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Selvaraj S, Weerasinghe L. The Role of Nanotechnology in Understanding the Pathophysiology of Traumatic Brain Injury. Cent Nerv Syst Agents Med Chem 2025; 25:20-38. [PMID: 38676493 DOI: 10.2174/0118715249291999240418112531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 03/19/2024] [Accepted: 03/28/2024] [Indexed: 04/29/2024]
Abstract
Recently, traumatic brain injury (TBI) has been a growing disorder due to frequent brain dysfunction. The Glasgow Coma Scale expresses TBI as classified as having mild, moderate, or severe brain effects, according to the effects on the brain. Brain receptors undergo various modifications in their pathology through chemical synaptic pathways, leading to depression, Alzheimer's, and Parkinson's disease. These brain disorders can be controlled using central receptors such as dopamine, glutamate, and γ-aminobutyric acid, which are clearly explained in this review. Furthermore, there are many complications in TBI's clinical trials and diagnostics, leading to insignificant treatment, causing permanent neuro-damage, physical disability, and even death. Bio-screening and conventional molecular-based therapies are inappropriate due to poor preclinical testing and delayed recovery. Hence, modern nanotechnology utilizing nanopulsed laser therapy and advanced nanoparticle insertion will be suitable for TBI's diagnostics and treatment. In recent days, nanotechnology has an important role in TBI control and provides a higher success rate than conventional therapies. This review highlights the pathophysiology of TBI by comprising the drawbacks of conventional techniques and supports suitable modern alternates for treating TBI.
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Affiliation(s)
- Saranya Selvaraj
- Department of Chemistry, Faculty of Applied sciences, University of Sri Jayewardenepura, Gangodawila, Nugegoda, Sri Lanka
| | - Laksiri Weerasinghe
- Department of Chemistry, Faculty of Applied sciences, University of Sri Jayewardenepura, Gangodawila, Nugegoda, Sri Lanka
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2
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He Z, Chen Q, Wang K, Lin J, Peng Y, Zhang J, Yan X, Jie Y. Single-cell transcriptomics analysis of cellular heterogeneity and immune mechanisms in neurodegenerative diseases. Eur J Neurosci 2024; 59:333-357. [PMID: 38221677 DOI: 10.1111/ejn.16242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 12/04/2023] [Accepted: 12/12/2023] [Indexed: 01/16/2024]
Abstract
Single-cell transcriptomics analysis is an advanced technology that can describe the intracellular transcriptome in complex tissues. It profiles and analyses datasets by single-cell RNA sequencing. Neurodegenerative diseases are identified by the abnormal apoptosis of neurons in the brain with few or no effective therapy strategies at present, which has been a growing healthcare concern and brought a great burden to society. The transcriptome of individual cells provides deep insights into previously unforeseen cellular heterogeneity and gene expression differences in neurodegenerative disorders. It detects multiple cell subsets and functional changes during pathological progression, which deepens the understanding of the molecular underpinnings and cellular basis of neurodegenerative diseases. Furthermore, the transcriptome analysis of immune cells shows the regulation of immune response. Different subtypes of immune cells and their interaction are found to contribute to disease progression. This finding enables the discovery of novel targets and biomarkers for early diagnosis. In this review, we emphasize the principles of the technology, and its recent progress in the study of cellular heterogeneity and immune mechanisms in neurodegenerative diseases. The application of single-cell transcriptomics analysis in neurodegenerative disorders would help explore the pathogenesis of these diseases and develop novel therapeutic methods.
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Affiliation(s)
- Ziping He
- Department of Forensic Science, School of Basic Medical Science, Central South University, Changsha, China
- Clinical Medicine Eight-Year Program, Xiangya School of Medicine, Central South University, Changsha, China
| | - Qianqian Chen
- Department of Forensic Science, School of Basic Medical Science, Central South University, Changsha, China
| | - Kaiyue Wang
- Department of Forensic Science, School of Basic Medical Science, Central South University, Changsha, China
- Clinical Medicine Eight-Year Program, Xiangya School of Medicine, Central South University, Changsha, China
| | - Jiang Lin
- Department of Forensic Science, School of Basic Medical Science, Central South University, Changsha, China
| | - Yilin Peng
- Department of Forensic Science, School of Basic Medical Science, Central South University, Changsha, China
| | - Jinlong Zhang
- Department of Forensic Science, School of Basic Medical Science, Central South University, Changsha, China
- Department of Forensic Science, School of Basic Medical Science, Xinjiang Medical University, Urumqi, China
| | - Xisheng Yan
- Department of Cardiovascular Medicine, Wuhan Third Hospital & Tongren Hospital of Wuhan University, Wuhan, China
| | - Yan Jie
- Department of Forensic Science, School of Basic Medical Science, Central South University, Changsha, China
- Department of Forensic Science, School of Basic Medical Science, Xinjiang Medical University, Urumqi, China
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3
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Abstract
Psychiatric illness is associated with both chronic pain syndromes and opioid use disorder, further complicating how we care for patients with psychiatric issues. We report a unique case of a de novo and persistent psychotic disorder after complicated opioid withdrawal in a patient without any psychiatric history. The patient developed persistent auditory hallucinations after discontinuation of chronic opioid therapy that responded only to atypical antipsychotic (olanzapine) treatment. This case illustrates the neuropsychiatric effects of chronic opioid exposure, as well as layered clinical management dimensions related to opioid detoxification and psychosis treatment. Long-term opioid therapy may have lasting neuropsychiatric effects, including playing a role in the development and/or expression of psychotic disorders. Here we review the limited literature on the effects of opioids on psychosis. This complex case also demonstrates a clinical approach for effectively co-managing psychiatric symptoms in the context of chronic pain and chronic opioid therapy.
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Valdés-Tovar M, Rodríguez-Ramírez AM, Rodríguez-Cárdenas L, Sotelo-Ramírez CE, Camarena B, Sanabrais-Jiménez MA, Solís-Chagoyán H, Argueta J, López-Riquelme GO. Insights into myelin dysfunction in schizophrenia and bipolar disorder. World J Psychiatry 2022; 12:264-285. [PMID: 35317338 PMCID: PMC8900585 DOI: 10.5498/wjp.v12.i2.264] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 08/10/2021] [Accepted: 01/17/2022] [Indexed: 02/06/2023] Open
Abstract
Schizophrenia and bipolar disorder are disabling psychiatric disorders with a worldwide prevalence of approximately 1%. Both disorders present chronic and deteriorating prognoses that impose a large burden, not only on patients but also on society and health systems. These mental illnesses share several clinical and neurobiological traits; of these traits, oligodendroglial dysfunction and alterations to white matter (WM) tracts could underlie the disconnection between brain regions related to their symptomatic domains. WM is mainly composed of heavily myelinated axons and glial cells. Myelin internodes are discrete axon-wrapping membrane sheaths formed by oligodendrocyte processes. Myelin ensheathment allows fast and efficient conduction of nerve impulses through the nodes of Ranvier, improving the overall function of neuronal circuits. Rapid and precisely synchronized nerve impulse conduction through fibers that connect distant brain structures is crucial for higher-level functions, such as cognition, memory, mood, and language. Several cellular and subcellular anomalies related to myelin and oligodendrocytes have been found in postmortem samples from patients with schizophrenia or bipolar disorder, and neuroimaging techniques have revealed consistent alterations at the macroscale connectomic level in both disorders. In this work, evidence regarding these multilevel alterations in oligodendrocytes and myelinated tracts is discussed, and the involvement of proteins in key functions of the oligodendroglial lineage, such as oligodendrogenesis and myelination, is highlighted. The molecular components of the axo-myelin unit could be important targets for novel therapeutic approaches to schizophrenia and bipolar disorder.
