DOCSLIB.ORG

Beyond Neurons: the Role of the Oligodendrocyte-Specific Gene Cnp1 in Major Depressive Disorder

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Beyond Neurons: the Role of the Oligodendrocyte-Specific Gene Cnp1 in Major Depressive Disorder BEYOND NEURONS: THE ROLE OF THE OLIGODENDROCYTE-SPECIFIC GENE CNP1 IN MAJOR DEPRESSIVE DISORDER by Nicole M. Edgar B.S. in Biology, Virginia Tech, 2001 M.S. in Biology, Virginia Tech, 2004 Submitted to the Graduate Faculty of the School of Medicine in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2011 UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE This dissertation was presented by Nicole M. Edgar It was defended on June 23rd, 2011 and was approved by Dr. J. Patrick Card, Professor, Neuroscience Dr. Gregg E. Homanics, Professor, Anesthesiology, Pharmacology and Chemical Biology Dr. David Lewis, Chair and Professor, Psychiatry Dr. Floh Thiels, Assistant Professor, Neurobiology Dr. Irwin Lucki, Professor, Psychiatry and Pharmacology Dissertation Advisor: Dr. Etienne Sibille, Professor, Psychiatry ii Copyright © by Nicole M. Edgar 2011 iii BEYOND NEURONS: THE ROLE OF THE OLIGODENDROCYTE-SPECIFIC GENE CNP1 IN MAJOR DEPRESSIVE DISORDER Nicole M. Edgar, M.S., Ph.D. University of Pittsburgh, 2011 Altered oligodendrocyte structure and function is implicated in major mental illnesses, including low density and reduced expression of oligodendrocyte-specific gene transcripts in major depressive disorder (MDD). These features are also observed in the unpredictable chronic mild stress (UCMS) and chronic corticosterone (CORT) rodent models of the illness; however, whether oligodendrocyte changes are a causal component of MDD is not known. The oligodendrocyte-specific gene 2’-3’-cyclic nucleotide-3’-phosphodiesterase (CNP1) is a key component of axoglial communication and has previously been implicated in psychiatric disorders. A recent study in our lab found decreased levels of CNP1 in the amygdala (a central region of mood regulation) of human post-mortem MDD subjects and mice exposed to UCMS. In an attempt to determine whether altered CNP1 (or disrupted oligodendrocyte integrity) represents a causal factor in MDD, we investigated MDD-related features in mice lacking CNP1 (CNP1KO mice). In terms of technical development, we: 1) initiated use of a novel Z-score normalization procedure to counteract variability and extract a more comprehensive and translational view of our behavioral analyses, and 2) propose that the fear conditioning paradigm can be used to assess corticolimbic dysfunctions relating to mechanisms of MDD. Together, our studies in CNP1KO mice reveal a surprising profile of behavioral resilience that is accompanied by patterns of amygdala- iv related dysfunction. In addition, we show robust upregulation of oligodendrocyte and immune related transcripts in the basolateral amygdala of CNP1KO mice. This pattern is suggestive of compensatory changes for oligodendrocyte structure/function and indicative of an association between oligodendrocytes and immune function. Together, these studies demonstrate that disruption of oligodendrocyte function (via CNP1 ablation) can impact circuits mediating emotionality in mice resulting in abnormal affective behaviors. However, downstream molecular changes combined with the observation of longterm detrimental consequences in these mice (e.g. neurodegeneration), is suggestive of a maladaptive role for CNP1 in MDD. v TABLE OF CONTENTS 1.0 INTRODUCTION ............................................................................................ 16 1.1 MAJOR DEPRESSIVE DISORDER ....................................................... 17 1.1.1 Relevant Clinical Risk Factors for MDD ........................................ 19 1.1.1.1 Sex Differences in MDD ......................................................... 19 1.1.1.2 MDD and Age .......................................................................... 21 1.1.2 Neurobiology of MDD ..................................................................... 22 1.1.2.1 Neurocircuitry of MDD ........................................................... 22 1.1.2.2 Stress and Neuroendocrine Changes in MDD ..................... 26 1.1.2.3 Genetics of MDD ..................................................................... 27 1.2 USING RODENTS TO INVESTIGATE MDD .......................................... 28 1.2.1 Difficulties in Using Rodents to Investigate MDD ........................ 28 1.2.2 UCMS and CORT Rodents Models of Depression ....................... 30 1.2.2.1 Behavioral Correlates of MDD ............................................... 30 1.2.2.2 Cellular and Physiological Effects ........................................ 31 1.2.3 Circuitry Underlying Fear and Emotion in Rodents ..................... 34 1.2.3.1 Fear Conditioning ................................................................... 