Oklahoma Center for Neuroscience

Oklahoma City, OK, United States

Oklahoma Center for Neuroscience

Oklahoma City, OK, United States
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Moloney R.D.,University College Cork | Moloney R.D.,The University of Oklahoma Health Sciences Center | Johnson A.C.,The University of Oklahoma Health Sciences Center | O'Mahony S.M.,University College Cork | And 5 more authors.
CNS Neuroscience and Therapeutics | Year: 2016

Visceral pain is a global term used to describe pain originating from the internal organs of the body, which affects a significant proportion of the population and is a common feature of functional gastrointestinal disorders (FGIDs) such as irritable bowel syndrome (IBS). While IBS is multifactorial, with no single etiology to completely explain the disorder, many patients also experience comorbid behavioral disorders, such as anxiety or depression; thus, IBS is described as a disorder of the gut-brain axis. Stress is implicated in the development and exacerbation of visceral pain disorders. Chronic stress can modify central pain circuitry, as well as change motility and permeability throughout the gastrointestinal (GI) tract. More recently, the role of the gut microbiota in the bidirectional communication along the gut-brain axis, and subsequent changes in behavior, has emerged. Thus, stress and the gut microbiota can interact through complementary or opposing factors to influence visceral nociceptive behaviors. This review will highlight the evidence by which stress and the gut microbiota interact in the regulation of visceral nociception. We will focus on the influence of stress on the microbiota and the mechanisms by which microbiota can affect the stress response and behavioral outcomes with an emphasis on visceral pain. © 2016 John Wiley & Sons Ltd.

Zhong Y.,The University of Oklahoma Health Sciences Center | Zhong Y.,University of Oklahoma | Zhong Y.,Sun Yat Sen University | Li J.,The University of Oklahoma Health Sciences Center | And 19 more authors.
PLoS ONE | Year: 2012

Damage to the retinal pigment epithelium (RPE) is an early event in the pathogenesis of age-related macular degeneration (AMD). X-box binding protein 1 (XBP1) is a key transcription factor that regulates endoplasmic reticulum (ER) homeostasis and cell survival. This study aimed to delineate the role of endogenous XBP1 in the RPE. Our results show that in a rat model of light-induced retinal degeneration, XBP1 activation was suppressed in the RPE/choroid complex, accompanied by decreased anti-oxidant genes and increased oxidative stress. Knockdown of XBP1 by siRNA resulted in reduced expression of SOD1, SOD2, catalase, and glutathione synthase and sensitized RPE cells to oxidative damage. Using Cre/LoxP system, we generated a mouse line that lacks XBP1 only in RPE cells. Compared to wildtype littermates, RPE-XBP1 KO mice expressed less SOD1, SOD2, and catalase in the RPE, and had increased oxidative stress. At age 3 months and older, these mice exhibited apoptosis of RPE cells, decreased number of cone photoreceptors, shortened photoreceptor outer segment, reduced ONL thickness, and deficit in retinal function. Electron microscopy showed abnormal ultrastructure, Bruch's membrane thickening, and disrupted basal membrane infolding in XBP1-deficient RPE. These results indicate that XBP1 is an important gene involved in regulation of the anti-oxidant defense in the RPE, and that impaired activation of XBP1 may contribute to RPE dysfunction and cell death during retinal degeneration and AMD. © 2012 Zhong et al.

Donica C.L.,Oklahoma Center for Neuroscience | Awwad H.O.,Oklahoma Center for Neuroscience | Awwad H.O.,The University of Oklahoma Health Sciences Center | Thakker D.R.,University of Houston | And 2 more authors.
Molecular Pharmacology | Year: 2013

The nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor is the fourth and most recently discovered member of the opioid receptor superfamily that also includes m, d, and k opioid receptor subtypes (MOR, DOR, and KOR, respectively). The widespread anatomic distribution of the NOP receptor enables the modulation of several physiologic processes by its endogenous agonist, N/OFQ. Accordingly, the NOP receptor has gained a lot of attention as a potential target for the development of ligands with therapeutic use in several pathophysiological states. NOP receptor activation frequently results in effects opposing classic opioid receptor action; therefore, regulation of the NOP receptor and conditions affecting its modulatory tone are important to understand. Mounting evidence reveals a heterologous interaction of the NOP receptor with other G protein-coupled receptors, including MOR, DOR, and KOR, which may subsequently influence their function. Our focus in this review is to summarize and discuss the findings that delineate the cellular mechanisms of NOP receptor signaling and regulation and the regulation of other receptors by N/OFQ and the NOP receptor. © 2013 by The American Society for Pharmacology and Experimental Therapeutics.