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Affiliation(s)
- Marcela Valdés-Tovar
- Departamento de Farmacogenética, Subdirección de Investigaciones Clínicas, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Mexico City 14370, Mexico
| | | | - Leslye Rodríguez-Cárdenas
- Departamento de Farmacogenética, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Mexico City 14370, Mexico
| | - Carlo E Sotelo-Ramírez
- Departamento de Farmacogenética, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Mexico City 14370, Mexico
- Doctorado en Biología Experimental, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City 09340, Mexico
| | - Beatriz Camarena
- Departamento de Farmacogenética, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Mexico City 14370, Mexico
| | | | - Héctor Solís-Chagoyán
- Laboratorio de Neurofarmacología, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Mexico City 14370, Mexico
| | - Jesús Argueta
- Doctorado en Biología Experimental, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City 09340, Mexico
- Laboratorio de Neurofarmacología, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Mexico City 14370, Mexico
| | - Germán Octavio López-Riquelme
- Laboratorio de Socioneurobiología, Centro de Investigación en Ciencias Cognitivas, Universidad del Estado de Morelos, Cuernavaca 62209, Morelos, Mexico
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Tao B, Xiao Y, Cao H, Zhang W, Yang C, Lencer R, Gong Q, Lui S. Characteristics of the corpus callosum in chronic schizophrenia treated with clozapine or risperidone and those never-treated. BMC Psychiatry 2021; 21:538. [PMID: 34715831 PMCID: PMC8556985 DOI: 10.1186/s12888-021-03552-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 10/13/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND The corpus callosum (CC) deficits have been well documented in chronic schizophrenia. However, the long-term impacts of antipsychotic monotherapies on callosal anatomy remain unclear. This cross-sectional study sought to explore micro- and macro-structural characteristics of the CC in never-treated patients and those with long-term mono-antipsychotic treatment. METHODS The study included 23 clozapine-treated schizophrenia patients (CT-SCZ), 19 risperidone-treated schizophrenia patients (RT-SCZ), 23 never-treated schizophrenia patients (NT-SCZ), and 35 healthy controls (HCs). High resolution structural images and diffusion tensor imaging (DTI) data for each participant were obtained via a 3.0 T MR scanner. FreeSurfer was used to examine the volumes and fractional anisotropy (FA) values of the CC for each participant. RESULTS There were significant deficits in the total and sub-regional CC volume and white matter integrity in NT-SCZ in comparison with healthy subjects. Compared with NT-SCZ, both CT-SCZ and RT-SCZ showed significantly increased FA values in the anterior CC region, while only RT-SCZ showed significantly increased volume in the mid-anterior CC region. Moreover, the volume of the mid-anterior CC region was significantly smaller in CT-SCZ compared to HCs. No correlations of clinical symptoms with callosal metrics were observed in schizophrenia patients. CONCLUSIONS Our findings provide insight into micro- and macro-structural characteristics of the CC in chronic schizophrenia patients with or without antipsychotics. These results suggest that the pathology itself is responsible for cerebral abnormalities in schizophrenia and that chronic exposure to antipsychotics may have an impact on white matter structure of schizophrenia patients, especially in those with risperidone treatment.
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Affiliation(s)
- Bo Tao
- grid.412901.f0000 0004 1770 1022Huaxi MR Research Center (HMRRC), Functional and Molecular Imaging Key Laboratory of Sichuan Province, Department of Radiology, West China Hospital, Sichuan University, 37 Guo Xuexiang, Chengdu, 610041 China ,grid.412901.f0000 0004 1770 1022Psychoradiology Research Unit of the Chinese Academy of Medical Sciences, West China Hospital of Sichuan University, Chengdu, China
| | - Yuan Xiao
- grid.412901.f0000 0004 1770 1022Huaxi MR Research Center (HMRRC), Functional and Molecular Imaging Key Laboratory of Sichuan Province, Department of Radiology, West China Hospital, Sichuan University, 37 Guo Xuexiang, Chengdu, 610041 China ,grid.412901.f0000 0004 1770 1022Psychoradiology Research Unit of the Chinese Academy of Medical Sciences, West China Hospital of Sichuan University, Chengdu, China
| | - Hengyi Cao
- grid.250903.d0000 0000 9566 0634Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, NY USA ,grid.440243.50000 0004 0453 5950Division of Psychiatry Research, Zucker Hillside Hospital, Glen Oaks, NY USA
| | - Wenjing Zhang
- grid.412901.f0000 0004 1770 1022Huaxi MR Research Center (HMRRC), Functional and Molecular Imaging Key Laboratory of Sichuan Province, Department of Radiology, West China Hospital, Sichuan University, 37 Guo Xuexiang, Chengdu, 610041 China ,grid.412901.f0000 0004 1770 1022Psychoradiology Research Unit of the Chinese Academy of Medical Sciences, West China Hospital of Sichuan University, Chengdu, China
| | - Chengmin Yang
- grid.412901.f0000 0004 1770 1022Huaxi MR Research Center (HMRRC), Functional and Molecular Imaging Key Laboratory of Sichuan Province, Department of Radiology, West China Hospital, Sichuan University, 37 Guo Xuexiang, Chengdu, 610041 China ,grid.412901.f0000 0004 1770 1022Psychoradiology Research Unit of the Chinese Academy of Medical Sciences, West China Hospital of Sichuan University, Chengdu, China
| | - Rebekka Lencer
- grid.4562.50000 0001 0057 2672Department of Psychiatry and Psychotherapy, University of Lübeck, Lübeck, Germany
| | - Qiyong Gong
- grid.412901.f0000 0004 1770 1022Huaxi MR Research Center (HMRRC), Functional and Molecular Imaging Key Laboratory of Sichuan Province, Department of Radiology, West China Hospital, Sichuan University, 37 Guo Xuexiang, Chengdu, 610041 China ,grid.412901.f0000 0004 1770 1022Psychoradiology Research Unit of the Chinese Academy of Medical Sciences, West China Hospital of Sichuan University, Chengdu, China
| | - Su Lui
- Huaxi MR Research Center (HMRRC), Functional and Molecular Imaging Key Laboratory of Sichuan Province, Department of Radiology, West China Hospital, Sichuan University, 37 Guo Xuexiang, Chengdu, 610041, China. .,Psychoradiology Research Unit of the Chinese Academy of Medical Sciences, West China Hospital of Sichuan University, Chengdu, China.