34 1.2.3.2 Fear Extinction ........................................................................ 35 1.2.3.3 Corticolimbic Coordination in Fear Conditioning ................ 37 1.2.3.4 Effects of Stress on Fear Conditioning ................................ 37 1.2.4 Using Knockout Mice ..................................................................... 38 1.3 THE ROLE OF GLIA IN MDD ................................................................ 39 1.3.1 Glial Structure and Function ......................................................... 39 1.3.1.1 Microglia .................................................................................. 40 1.3.1.2 Astrocytes ............................................................................... 41 vi 1.3.1.3 Oligodendrocytes ................................................................... 42 1.3.1.4 NG2 Cells................................................................................. 45 1.3.2 Glial Alterations in MDD ................................................................. 46 1.4 CNP ........................................................................................................ 50 1.4.1 Structure and Localization of CNP ................................................ 50 1.4.2 Function of CNP .............................................................................. 52 1.5 SUMMARY OF INTRODUCTION AND SIGNIFICANCE OF RESEARCH. ................................................................................................................ 54 2.0 PAPER 1: INTEGRATED BEHAVIORAL Z-SCORING INCREASES THE SENSITIVITY AND RELIABILITY OF BEHAVIORAL PHENOTYPING IN MICE: RELEVANCE TO EMOTIONALITY AND SEX ............................................................. 55 2.1 ABSTRACT ............................................................................................ 56 2.2 INTRODUCTION .................................................................................... 57 2.3 METHODS .............................................................................................. 59 2.4 RESULTS ............................................................................................... 64 2.5 DISCUSSION ......................................................................................... 80 3.0 PAPER 2: RESILIENT EMOTIONALITY AND MOLECULAR COMPENSATION IN MICE LACKING THE OLIGODENDROCYTE-SPECIFIC GENE CNP1 ....................................................................................................................... 86 3.1 ABSTRACT ............................................................................................ 87 3.2 INTRODUCTION .................................................................................... 88 3.3 MATERIALS AND METHODS ............................................................... 90 3.4 RESULTS ............................................................................................... 94 3.5 DISCUSSION ....................................................................................... 107 4.0 GENERAL DISCUSSION ............................................................................ 112 4.1 METHODOLOGICAL CONSIDERATIONS IN INVESTIGATING EMOTIONALITY .................................................................................................. 112 4.1.1 Z-score Normalization and Assessment of Emotionality .......... 113 4.1.2 Fear Conditioning and Assessment of Corticolimbic Function 114 4.1.3 Convergent Methodological Approaches Reveal Resilient Emotionality in CNP1KO Mice .................................................................... 118 vii 4.2 INFLUENCE OF EXAMINED RISK FACTORS ON BEHAVIORAL OUTPUTS............................................................................................................ 119 4.2.1 Effects of Risk Factors on Emotionality Outputs ...................... 119 4.2.1.1 Age ......................................................................................... 119 4.2.1.2 Sex ......................................................................................... 121 4.2.2 Effects of Risk Factors on Locomotor Outputs ......................... 123 4.3 INFLUENCE OF CNP1 ON THE NEUROBIOLOGY OF MOOD REGULATION ..................................................................................................... 124 4.3.1 Molecular Effects of CNP1 Ablation ............................................ 125 4.3.2 Cellular Effects of CNP1 Ablation ............................................... 127 4.3.2.1 Neuronal Alterations ............................................................ 127 4.3.2.2 Oligodendrocyte Alterations ............................................... 128 4.3.2.3 Paranodal Alterations .......................................................... 129 4.3.3 Circuit-Level Effects of CNP1 Ablation ......................................
