity to bias Th1 versus Th2 T cell activation responses. CONCLUSION: Macrophages from each strain responded to LPS with unique gene expression profiles. The variation apparent between genetic backgrounds provides insights into the breadth of possible inflammatory responses, and paradoxically, this divergence was used to identify a common transcriptional program that responds to TLR4 signalling, irrespective of genetic background. Our data indicates that many additional genetic loci control the nature and the extent of transcriptional responses promoted by a single pathogen-associated molecular pattern (PAMP), such as LPS.
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ItemNo Preview AvailableLocalisation of GPR30, a novel G protein-coupled oestrogen receptor, suggests multiple functions in rodent brain and peripheral tissues(BIOSCIENTIFICA LTD, 2009-08)Recently, the G protein-coupled receptor GPR30 has been identified as a novel oestrogen receptor (ER). The distribution of the receptor has been thus far mapped only in the rat central nervous system. This study was undertaken to map the distribution of GPR30 in the mouse brain and rodent peripheral tissues. Immunohistochemistry using an antibody against GPR30 revealed high levels of GPR30 immunoreactivity (ir) in the forebrain (e.g. cortex, hypothalamus and hippocampus), specific nuclei of the midbrain (e.g. the pontine nuclei and locus coeruleus) and the trigeminal nuclei and cerebellum Purkinje layer of the hindbrain in the adult mouse brain. In the rat and mouse periphery, GPR30-ir was detected in the anterior, intermediate and neural lobe of the pituitary, adrenal medulla, renal pelvis and ovary. In situ hybridisation histochemistry using GPR30 riboprobes, revealed intense hybridisation signal for GPR30 in the paraventricular nucleus and supraoptic nucleus (SON) of the hypothalamus, anterior and intermediate lobe of the pituitary, adrenal medulla, renal pelvis and ovary of both rat and mouse. Double immunofluorescence revealed GPR30 was present in both oxytocin and vasopressin neurones of the paraventricular nucleus and SON of the rat and mouse brain. The distribution of GPR30 is distinct from the other traditional ERs and offers an additional way in which oestrogen may mediate its effects in numerous brain regions and endocrine systems in the rodent.
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ItemNo Preview AvailablemGluR1 receptors contribute to non-purinergic slow excitatory transmission to submucosal VIP neurons of guinea-pig ileum(FRONTIERS MEDIA SA, 2009)Vasoactive intestinal peptide (VIP) immunoreactive secretomotor neurons in the submucous plexus are involved in mediating bacterial toxin-induced hypersecretion leading to diarrhoea. VIP neurons become hyperexcitable after the mucosa is exposed to cholera toxin, which suggests that the manipulation of the excitability of these neurons may be therapeutic. This study used standard intracellular recording methods to systematically characterize slow excitatory postsynaptic potentials (EPSPs) evoked in submucosal VIP neurons by different stimulus regimes (1, 3 and 15 pulse 30 Hz stimulation), together with their associated input resistances and pharmacology. All slow EPSPs were associated with a significant increase in input resistance compared to baseline values. Slow EPSPs evoked by a single stimulus were confirmed to be purinergic, however, slow EPSPs evoked by 15 pulse trains were non-purinergic and those evoked by 3 pulse trains were mixed. NK(1) or NK(3) receptor antagonists did not affect slow EPSPs. The group I mGluR receptor antagonist, PHCCC reduced the amplitude of purinergic and non-purinergic slow EPSPs. Blocking mGluR(1) receptors depressed the overall response to 3 and 15 pulse trains, but this effect was inconsistent, while blockade of mGluR(5) receptors had no effect on the non-purinergic slow EPSPs. Thus, although other receptors are almost certainly involved, our data indicate that there are at least two pharmacologically distinct types of slow EPSPs in the VIP secretomotor neurons: one mediated by P2Y receptors and the other in part by mGluR(1) receptors.
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ItemNo Preview AvailableDevelopment of enteric neuron diversity(WILEY, 2009-07)The mature enteric nervous system (ENS) is composed of many different neuron subtypes and enteric glia, which all arise from the neural crest. How this diversity is generated from neural crest-derived cells is a central question in neurogastroenterology, as defects in these processes are likely to underlie some paediatric motility disorders. Here we review the developmental appearance (the earliest age at which expression of specific markers can be localized) and birthdates (the age at which precursors exit the cell cycle) of different enteric neuron subtypes, and their projections to some targets. We then focus on what is known about the mechanisms underlying the generation of enteric neuron diversity and axon pathfinding. Finally, we review the development of the ENS in humans and the etiologies of a number of paediatric motility disorders.