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6
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Shi-Zhen-An-Shen Decoction, a Herbal Medicine That Reverses Cuprizone-Induced Demyelination and Behavioral Deficits in Mice Independent of the Neuregulin-1 Pathway. Neural Plast 2021; 2021:8812362. [PMID: 33708250 PMCID: PMC7932787 DOI: 10.1155/2021/8812362] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 01/15/2021] [Accepted: 02/06/2021] [Indexed: 11/25/2022] Open
Abstract
Shi-Zhen-An-Shen decoction (SZASD), a Chinese herbal medicine that is a liquor extracted from plants by boiling, has been reported to be effective in treating schizophrenia. However, the mechanism is unclear. Abnormal demyelination has been implicated in schizophrenia. The aim of this study was to investigate the effect of SZASD on myelin in demyelinated mice exhibiting schizophrenia-like behaviors. Sixty male C57BL/6 mice were randomly divided into six groups (n = 10 per group): (1) control group, (2) cuprizone (CPZ, a copper chelator that induced demyelination, 0.2% w/w)+saline, (3) CPZ+low-dose SZASD (8.65 g·kg−1·d−1), (4) CPZ+medium-dose SZASD (17.29 g·kg−1·d−1), (5) CPZ+high-dose SZASD (25.94 g·kg−1·d−1), and (6) CPZ+quetiapine (QTP, an atypical antipsychotic that served as a positive treatment control, 10 mg·kg−1·d−1). Mice in groups 2-6 were treated with CPZ added to rodent chow for six weeks to induce demyelination. During the last two weeks, these mice were given an oral gavage of sterile saline, SZASD, or quetiapine. Behavioral tests and brain analyses were conducted after the last treatment. The brain expression of myelin basic protein (MBP) and neuregulin-1 (NRG-1) was assessed using immunohistochemistry and Western blots. CPZ induced significant schizophrenia-like behaviors in the mice, including reduced nest-building activity and sensory gating deficits. Hyperlocomotor activity was accompanied by significant reductions in MBP expression in the corpus callosum, hippocampus, and cerebral cortex. However, both QTP and SZASD significantly reversed the schizophrenia-like behaviors and demyelination in CPZ-fed mice. The QTP and medium-dose SZASD resulted in better therapeutic effects compared to the low and high SZASD doses. Reduced NRG-1 expression was observed in CPZ-fed mice compared with controls, but neither QTP nor SZASD showed significant influence on NRG-1 expression in the hippocampus. Together, SZASD showed a therapeutic effect on demyelinated mice, and the improvement of demyelination might not be through the NRG-1 pathway.
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7
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Zhou B, Zhu Z, Ransom BR, Tong X. Oligodendrocyte lineage cells and depression. Mol Psychiatry 2021; 26:103-117. [PMID: 33144710 PMCID: PMC7815509 DOI: 10.1038/s41380-020-00930-0] [Citation(s) in RCA: 127] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 10/01/2020] [Accepted: 10/22/2020] [Indexed: 12/25/2022]
Abstract
Depression is a common mental illness, affecting more than 300 million people worldwide. Decades of investigation have yielded symptomatic therapies for this disabling condition but have not led to a consensus about its pathogenesis. There are data to support several different theories of causation, including the monoamine hypothesis, hypothalamic-pituitary-adrenal axis changes, inflammation and immune system alterations, abnormalities of neurogenesis and a conducive environmental milieu. Research in these areas and others has greatly advanced the current understanding of depression; however, there are other, less widely known theories of pathogenesis. Oligodendrocyte lineage cells, including oligodendrocyte progenitor cells and mature oligodendrocytes, have numerous important functions, which include forming myelin sheaths that enwrap central nervous system axons, supporting axons metabolically, and mediating certain forms of neuroplasticity. These specialized glial cells have been implicated in psychiatric disorders such as depression. In this review, we summarize recent findings that shed light on how oligodendrocyte lineage cells might participate in the pathogenesis of depression, and we discuss new approaches for targeting these cells as a novel strategy to treat depression.
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Affiliation(s)
- Butian Zhou
- Center for Brain Science, Shanghai Children's Medical Center; Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhongqun Zhu
- Department of Cardiothoracic Surgery, Center for Brain Science, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bruce R Ransom
- Neuroscience Department, City University of Hong Kong, Hong Kong, China.
| | - Xiaoping Tong
- Center for Brain Science, Shanghai Children's Medical Center; Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Mei R, Fu J, Jiang C, Yang J, Zheng K, Yang A, Qiu M, Zhao X. TAPP1 Represses the Differentiation of Oligodendrocyte and its Deficiency Accelerates Myelin Regeneration after Demyelinating Injuries. Neurosci Bull 2020; 37:385-388. [PMID: 33190191 DOI: 10.1007/s12264-020-00609-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Accepted: 08/12/2020] [Indexed: 12/22/2022] Open
Affiliation(s)
- Ruyi Mei
- Institute of Developmental and Regenerative Biology, Zhejiang Key Laboratory of Organ Development and Regeneration, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, 310036, China.,The College of Life Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Jiaying Fu
- Institute of Developmental and Regenerative Biology, Zhejiang Key Laboratory of Organ Development and Regeneration, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, 310036, China
| | - Chunxia Jiang
- Institute of Developmental and Regenerative Biology, Zhejiang Key Laboratory of Organ Development and Regeneration, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, 310036, China.,The College of Life Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Junlin Yang
- Institute of Developmental and Regenerative Biology, Zhejiang Key Laboratory of Organ Development and Regeneration, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, 310036, China
| | - Kang Zheng
- Institute of Developmental and Regenerative Biology, Zhejiang Key Laboratory of Organ Development and Regeneration, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, 310036, China
| | - Aifen Yang
- Institute of Developmental and Regenerative Biology, Zhejiang Key Laboratory of Organ Development and Regeneration, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, 310036, China
| | - Mengsheng Qiu
- Institute of Developmental and Regenerative Biology, Zhejiang Key Laboratory of Organ Development and Regeneration, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, 310036, China
| | - Xiaofeng Zhao
- Institute of Developmental and Regenerative Biology, Zhejiang Key Laboratory of Organ Development and Regeneration, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, 310036, China.
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9
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Genetic Variation in CNS Myelination and Functional Brain Connectivity in Recombinant Inbred Mice. Cells 2020; 9:cells9092119. [PMID: 32961889 PMCID: PMC7564997 DOI: 10.3390/cells9092119] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 09/15/2020] [Accepted: 09/17/2020] [Indexed: 01/29/2023] Open
Abstract
Myelination greatly increases the speed of action potential propagation of neurons, thereby enhancing the efficacy of inter-neuronal communication and hence, potentially, optimizing the brain’s signal processing capability. The impact of genetic variation on the extent of axonal myelination and its consequences for brain functioning remain to be determined. Here we investigated this question using a genetic reference panel (GRP) of mouse BXD recombinant inbred (RI) strains, which partly model genetic diversity as observed in human populations, and which show substantial genetic differences in a variety of behaviors, including learning, memory and anxiety. We found coherent differences in the expression of myelin genes in brain tissue of RI strains of the BXD panel, with the largest differences in the hippocampus. The parental C57BL/6J (C57) and DBA/2J (DBA) strains were on opposite ends of the expression spectrum, with C57 showing higher myelin transcript expression compared with DBA. Our experiments showed accompanying differences between C57 and DBA in myelin protein composition, total myelin content, and white matter conduction velocity. Finally, the hippocampal myelin gene expression of the BXD strains correlated significantly with behavioral traits involving anxiety and/or activity. Taken together, our data indicate that genetic variation in myelin gene expression translates to differences observed in myelination, axonal conduction speed, and possibly in anxiety/activity related behaviors.