Load more

Recommended publications
  • Download PDF Version- Volume 12, July 2012
    Volume 11, July 2012 History of Enrichment in the ILAR Guide for the Care and Use of Laboratory Animals • Drivers for Enrichment in Directive 2010/63/EU • Using Enrichment to Improve Welfare & Reduce Suffering • Tailoring Enrichment to GA Mice • Enrichment and Cephalopods • Evaluating Enrichment is Essential • Reporting Enrichment in Research Papers Volume 12, July 2012 THE Publisher:Global Research Education and Training, LLC Email: [email protected] RECORD Website: http://enrichmentrecord.com A GLOBAL VIEW OF ENVIRONMENTAL ENRICHMENT 4 SPRING 2010 | ENRICHMENTRECORD.COM www.vetbiotech.com IN THIS ISSUE SUMMER 2012 THE RECORD 2 In Other Words Call for Proposals 5 EDITORIAL BOARD Tim Allen, M.S. 7 Animal Welfare Information Center Upcoming Meetings Genevieve Andrews-Kelly, B.S., LATG Huntingdon Life Sciences History of Enrichment in the ILAR 10 Guide for the Care and Use of Laboratory Animals Elizabeth Dodemaide, B.V.Sc., M.A., MACVSc Associate Director, Laboratory Animal Services Rutgers, The State University of New Jersey Drivers for Enrichment in Directive 2010/63/EU 13 Karen Froberg-Fejko, V.M.D., President, Bio-Serv Joanne Gere, Founder, BioScience Collaborative Using Enrichment to Improve Welfare & Reduce Suffering 16 G. Scott Lett, Ph.D., CEO, The BioAnalytics Group LLC Jayne Mackta Tailoring Enrichment in GA Mice 20 President & CEO, Global Research Education & Training LLC Emily G. Patterson-Kane, Ph.D. Enrichment and Cephalopods 24 American Veterinary Medical Association (AVMA) Animal Welfare Division 29 Kathleen L. Smiler, D.V.M., DACLAM Evaluating Enrichment is Essential Consultant, Laboratory Animal Medicine Rhoda Weiner, Weiner & Associates Resources 33 Joanne Zurlo, Ph.D. Director of Science Strategy The Center for Alternatives to Animal Testing (CAAT) Reporting Enrichment in Research Papers 34 Please direct all inquiries to Enriching Profile 36 Rhoda Weiner, Editor: [email protected] 38 We’d loVE TO HEAR FROM YOU! Meeting up We welcome your comments, observations and contributions to The Enrichment Record.
    [Show full text]
  • Determining Face, Predictive, Construct Validity and Novel Receptor Targets in a Spontaneous Compulsive-Like Mouse Model
    Determining face, predictive, construct validity and novel receptor targets in a spontaneous compulsive-like mouse model Item Type Thesis Authors Mitra, Swarup Download date 10/10/2021 23:13:18 Link to Item http://hdl.handle.net/11122/7895 DETERMINING FACE, PREDICTIVE, CONSTRUCT VALIDITY AND NOVEL RECEPTOR TARGETS IN A SPONTANEOUS COMPULSIVE-LIKE MOUSE MODEL By Swarup Mitra, B.S, M.S A Dissertation Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Biochemistry and Neuroscience University of Alaska Fairbanks August 2017 APPROVED: Abel Bult-Ito, Committee Chair Kelly Drew, Committee Member Lawrence K. Duffy, Committee Member Kriya Dunlap, Committee Member Thomas Green, Chair Department of Chemistry and Biochemistry Paul Layer, Dean College of Natural Science and Mathematics Michael Castellini, Dean of the Graduate School Abstract Obsessive-compulsive disorder (OCD) is one of the most prevalent neuropsychiatric disorders with no known etiology. Genetic variation, sex differences and physiological stages, such as pregnancy, postpartum and menopause in females, are important factors that are thought to modulate the pathophysiology of the disorder. Deeper understanding of these factors and their role in modulating behaviors is essential to unraveling the complex clinical heterogeneity of OCD. Using a novel mouse model that exhibits a spontaneous compulsive-like phenotype, I investigated the role of strain differences, sex differences, ovarian sex hormones and postpartum lactation in influencing compulsive-like and affective behaviors. Due to the lack of definite neural substrates and first line therapeutic options for treatment resistant patients, I also probed into the role of positive allosteric modulation of nicotinic acetylcholine receptor subtype as a therapeutic target for translational prospects.
    [Show full text]
  • The Effect of a 5-Ht2a Inverse Agonist on Animal Models Of
    THE EFFECT OF A 5-HT2A INVERSE AGONIST ON ANIMAL MODELS OF OBSESSIVE-COMPULSIVE DISORDER: MARBLE BURYING TASKS by Leah Jorewicz, B.S. THESIS Presented to the Faculty of The University of Houston-Clear Lake In Partial Fulfillment Of the Requirements For the Degree MASTER OF PSYCHOLOGY in Behavioral Neuroscience THE UNIVERSITY OF HOUSTON-CLEAR LAKE MAY, 2018 THE EFFECT OF A 5-HT2A INVERSE AGONIST ON ANIMAL MODELS OF OBSESSIVE-COMPULSIVE DISORDER: MARBLE BURYING TASKS by Leah Jorewicz APPROVED BY __________________________________________ David H. Malin, Ph.D., Chair __________________________________________ Christopher P. Ward, Ph.D., Committee Member APPROVED/RECEIVED BY THE COLLEGE OF HUMAN SCIENCES AND HUMANITIES Samuel Gladden, Ph.D., Associate Dean __________________________________________ Rick Short, Ph.D., Dean Dedication For my mother and father, who always pushed me to always strive to be the best you can be. For not only raising me believing education was the biggest privilege for self- betterment, but also that no matter where you start, you can always improve. I owe all my love for knowledge to them. Acknowledgments I would personally like to thank Dr. Cristopher P. Ward and Dr. David. H. Malin for all that they have taught me through my course of graduate school. It was a hard progress, but they helped me get through it. A special appreciation for both of them taking extra hours outside of office hours to help me because of my work schedule. I would not have been able to complete my degree without that extra help. My thesis would not have been a success if it wasn’t for the amazing classmates I had helping me.