Doblas S.,Oklahoma Medical Research Foundation | Doblas S.,French Institute of Health and Medical Research | He T.,Oklahoma Medical Research Foundation | He T.,Oklahoma Center for Neuroscience | And 8 more authors.
NMR in Biomedicine | Year: 2012

The assessment of metabolites by 1H MRS can provide information regarding glioma growth, and may be able to distinguish between different glioma models. Rat C6, 9L/LacZ, F98 and RG2, and mouse GL261, cells were intracerebrally implanted into the respective rodents, and human U87 MG cells were implanted into athymic rats. Ethyl-nitrosourea induction was also used. Glioma metabolites [e.g. total choline (tCho), total creatine (tCr), N-acetylaspartate (NAA), lactate (Lac), glutamine (Gln), glutamate (Glu), aspartate (Asp), guanosine (Gua), mobile lipids and macromolecules (MMs)] were assessed from 1H MRS using point-resolved spectroscopy (PRESS) [TE=24ms; TR=2500ms; variable pulse power and optimized relaxation delay (VAPOR) water suppression; 27-μL and 8-μL voxels in rats and mice, respectively] at 7T. Alterations in metabolites (Totally Automatic Robust Quantitation in NMR, TARQUIN) in tumors were characterized by increases in lipids (Lip1.3: 8.8-54.5m m for C6 and GL261) and decreases in NAA (1.3-2.0m m for RG2, GL261 and C6) and tCr (0.8-4.0m m for F98, RG2, GL261 and C6) in some models. F98, RG2, GL261 and C6 models all showed significantly decreased (p<0.05) tCr, and RG2, GL261 and C6 models all exhibited significantly decreased (p<0.05) NAA. The RG2 model showed significantly decreased (p<0.05) Gln and Glu, the C6 model significantly decreased (p<0.05) Asp, and the F98 and U87 models significantly decreased (p<0.05) Gua, compared with controls. The GL261 model showed the greatest alterations in metabolites. 1H MRS was able to differentiate the metabolic profiles in many of the seven rodent glioma models assessed. These models are considered to resemble certain characteristics of human glioblastomas, and this study may be helpful in selecting appropriate models. © 2011 John Wiley & Sons, Ltd.

Zhou X.,University of Oklahoma | Zhou X.,Massachusetts Eye and Ear Infirmary | Wong L.L.,University of Oklahoma | Karakoti A.S.,University of Oklahoma | And 6 more authors.
PLoS ONE | Year: 2011

Many neurodegenerative diseases are known to occur and progress because of oxidative stress, the presence of reactive oxygen species (ROS) in excess of the cellular defensive capabilities. Age related macular degeneration (AMD), diabetic retinopathy (DR) and inherited retinal degeneration share oxidative stress as a common node upstream of the blinding effects of these diseases. Knockout of the Vldlr gene results in a mouse that develops intraretinal and subretinal neovascular lesions within the first month of age and is an excellent model for a form of AMD called retinal angiomatous proliferation (RAP). Cerium oxide nanoparticles (nanoceria) catalytically scavenge ROS by mimicking the activities of superoxide dismutase and catalase. A single intravitreal injection of nanoceria into the Vldlr-/- eye was shown to inhibit: the rise in ROS in the Vldlr-/- retina, increases in vascular endothelial growth factor (VEGF) in the photoreceptor layer, and the formation of intraretinal and subretinal neovascular lesions. Of more therapeutic interest, injection of nanoceria into older mice (postnatal day 28) resulted in the regression of existing vascular lesions indicating that the pathologic neovessels require the continual production of excessive ROS. Our data demonstrate the unique ability of nanoceria to prevent downstream effects of oxidative stress in vivo and support their therapeutic potential for treatment of neurodegenerative diseases such as AMD and DR. © 2011 Zhou et al.