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Pitzianti M, Pontillo M, Vicari S, Armando M, Pasini A. 22q11 microdeletion syndrome and ultra-high risk for psychosis: The role of neurological soft signs as an independent marker of vulnerability for psychosis. Early Interv Psychiatry 2019; 13:1191-1198. [PMID: 30478947 DOI: 10.1111/eip.12754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Revised: 10/03/2018] [Accepted: 10/16/2018] [Indexed: 11/28/2022]
Abstract
AIM 22q11 microdeletion syndrome has an increased risk for psychosis, similar to subjects at ultra-high risk for psychosis. Neurological soft signs are considered an endophenotype of psychotic disorders and a marker of vulnerability to Schizophrenia, consisting of overflow movements, dysrhythmia and speed of timed activities. To date, there are no studies that have evaluated the presence of the neurological soft signs in subjects with 22q11 microdeletion syndrome and there are a few studies that have analysed this issue in subjects at ultra-high risk. METHODS We sought to measure neurological soft signs in these two conditions, compared to healthy controls and to analyse the possible correlation between neurological soft signs and positive/negative symptoms both in 22q11 microdeletion syndrome and ultra-high-risk groups. 54 drug-naive patients (29 with 22q11 microdeletion syndrome and 25 at ultra-high risk for psychosis) and 25 healthy controls were evaluated for neurological soft signs. RESULTS Both clinical groups showed a greater number of neurological soft signs compared to healthy control, although the two clinical groups did not differ for the number of neurological soft signs. Positive correlation between speed of timed activities and negative symptoms was found in subjects at ultra-high risk. CONCLUSION Neurological soft signs could represent a marker of atypical neurodevelopment in the two populations examined. Since we did not found a strong correlation between neurological soft signs and positive/negative symptoms, we suggest that neurological soft signs could be indicators of vulnerability to psychosis independent from the psychopathology.
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Affiliation(s)
- Mariabernarda Pitzianti
- Department of Systems Medicine, Unit of Child Neurology and Psychiatry, "Tor Vergata" University of Rome, Rome, Italy.,Department of neuroscience, USL Umbria 2, Terni, Italy
| | - Maria Pontillo
- Department of Neuroscience, Unit of Child Neuropsychiatry, Children's Hospital Bambino Gesù, IRCCS, Rome, Italy
| | - Stefano Vicari
- Department of Neuroscience, Unit of Child Neuropsychiatry, Children's Hospital Bambino Gesù, IRCCS, Rome, Italy
| | - Marco Armando
- Department of Neuroscience, Unit of Child Neuropsychiatry, Children's Hospital Bambino Gesù, IRCCS, Rome, Italy
| | - Augusto Pasini
- Department of Systems Medicine, Unit of Child Neurology and Psychiatry, "Tor Vergata" University of Rome, Rome, Italy.,Department of neuroscience, USL Umbria 2, Terni, Italy
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11
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The myeloarchitecture of impulsivity: premature responding in youth is associated with decreased myelination of ventral putamen. Neuropsychopharmacology 2019; 44:1216-1223. [PMID: 30770890 PMCID: PMC6544540 DOI: 10.1038/s41386-019-0343-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 02/06/2019] [Accepted: 02/07/2019] [Indexed: 12/11/2022]
Abstract
Impulsivity has been suggested as a neurocognitive endophenotype conferring risk across a number of neuropsychiatric conditions, including substance and behavioural addictions, eating disorders, and attention deficit/hyperactivity disorder. We used a paradigm with interspecies translation validity (the four-choice serial reaction time task, 4CSRTT) to assess 'waiting' impulsivity in a youth sample (N = 99, aged 16-26 years). We collected magnetization prepared two rapid acquisition gradient echo (MP2RAGE) scans, which enabled us to measure R1, the longitudinal relaxation rate, a parameter closely related to tissue myelin content, as well as quantify grey matter volume. We also assessed inhibitory control (commission errors) on a Go/NoGo task and measured decisional impulsivity (delay discounting) using the Monetary Choice Questionnaire (MCQ). We found R1 of the bilateral ventral putamen was negatively correlated with premature responding, the index of waiting impulsivity on the 4CSRTT. Heightened impulsivity in youth was significantly and specifically associated with lower levels of myelination in the ventral putamen. Impulsivity was not associated with grey matter volume. The association with myelination was specific to waiting impulsivity: R1 was not associated with decisional impulsivity on the MCQ or inhibitory control on the Go/NoGo task. We report that heightened waiting impulsivity, measured as premature responding on the 4CSRTT, is specifically associated with lower levels of ventral putaminal myelination, measured using R1. This may represent a neural signature of vulnerability to diseases associated with excessive impulsivity and demonstrates the added explanatory power of quantifying the mesoscopic organization of the human brain, over and above macroscopic volumetric measurements.
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12
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Rice J, Gu C. Function and Mechanism of Myelin Regulation in Alcohol Abuse and Alcoholism. Bioessays 2019; 41:e1800255. [PMID: 31094014 DOI: 10.1002/bies.201800255] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 03/31/2019] [Indexed: 12/26/2022]
Abstract
Excessive alcohol use has adverse effects on the central nervous system (CNS) and can lead to alcohol use disorders (AUDs). Recent studies have suggested that myelin reductions may directly contribute to CNS dysfunctions associated with AUDs. Myelin consists of compact lipid membranes wrapped around axons to provide electrical insulation and trophic support. Regulation of myelin is considered as a new form of neural plasticity due to its profound impacts on the computation of neural networks. In this review, the authors first discuss experimental evidence showing how alcohol exposure causes demyelination in different brain regions, often accompanied by deficits in cognition and emotion. Next, they discuss postulated molecular and cellular mechanisms underlying alcohol's impact on myelin. It is clear that more extensive investigations are needed in this important but underexplored research field in order to gain a better understanding of the myelin-behavior relationship and to develop new treatment strategies for AUDs.
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Affiliation(s)
- James Rice
- Department of Biological Chemistry and Pharmacology, The Ohio State University, 1060 Carmack Road, Columbus, OH, 43210, USA
| | - Chen Gu
- Department of Biological Chemistry and Pharmacology, The Ohio State University, 1060 Carmack Road, Columbus, OH, 43210, USA
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Antipsychotics Do Not Influence Neurological Soft Signs in Children and Adolescents at Ultra-High Risk for Psychosis: A Pilot Study. J Psychiatr Pract 2019; 25:186-191. [PMID: 31083030 DOI: 10.1097/pra.0000000000000387] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVE Ultra-high risk for psychosis (UHR) is considered as the condition that temporally precedes the onset of psychotic symptoms. In addition to the core symptoms, patients with schizophrenia show motor abnormalities, also known as neurological soft signs (NSS), that are considered an endophenotype for psychotic disorders and particularly for schizophrenia. Antipsychotic medications do not appear to influence NSS in individuals with schizophrenia. However, NSS in UHR subjects have been poorly studied and, to date, we do not know what effects antipsychotics have in early treated UHR subjects. Therefore, we evaluated NSS in treated UHR subjects in comparison with drug-naive UHR subjects and a group of healthy control subjects and the effect of pharmacological treatment on early treated UHR children and adolescents. PATIENTS AND METHODS Fifteen UHR subjects receiving pharmacological treatment, 15 drug-naive UHR subjects, and 25 healthy control subjects were evaluated for NSS to analyze any differences between clinical subjects and healthy controls and to evaluate the effect of antipsychotic medications in early treated UHR subjects. RESULTS Both clinical groups showed a greater number of NSS compared with the healthy control subjects. However, no significant differences in NSS were found between treated and drug-naive UHR subjects. CONCLUSIONS Consistent with what has been observed in the population of patients with a first psychotic episode and/or with schizophrenia, our results support the conclusion that antipsychotic medications do not influence NSS in children and adolescents who are at high risk for psychosis.