    [Show full text]
  • Human Amniotic Epithelial Cell Transplantation Promotes
    Zhang et al. Stem Cell Research & Therapy (2019) 10:153 https://doi.org/10.1186/s13287-019-1267-0 RESEARCH Open Access Human amniotic epithelial cell transplantation promotes neurogenesis and ameliorates social deficits in BTBR mice Ruiyu Zhang1, Yulong Cai1, Rui Xiao1, Hongyu Zhong1, Xin Li1, Lihe Guo2, Haiwei Xu3* and Xiaotang Fan1* Abstract Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairments in social interactions and communication and stereotypical patterns of behaviors, interests, or activities. Even with the increased prevalence of ASD, there is no defined standard drug treatment for ASD patients. Currently, stem cells, including human amniotic epithelial cell (hAEC) transplantation, seem to be a promising treatment for ASD, but the effectiveness needs to be verified, and the mechanism has not been clarified. Methods: We intraventricularly transplanted hAECs into a 2-month-old BTBR T+tf/J (BTBR) mouse model of ASD. Behavior tests were detected 1 month later; hippocampal neurogenesis, neuroprogenitor cell (NPC) pool, and microglia activation were analyzed with immunohistochemistry and immunofluorescence; the levels of pro-inflammatory cytokines, brain-derived neurotrophic factor (BDNF), and TrkB in the hippocampus were determined by real-time PCR or western blotting. Results: After intraventricular injection of hAECs into adult males, social deficits in BTBR mice were significantly ameliorated. In addition, hAEC transplantation restored the decline of neurogenesis and NPCs in the hippocampus of BTBR mice by expanding the stem cell pool, and the decreased levels of BDNF and TrkB were also rescued in the hippocampus of the hAEC-injected BTBR mice. Meanwhile, the transplantation of hAECs did not induce microglial overactivation or excessive production of pro-inflammatory cytokines in the hippocampus of BTBR mice.
    [Show full text]
  • (SOP): Use of the Rodent Behavior Core (RBC) Elizabeth Engler-Chiurazzi- Director
    WVU ACUC STANDARD OPERATING PROCEDURE (SOP): Use of the Rodent Behavior Core (RBC) Elizabeth Engler-Chiurazzi- Director 1. Background The Rodent Behavior Core (RBC) provides validated and optimized animal behavioral tests to West Virginia University (WVU) researchers and their collaborators. The RBC is conveniently located within the WVU Health Sciences Center (HSC) building in the Office of Laboratory Animal Resources (OLAR) vivarium rooms 201, 201a, 202, and 203 a-c. The RBC is managed by the RBC Director (Dr. Engler-Chiurazzi; post-doctoral fellow under the mentorship of Dr. Simpkins). Behavioral equipment is available for use by WVU investigators free of charge. This use includes access to expert consultation regarding experimental design, task selection, training, data analysis, and dissemination of results. Because most behavioral testing involves working directly with animals with minimal engineering controls outside their cages and change stations, full personal protective equipment (PPE) is typically required. Although two animal species (mouse and rat) are used, the basic procedures for handling the animals will be the same. All animals used in the RBC are from various investigators at WVU. The animals remain on the individual investigator’s protocol, which references this SOP. The investigator’s protocol indicates rationale for requesting experimental animals, experimental groups, numbers of animals needed, behavioral tests to be conducted, assurances or justifications regarding duplication of previous work, and/or length of the study (as appropriate for the tests being utilized). All appropriate RBC staff members must be included in each animal protocol in order to provide any hands-on service. Animal models have and will continue to play a vital role in the study of mechanism(s) of human disease stroke, as well as in the assessment of potential drug and alternative therapies for prevention, treatment and recovery from stroke.
    [Show full text]