Doblas S.,Oklahoma Medical Research Foundation | He T.,Oklahoma Medical Research Foundation | He T.,Oklahoma Center for Neuroscience | Saunders D.,Oklahoma Medical Research Foundation | And 6 more authors.
Journal of Magnetic Resonance Imaging | Year: 2010

Purpose: To evaluate the added value of non-contrast-enhanced MR angiography (MRA) to conventional MR imaging for a detailed characterization of different rodent glioma models. Materials and Methods: Intracerebral tumor cell implantation and chemical induction methods were implemented to obtain rat C6, 9L/LacZ, F98, RG2, and ethyl-nitrosourea (ENU) -induced glioma models, a human U87 MG tumor model as well as a mouse GL261 glioma model. MR assessments were regularly conducted on a 7 Tesla Bruker BioSpin system. The tumor border sharpness and growth characteristics of each glioma model were assessed from T 2-weighted images. Neovascularization and vascular alterations inherent to each model were characterized by assessing absolute blood volumes, vessel density, length, and diameter using Mathematica and Amira software. Results: The 9L/LacZ and ENU gliomas both presented flaws that hinder their use as reliable brain tumor models. C6 gliomas were slightly invasive and induced moderate vascular alterations, whereas GL261 tumors dramatically altered the brain vessels in the glioma region. F98, RG2, and U87 are infiltrative models that produced dramatic vascular alterations. Conclusion: MRI and MRA provided crucial in vivo information to identify a distinctive "fingerprint" for each of our seven rodent glioma models. © 2010 Wiley-Liss, Inc.

PubMed | The University of Oklahoma Health Sciences Center, Oklahoma Center for Neuroscience, Reynolds Oklahoma Center on Aging, Pennsylvania State University and 2 more.
Type: | Journal: Epigenetics & chromatin | Year: 2016

Changes to the epigenome with aging, and DNA modifications in particular, have been proposed as a central regulator of the aging process, a predictor of mortality, and a contributor to the pathogenesis of age-related diseases. In the central nervous system, control of learning and memory, neurogenesis, and plasticity require changes in cytosine methylation and hydroxymethylation. Although genome-wide decreases in methylation with aging are often reported as scientific dogma, primary research reports describe decreases, increases, or lack of change in methylation and hydroxymethylation and their principle regulators, DNA methyltransferases and ten-eleven translocation dioxygenases in the hippocampus. Furthermore, existing data are limited to only male animals.Through examination of the hippocampus in young, adult, and old male and female mice by antibody-based, pyrosequencing, and whole-genome oxidative bisulfite sequencing methods, we provide compelling evidence that contradicts the genomic hypomethylation theory of aging. We also demonstrate that expression of DNA methyltransferases and ten-eleven translocation dioxygenases is not differentially regulated with aging or between the sexes, including the proposed cognitive aging regulator DNMT3a2. Using oxidative bisulfite sequencing that discriminates methylation from hydroxymethylation and by cytosine (CG and non-CG) context, we observe sex differences in average CG methylation and hydroxymethylation of the X chromosome, and small age-related differences in hydroxymethylation of CG island shores and shelves, and methylation of promoter regions.These findings clarify a long-standing misconception of the epigenomic response to aging and demonstrate the need for studies of base-specific methylation and hydroxymethylation with aging in both sexes.

Chaloner A.,Medical Center 151G | Chaloner A.,Oklahoma Center for Neuroscience | Greenwood-Van Meerveld B.,Medical Center 151G | Greenwood-Van Meerveld B.,Oklahoma Center for Neuroscience | Greenwood-Van Meerveld B.,The University of Oklahoma Health Sciences Center
Journal of Pain | Year: 2013