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14
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Tannous J, Mwangi B, Hasan KM, Narayana PA, Steinberg JL, Walss-Bass C, Moeller FG, Schmitz JM, Lane SD. Measures of possible allostatic load in comorbid cocaine and alcohol use disorder: Brain white matter integrity, telomere length, and anti-saccade performance. PLoS One 2019; 14:e0199729. [PMID: 30625144 PMCID: PMC6326479 DOI: 10.1371/journal.pone.0199729] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Accepted: 12/07/2018] [Indexed: 12/03/2022] Open
Abstract
Chronic cocaine and alcohol use impart significant stress on biological and cognitive systems, resulting in changes consistent with an allostatic load model of neurocognitive impairment. The present study measured potential markers of allostatic load in individuals with comorbid cocaine/alcohol use disorders (CUD/AUD) and control subjects. Measures of brain white matter (WM), telomere length, and impulsivity/attentional bias were obtained. WM (CUD/AUD only) was indexed by diffusion tensor imaging metrics, including radial diffusivity (RD) and fractional anisotropy (FA). Telomere length was indexed by the telomere to single copy gene (T/S) ratio. Impulsivity and attentional bias to drug cues were measured via eye-tracking, and were also modeled using the Hierarchical Diffusion Drift Model (HDDM). Average whole-brain RD and FA were associated with years of cocaine use (R2 = 0.56 and 0.51, both p < .005) but not years of alcohol use. CUD/AUD subjects showed more anti-saccade errors (p < .01), greater attentional bias scores (p < .001), and higher HDDM drift rates on cocaine-cue trials (Bayesian probability CUD/AUD > control = p > 0.99). Telomere length was shorter in CUD/AUD, but the difference was not statistically significant. Within the CUD/AUD group, exploratory regression using an elastic-net model determined that more years of cocaine use, older age, larger HDDM drift rate differences and shorter telomere length were all predictive of WM as measured by RD (model R2 = 0.79). Collectively, the results provide modest support linking CUD/AUD to putative markers of allostatic load.
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Affiliation(s)
- Jonika Tannous
- Program in Neuroscience, UTHealth Graduate School of Biomedical Sciences, Houston, Texas, United States of America
| | - Benson Mwangi
- Department of Psychiatry & Behavioral Sciences, UTHealth McGovern Medical School, Houston, Texas, United States of America
| | - Khader M. Hasan
- Department of Diagnostic and Interventional Imaging, UTHealth McGovern Medical School, Houston, Texas, United States of America
| | - Ponnada A. Narayana
- Program in Neuroscience, UTHealth Graduate School of Biomedical Sciences, Houston, Texas, United States of America
- Department of Diagnostic and Interventional Imaging, UTHealth McGovern Medical School, Houston, Texas, United States of America
| | - Joel L. Steinberg
- Department of Psychiatry, Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, Virginia, United States of America
| | - Consuelo Walss-Bass
- Program in Neuroscience, UTHealth Graduate School of Biomedical Sciences, Houston, Texas, United States of America
- Department of Psychiatry & Behavioral Sciences, UTHealth McGovern Medical School, Houston, Texas, United States of America
| | - F. Gerard Moeller
- Department of Psychiatry, Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, Virginia, United States of America
| | - Joy M. Schmitz
- Department of Psychiatry & Behavioral Sciences, UTHealth McGovern Medical School, Houston, Texas, United States of America
| | - Scott D. Lane
- Program in Neuroscience, UTHealth Graduate School of Biomedical Sciences, Houston, Texas, United States of America
- Department of Psychiatry & Behavioral Sciences, UTHealth McGovern Medical School, Houston, Texas, United States of America
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15
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Jiang C, Yang W, Fan Z, Teng P, Mei R, Yang J, Yang A, Qiu M, Zhao X. AATYK is a Novel Regulator of Oligodendrocyte Differentiation and Myelination. Neurosci Bull 2018; 34:527-533. [PMID: 29556912 DOI: 10.1007/s12264-018-0218-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Accepted: 11/21/2017] [Indexed: 12/20/2022] Open
Abstract
Oligodendrocytes (OLs) are myelinating glial cells that form myelin sheaths around axons to ensure rapid and focal conduction of action potentials. Here, we found that an axonal outgrowth regulatory molecule, AATYK (apoptosis-associated tyrosine kinase), was up-regulated with OL differentiation and remyelination. We therefore studied its role in OL differentiation. The results showed that AATYK knockdown inhibited OL differentiation and the expression of myelin genes in vitro. Moreover, AATYK-deficiency maintained the proliferation status of OLs but did not affect their survival. Thus, AATYK is essential for the differentiation of OLs.
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Affiliation(s)
- Chunxia Jiang
- Institute of Developmental and Regenerative Biology, Zhejiang Key Laboratory of Organ Development and Regeneration, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, 310036, China
| | - Wanqing Yang
- Institute of Developmental and Regenerative Biology, Zhejiang Key Laboratory of Organ Development and Regeneration, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, 310036, China
| | - Zhihong Fan
- Institute of Developmental and Regenerative Biology, Zhejiang Key Laboratory of Organ Development and Regeneration, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, 310036, China
| | - Peng Teng
- College of Life Sciences, Zhejiang University, Hangzhou, 310036, China
| | - Ruyi Mei
- College of Life Sciences, Zhejiang University, Hangzhou, 310036, China
| | - Junlin Yang
- Institute of Developmental and Regenerative Biology, Zhejiang Key Laboratory of Organ Development and Regeneration, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, 310036, China
| | - Aifen Yang
- Institute of Developmental and Regenerative Biology, Zhejiang Key Laboratory of Organ Development and Regeneration, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, 310036, China
| | - Mengsheng Qiu
- Institute of Developmental and Regenerative Biology, Zhejiang Key Laboratory of Organ Development and Regeneration, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, 310036, China. .,Department of Anatomical Sciences and Neurobiology, School of Medicine, University of Louisville, Louisville, KY, 40202, USA.
| | - Xiaofeng Zhao
- Institute of Developmental and Regenerative Biology, Zhejiang Key Laboratory of Organ Development and Regeneration, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, 310036, China.
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16
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Li N, Han J, Tang J, Ying Y. IGFBP-7 inhibits the differentiation of oligodendrocyte precursor cells via regulation of Wnt/β-Catenin signaling. J Cell Biochem 2018; 119:4742-4750. [PMID: 29280192 DOI: 10.1002/jcb.26654] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2017] [Accepted: 12/20/2017] [Indexed: 11/09/2022]
Abstract
Oligodendrocytes (OLs) are glial cells that form myelin sheaths in the central nervous system. Myelin sheath plays important role in nervous system and loss of it in neurodegenerative diseases can lead to impairment of movement. Understanding the signals and factors that regulate OL differentiation can help to address novel strategies for improving myelin repair in neurodegenerative diseases. The aim of this study was to investigate the role of insulin-like growth factor-binding proteins 7 (IGFBP-7) in differentiating OL precursor cells (OPCs). It was found that oligodendrocyte precursors undergoing differentiation were accompanied by selective expression of IGFBP-7. In addition, knockdown of IGFBP-7 promoted differentiation of oligodendrocytes and increased formation of myelin in cultured cells. In contrast, excessive expression of IGFBP-7 inhibited differentiation of oligodendrocytes. Furthermore, overexpression of IGFBP-7 in oligodendrocyte precursor cells increased transcription of Wnt target genes and promoted β-Catenin nuclear translocation. These findings suggest that IGFBP-7 negatively regulates differentiation of oligodendrocyte precursor cells via regulation of Wnt/β-Catenin signaling.
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Affiliation(s)
- Nan Li
- Department of Intensive Care Unit, The First Hospital of Jilin University, Changchun, China
| | - Jinfeng Han
- Department of Intensive Care Unit, The First Hospital of Jilin University, Changchun, China
| | - Jing Tang
- Jinzhou Maternal and Children Healthy Care Hospital, Jinzhou, China
| | - Yanqin Ying
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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17
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Treble-Barna A, Wade SL, Martin LJ, Pilipenko V, Yeates KO, Taylor HG, Kurowski BG. Influence of Dopamine-Related Genes on Neurobehavioral Recovery after Traumatic Brain Injury during Early Childhood. J Neurotrauma 2017; 34:1919-1931. [PMID: 28323555 DOI: 10.1089/neu.2016.4840] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The present study examined the association of dopamine-related genes with short- and long-term neurobehavioral recovery, as well as neurobehavioral recovery trajectories over time, in children who had sustained early childhood traumatic brain injuries (TBI) relative to children who had sustained orthopedic injuries (OI). Participants were recruited from a prospective, longitudinal study evaluating outcomes of children who sustained a TBI (n = 68) or OI (n = 72) between the ages of 3 and 7 years. Parents completed ratings of child executive function and behavior at the immediate post-acute period (0-3 months after injury); 6, 12, and 18 months after injury; and an average of 3.5 and 7 years after injury. Thirty-two single nucleotide polymorphisms (SNPs) in dopamine-related genes (dopamine receptor D2 [DRD2], solute carrier family 6 member 3 [SLC6A3], solute carrier family 18 member A2 [SLC18A2], catechol-o-methyltransferase [COMT], and ankyrin repeat and kinase domain containing 1 [ANKK1]) were examined in association with short- and long-term executive function and behavioral adjustment, as well as their trajectories over time. After controlling for premorbid child functioning, genetic variation within the SLC6A3 (rs464049 and rs460000) gene was differentially associated with neurobehavioral recovery trajectories over time following TBI relative to OI, with rs464049 surviving multiple testing corrections. In addition, genetic variation within the ANKK1 (rs1800497 and rs2734849) and SLC6A3 (rs464049, rs460000, and rs1042098) genes was differentially associated with short- and long-term neurobehavioral recovery following TBI, with rs460000 and rs464049 surviving multiple testing corrections. The findings provide preliminary evidence that genetic variation in genes involved in DRD2 expression and density (ANKK1) and dopamine transport (SLC6A3) plays a role in neurobehavioral recovery following pediatric TBI.
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Affiliation(s)
- Amery Treble-Barna
- 1 Division of Physical Medicine and Rehabilitation, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania
| | - Shari L Wade
- 2 Division of Physical Medicine and Rehabilitation, Department of Pediatrics, Cincinnati Children's Hospital Medical Center , Cincinnati, Ohio
| | - Lisa J Martin
- 3 Division of Human Genetics, Cincinnati Children's Hospital Medical Center , Cincinnati, Ohio
| | - Valentina Pilipenko
- 3 Division of Human Genetics, Cincinnati Children's Hospital Medical Center , Cincinnati, Ohio
| | - Keith Owen Yeates
- 4 Department of Psychology, Alberta Children's Hospital Research Institute, Hotchkiss Brain Institute, University of Calgary , Calgary, Alberta, Canada
| | - H Gerry Taylor
- 5 Division of Developmental and Behavioral Pediatrics and Psychology, Department of Pediatrics, Case Western Reserve University and Rainbow Babies and Children's Hospital , Cleveland, Ohio
| | - Brad G Kurowski
- 2 Division of Physical Medicine and Rehabilitation, Department of Pediatrics, Cincinnati Children's Hospital Medical Center , Cincinnati, Ohio
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18
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19
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Glutamate signalling: A multifaceted modulator of oligodendrocyte lineage cells in health and disease. Neuropharmacology 2016; 110:574-585. [PMID: 27346208 DOI: 10.1016/j.neuropharm.2016.06.014] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Revised: 05/27/2016] [Accepted: 06/16/2016] [Indexed: 01/10/2023]
Abstract
Myelin is essential for the mammalian brain to function efficiently. Whilst many factors have been associated with regulating the differentiation of oligodendroglia and myelination, glutamate signalling might be particularly important for learning-dependent myelination. The majority of myelinated projection neurons are glutamatergic. Oligodendrocyte precursor cells receive glutamatergic synaptic inputs from unmyelinated axons and oligodendrocyte lineage cells express glutamate receptors which enable them to monitor and respond to changes in neuronal activity. Yet, what role glutamate plays for oligodendroglia is not fully understood. Here, we review glutamate signalling and its effects on oligodendrocyte lineage cells, and myelination in health and disease. Furthermore, we discuss whether glutamate signalling between neurons and oligodendroglia might lay the foundation to activity-dependent white matter plasticity. This article is part of the Special Issue entitled 'Oligodendrocytes in Health and Disease'.
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20
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Tang VK, Pato MT, Sobell JL, Hammond TC, Valdez MM, Lane CJ, Pato CN. Substance use associated with short sleep duration in patients with schizophrenia or schizoaffective disorder. Am J Med Genet B Neuropsychiatr Genet 2016; 171:525-33. [PMID: 26345478 DOI: 10.1002/ajmg.b.32374] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2015] [Accepted: 08/18/2015] [Indexed: 11/05/2022]
Abstract
STUDY OBJECTIVES To examine the association between substance use and short sleep duration in individuals with schizophrenia or schizoaffective disorder, depressive type (SADD). DESIGN Cross-sectional, retrospective study. SETTING Urban, suburban, and rural centers across the United States. PARTICIPANTS 2,462 consented, adult individuals with schizophrenia or schizoaffective disorder, depressive type (SADD). Participants included inpatients in acute or chronic care settings as well as outpatients and residents in community dwellings. MEASUREMENTS Substance use was assessed with 10 questions adopted from well-validated measures (e.g., CAGE questionnaire) for alcohol, marijuana, and illicit drugs. Short sleep duration was defined as <6 hr of self-reported sleep per night. RESULTS Close to 100% of our sample used nicotine while 83% used substances other than nicotine. More importantly, there was a significant association between substance use and short sleep duration. Interestingly, this association was strongest among African-Americans with schizophrenia or SADD. CONCLUSIONS Because psychiatric medications often target chemical receptors involved with both sleep and substance use, understanding the association between short sleep duration and substance use in individuals with schizophrenia and SADD is important. Given that the majority of premature deaths in individuals with psychotic illness are due to medical conditions associated with modifiable risk factors, prospective studies designed to examine the effect of short sleep duration on behaviors like substance use should be undertaken. Finally, analyzing genetic and environmental data in a future study might help illuminate the strong association found between short sleep duration and substance use in African-Americans with schizophrenia and SADD. © 2015 Wiley Periodicals, Inc.