Visceral pain is the hallmark feature of irritable bowel syndrome (IBS), a gastrointestinal disorder, which is more commonly diagnosed in women. Female IBS patients frequently report a history of early life adversity (ELA); however, sex differences in ELA-induced visceral pain and the role of ovarian hormones have yet to be investigated. Therefore, we tested the hypothesis that ELA induces visceral hypersensitivity through a sexually dimorphic mechanism mediated via estradiol. As a model of ELA, neonatal rats were exposed to different pairings of an odor and shock to control for trauma predictability. In adulthood, visceral sensitivity was assessed via a visceromotor response to colorectal distension. Following ovariectomy and estradiol replacement in a separate group of rats, the visceral sensitivity was quantified. We found that females that received unpredictable odor-shock developed visceral hypersensitivity in adulthood. In contrast, visceral sensitivity was not significantly different following ELA in adult males. Ovariectomy reversed visceral hypersensitivity following unpredictable ELA, whereas estradiol replacement reestablished visceral hypersensitivity in the unpredictable group. This study is the first to show sex-related differences in visceral sensitivity following unpredictable ELA. Our data highlight the activational effect of estradiol as a pivotal mechanism in maintaining visceral hypersensitivity. Perspective: This article directly implicates a critical role for ovarian hormones in maintaining visceral hypersensitivity following ELA, specifically identifying the activational effect of estradiol as a key modulator of visceral sensitivity. These data suggest that ELA induces persistent functional abdominal pain in female IBS patients through an estrogen-dependent mechanism. © 2013 by the American Pain Society.

Tran L.,Oklahoma Center for Neuroscience | Greenwood-Van Meerveld B.,Oklahoma Center for Neuroscience | Greenwood-Van Meerveld B.,The University of Oklahoma Health Sciences Center
Journals of Gerontology - Series A Biological Sciences and Medical Sciences | Year: 2013

Disorders of the gastrointestinal tract are common in the elderly people; however, the precise trait(s) of aging that contribute to the vulnerability of the gastrointestinal tract are poorly understood. Recent evidence suggests that patients with gastrointestinal disorders have increased intestinal permeability. Here, we address the hypothesis that disruption of the intestinal barrier is associated with aging. Our results demonstrated that permeability was significantly higher in colonic biopsies collected from old baboons compared with young baboons. Additionally, colonic tissue from the older animals had decreased zonula occluden-1, occludin, and junctional adhesion molecule-A tight junction protein expression and increased claudin-2 expression. Upregulation of miR-29a and inflammatory cytokines IFN-γ, IL-6, and IL-1β was also found in colonic biopsies from old baboons relative to young baboons. These results show for the first time that a pivotal contributing factor to geriatric vulnerability to gastrointestinal dysfunction may be increased colonic permeability via age-associated remodeling of intestinal epithelial tight junction proteins. © 2013 The Author.

Griffith G.L.,The University of Oklahoma Health Sciences Center | Russell R.A.,The University of Oklahoma Health Sciences Center | Kasus-Jacobi A.,The University of Oklahoma Health Sciences Center | Kasus-Jacobi A.,Oklahoma Center for Neuroscience | And 5 more authors.
Investigative Ophthalmology and Visual Science | Year: 2013

PURPOSE. The objective of this study was to elucidate the signaling pathway through which cationic antimicrobial protein of 37 kDa (CAP37) mediates human corneal epithelial cell (HCEC) chemotaxis. METHODS. Immortalized HCECs were treated with pertussis toxin (10 and 1000 ng/mL), protein kinase C (PKC) inhibitors (calphostin c, 50 nM and Ro-31-8220, 100 nM), phorbol esters (phorbol 12,13-dibutyrate, 200 nM and phorbol 12-myristate 13-acetate, 1 lM) known to deplete PKC isoforms, and siRNAs (400 nM) before a modified Boyden chamber assay was used to determine the effect of these inhibitors and siRNAs on CAP37-directed HCEC migration. PKCd protein levels, PKCd-Thr505 phosphorylation, and PKCd kinase activity was assessed in CAP37-treated HCECs using immunohistochemistry, Western blotting, and a kinase activity assay, respectively. RESULTS. Chemotaxis studies revealed that treatment with pertussis toxin, PKC inhibitors, phorbol esters, and siRNAs significantly inhibited CAP37-mediated chemotaxis compared with untreated controls. CAP37 treatment increased PKCδ protein levels and led to PKCd phosphorylation on residue Thr505. Direct activation of PKCδ by CAP37 was demonstrated using a kinase activity assay. CONCLUSIONS. These findings lead us to conclude that CAP37 is an important regulator of corneal epithelial cell migration and mediates its effects through PKCδ. © 2013 The Association for Research in Vision and Ophthalmology, Inc.

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