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Affiliation(s)
- Vivian K Tang
- Department of Psychiatry and Behavioral Sciences, Keck School of Medicine, Los Angeles, California
| | - Michele T Pato
- Department of Psychiatry and Behavioral Sciences, Keck School of Medicine, Los Angeles, California
| | - Janet L Sobell
- Department of Psychiatry and Behavioral Sciences, Keck School of Medicine, Los Angeles, California
| | - Terese C Hammond
- Division of Pulmonary, Critical Care and Sleep Medicine, Keck School of Medicine, Los Angeles, California
| | - Mark M Valdez
- Division of Pulmonary, Critical Care and Sleep Medicine, Keck School of Medicine, Los Angeles, California
| | - Christianne J Lane
- Department of Preventive Medicine, Keck School of Medicine, Los Angeles, California
| | | | - Carlos N Pato
- Department of Psychiatry and Behavioral Sciences, Keck School of Medicine, Los Angeles, California
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21
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Chen Y, Mei R, Teng P, Yang A, Hu X, Zhang Z, Qiu M, Zhao X. TAPP1 inhibits the differentiation of oligodendrocyte precursor cells via suppressing the Mek/Erk pathway. Neurosci Bull 2015; 31:517-26. [PMID: 26242484 DOI: 10.1007/s12264-015-1537-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2015] [Accepted: 05/19/2015] [Indexed: 12/21/2022] Open
Abstract
Oligodendrocytes (OLs) are glial cells that form myelin sheaths around axons in the central nervous system (CNS). Loss of the myelin sheath in demyelinating and neurodegenerative diseases can lead to severe impairment of movement. Understanding the extracellular signals and intracellular factors that regulate OL differentiation and myelination during development can help to develop novel strategies for enhancing myelin repair in neurological disorders. Here, we report that TAPP1 was selectively expressed in differentiating OL precursor cells (OPCs). TAPP1 knockdown promoted OL differentiation and myelin gene expression in culture. Conversely, over-expression of TAPP1 in immature OPCs suppressed their differentiation. Moreover, TAPP1 inhibition in OPCs altered the expression of Erk1/2 but not AKT. Taken together, our results identify TAPP1 as an important negative regulator of OPC differentiation through the Mek/Erk signaling pathway.
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Affiliation(s)
- Yidan Chen
- Institute of Developmental and Regenerative Biology, Zhejiang Key Laboratory of Organ Development and Regeneration, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, 310036, China
| | - Ruyi Mei
- Institute of Developmental and Regenerative Biology, Zhejiang Key Laboratory of Organ Development and Regeneration, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, 310036, China
| | - Peng Teng
- Institute of Developmental and Regenerative Biology, Zhejiang Key Laboratory of Organ Development and Regeneration, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, 310036, China
| | - Aifen Yang
- Institute of Developmental and Regenerative Biology, Zhejiang Key Laboratory of Organ Development and Regeneration, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, 310036, China
| | - Xuemei Hu
- Department of Anatomical Sciences and Neurobiology, School of Medicine, University of Louisville, Louisville, KY, 40202, USA
| | - Zunyi Zhang
- Institute of Developmental and Regenerative Biology, Zhejiang Key Laboratory of Organ Development and Regeneration, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, 310036, China
| | - Mengsheng Qiu
- Institute of Developmental and Regenerative Biology, Zhejiang Key Laboratory of Organ Development and Regeneration, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, 310036, China. .,Department of Anatomical Sciences and Neurobiology, School of Medicine, University of Louisville, Louisville, KY, 40202, USA.
| | - Xiaofeng Zhao
- Institute of Developmental and Regenerative Biology, Zhejiang Key Laboratory of Organ Development and Regeneration, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, 310036, China.
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22
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Mounce J, Luo L, Caprihan A, Liu J, Perrone-Bizzozero N, Calhoun V. Association of GRM3 polymorphism with white matter integrity in schizophrenia. Schizophr Res 2014; 155:8-14. [PMID: 24680030 PMCID: PMC4022143 DOI: 10.1016/j.schres.2014.03.003] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2013] [Revised: 03/01/2014] [Accepted: 03/03/2014] [Indexed: 11/30/2022]
Abstract
BACKGROUND While the functional disconnectivity hypothesis of schizophrenia has received considerable attention, fewer studies have investigated the contribution of genotype to structural connectivity between brain regions either in schizophrenia patients or in healthy controls. In this study, we obtained diffusion tensor imaging (DTI) data and genome-wide single nucleotide polymorphism (SNP) data from 74 cases and 87 age- and gender-matched controls. METHODS We used independent component analysis (ICA) to analyze fractional anisotropy (FA) values and correlated FA values with 121 SNPs in genes associated with myelination and/or schizophrenia risk. RESULTS Using ICA, we identified 6 maximally independent components in which the majority of the voxels corresponded to known white matter (WM) tracts. Among these WM-enriched components, two had FA values that were significantly decreased in patients. In addition, we examined the relationship between FA values and genotype and found that a SNP located in the intronic region of the metabotropic glutamate receptor 3 gene, GRM3, shows a significant correlation with FA values in a component containing tracts from the cortico-cerebellar-thalamic-cortical circuit of patients but not controls. CONCLUSIONS Our findings strengthen the evidence for an association between GRM3 genotype and schizophrenia and suggest a role for glutamate neurotransmission in the establishment and maintenance of myelinated fibers.
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Affiliation(s)
- Joanna Mounce
- Department of Neuroscience, University of New Mexico, Albuquerque, New Mexico, United States of America
| | - Li Luo
- The Mind Research Network (MRN) and Lovelace Biomedical and Environmental Research Institute, Albuquerque, NM, USA.
| | - Arvind Caprihan
- The Mind Research Network (MRN), Albuquerque, New Mexico, United States of America
| | - Jingyu Liu
- The Mind Research Network (MRN), Albuquerque, New Mexico, United States of America
| | - Nora Perrone-Bizzozero
- Department of Neuroscience, University of New Mexico, Albuquerque, New Mexico, United States of America
| | - Vince Calhoun
- Department of Neuroscience, University of New Mexico, Albuquerque, New Mexico, United States of America,The Mind Research Network (MRN), Albuquerque, New Mexico, United States of America,Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque, New Mexico, United States of America
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23
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Hattori T, Shimizu S, Koyama Y, Emoto H, Matsumoto Y, Kumamoto N, Yamada K, Takamura H, Matsuzaki S, Katayama T, Tohyama M, Ito A. DISC1 (disrupted-in-schizophrenia-1) regulates differentiation of oligodendrocytes. PLoS One 2014; 9:e88506. [PMID: 24516667 PMCID: PMC3917910 DOI: 10.1371/journal.pone.0088506] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2013] [Accepted: 01/08/2014] [Indexed: 02/05/2023] Open
Abstract
Disrupted-in-schizophrenia 1 (DISC1) is a gene disrupted by a translocation, t(1;11) (q42.1;q14.3), that segregates with major psychiatric disorders, including schizophrenia, recurrent major depression and bipolar affective disorder, in a Scottish family. Here we report that mammalian DISC1 endogenously expressed in oligodendroglial lineage cells negatively regulates differentiation of oligodendrocyte precursor cells into oligodendrocytes. DISC1 expression was detected in oligodendrocytes of the mouse corpus callosum at P14 and P70. DISC1 mRNA was expressed in primary cultured rat cortical oligodendrocyte precursor cells and decreased when oligodendrocyte precursor cells were induced to differentiate by PDGF deprivation. Immunocytochemical analysis showed that overexpressed DISC1 was localized in the cell bodies and processes of oligodendrocyte precursor cells and oligodendrocytes. We show that expression of the myelin related markers, CNPase and MBP, as well as the number of cells with a matured oligodendrocyte morphology, were decreased following full length DISC1 overexpression. Conversely, both expression of CNPase and the number of oligodendrocytes with a mature morphology were increased following knockdown of endogenous DISC1 by RNA interference. Overexpression of a truncated form of DISC1 also resulted in an increase in expression of myelin related proteins and the number of mature oligodendrocytes, potentially acting via a dominant negative mechanism. We also identified involvement of Sox10 and Nkx2.2 in the DISC1 regulatory pathway of oligodendrocyte differentiation, both well-known transcription factors involved in the regulation of myelin genes.
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Affiliation(s)
- Tsuyoshi Hattori
- Department of Molecular Neuropsychiatry, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
- * E-mail:
| | - Shoko Shimizu
- Division of Molecular Brain Science, Research Institute of Traditional Asian Medicine, Kinki University, Sayama, Osaka, Japan
| | - Yoshihisa Koyama
- Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Hisayo Emoto
- Pharmacology Research Laboratories, Dainippon Sumitomo Pharma Co, Ltd, Suita, Osaka, Japan
| | - Yuji Matsumoto
- Pharmacology Research Laboratories, Dainippon Sumitomo Pharma Co, Ltd, Suita, Osaka, Japan
| | - Natsuko Kumamoto
- Department of Neurobiology and Anatomy, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Aichi, Japan
| | - Kohei Yamada
- Department of Child Development & Molecular Brain Science, United Graduate School of Child Development, Osaka University, Kanazawa University and Hamamatsu University School of Medicine, Suita, Osaka, Japan
| | - Hironori Takamura
- Department of Child Development & Molecular Brain Science, United Graduate School of Child Development, Osaka University, Kanazawa University and Hamamatsu University School of Medicine, Suita, Osaka, Japan
| | - Shinsuke Matsuzaki
- Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
- Department of Child Development & Molecular Brain Science, United Graduate School of Child Development, Osaka University, Kanazawa University and Hamamatsu University School of Medicine, Suita, Osaka, Japan
| | - Taiichi Katayama
- Department of Child Development & Molecular Brain Science, United Graduate School of Child Development, Osaka University, Kanazawa University and Hamamatsu University School of Medicine, Suita, Osaka, Japan
| | - Masaya Tohyama
- Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
- Department of Child Development & Molecular Brain Science, United Graduate School of Child Development, Osaka University, Kanazawa University and Hamamatsu University School of Medicine, Suita, Osaka, Japan
- Division of Molecular Brain Science, Research Institute of Traditional Asian Medicine, Kinki University, Sayama, Osaka, Japan
| | - Akira Ito
- Department of Molecular Neuropsychiatry, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
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24
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Haney-Caron E, Caprihan A, Stevens MC. DTI-measured white matter abnormalities in adolescents with Conduct Disorder. J Psychiatr Res 2014; 48:111-20. [PMID: 24139595 PMCID: PMC3863548 DOI: 10.1016/j.jpsychires.2013.09.015] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2013] [Revised: 09/13/2013] [Accepted: 09/19/2013] [Indexed: 11/19/2022]
Abstract
Emerging research suggests that antisocial behavior in youth is linked to abnormal brain white matter microstructure, but the extent of such anatomical connectivity abnormalities remain largely untested because previous Conduct Disorder (CD) studies typically have selectively focused on specific frontotemporal tracts. This study aimed to replicate and extend previous frontotemporal diffusion tensor imaging (DTI) findings to determine whether noncomorbid CD adolescents have white matter microstructural abnormalities in major white matter tracts across the whole brain. Seventeen CD-diagnosed adolescents recruited from the community were compared to a group of 24 non-CD youth which did not differ in average age (12-18) or gender proportion. Tract-based spatial statistics (TBSS) fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD) measurements were compared between groups using FSL nonparametric two-sample t test, clusterwise whole-brain corrected, p < .05. CD FA and AD deficits were widespread, but unrelated to gender, verbal ability, or CD age of onset. CD adolescents had significantly lower FA and AD values in frontal lobe and temporal lobe regions, including frontal lobe anterior/superior corona radiata, and inferior longitudinal and fronto-occipital fasciculi passing through the temporal lobe. The magnitude of several CD FA deficits was associated with number of CD symptoms. Because AD, but not RD, differed between study groups, abnormalities of axonal microstructure in CD rather than myelination are suggested. This study provides evidence that adolescent antisocial disorder is linked to abnormal white matter microstructure in more than just the uncinate fasciculus as identified in previous DTI studies, or frontotemporal brain structures as suggested by functional neuroimaging studies. Instead, neurobiological risk specific to antisociality in adolescence is linked to microstructural abnormality in numerous long-range white matter connections among many diverse different brain regions.
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Affiliation(s)
- Emily Haney-Caron
- Olin Neuropsychiatry Research Center, The Institute of Living/Hartford Hospital, 200 Retreat Avenue, Hartford, CT 06106, USA
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25
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Beardsley PM, Hauser KF. Glial modulators as potential treatments of psychostimulant abuse. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2014; 69:1-69. [PMID: 24484974 DOI: 10.1016/b978-0-12-420118-7.00001-9] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Glia (including astrocytes, microglia, and oligodendrocytes), which constitute the majority of cells in the brain, have many of the same receptors as neurons, secrete neurotransmitters and neurotrophic and neuroinflammatory factors, control clearance of neurotransmitters from synaptic clefts, and are intimately involved in synaptic plasticity. Despite their prevalence and spectrum of functions, appreciation of their potential general importance has been elusive since their identification in the mid-1800s, and only relatively recently have they been gaining their due respect. This development of appreciation has been nurtured by the growing awareness that drugs of abuse, including the psychostimulants, affect glial activity, and glial activity, in turn, has been found to modulate the effects of the psychostimulants. This developing awareness has begun to illuminate novel pharmacotherapeutic targets for treating psychostimulant abuse, for which targeting more conventional neuronal targets has not yet resulted in a single, approved medication. In this chapter, we discuss the molecular pharmacology, physiology, and functional relationships that the glia have especially in the light in which they present themselves as targets for pharmacotherapeutics intended to treat psychostimulant abuse disorders. We then review a cross section of preclinical studies that have manipulated glial processes whose behavioral effects have been supportive of considering the glia as drug targets for psychostimulant-abuse medications. We then close with comments regarding the current clinical evaluation of relevant compounds for treating psychostimulant abuse, as well as the likelihood of future prospects.
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Affiliation(s)
| | - Kurt F Hauser
- Virginia Commonwealth University, Richmond, Virginia, USA
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26
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Bessette KL, Nave AM, Caprihan A, Stevens MC. White matter abnormalities in adolescents with major depressive disorder. Brain Imaging Behav 2013; 8:531-41. [DOI: 10.1007/s11682-013-9274-8] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
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Cao J, Dwyer JB, Gautier NM, Leslie FM, Li MD. Central myelin gene expression during postnatal development in rats exposed to nicotine gestationally. Neurosci Lett 2013; 553:115-20. [PMID: 23962570 DOI: 10.1016/j.neulet.2013.08.012] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2013] [Revised: 08/06/2013] [Accepted: 08/07/2013] [Indexed: 01/29/2023]
Abstract
Abnormal myelin gene expression in the central nervous system (CNS) is associated with many mental illnesses, including psychiatric disorders and drug addiction. We have previously shown that prenatal exposure to nicotine, the major psychoactive component in cigarette smoke, alters myelin gene expression in the CNS of adolescent rats. To examine whether this effect is specific for adolescents, we examined myelin gene expression in the CNS of juveniles and adults. Pregnant Sprague-Dawley rats were treated with nicotine (3 mg/kg/day; GN) or saline (GS) via osmotic mini pumps from gestational days 4-18. Both male and female offspring were sacrificed at postnatal day P20-21 (juveniles), P35-36 (adolescents), or P59-60 (adults). Three limbic brain regions, the prefrontal cortex (PFC), caudate putamen (CPu), and nucleus accumbens (NAc), were dissected. The expression of genes encoding major myelin components was evaluated using quantitative RT-PCR. We found that GN altered myelin gene expression in juveniles with brain region and sex differences. The pattern of alteration was different from that observed in adolescents. Although these genes were expressed normally in male adults, we observed decreased expression in GN-treated female adults, especially in the CPu. Thus, GN altered myelin gene expression throughout postnatal development and adulthood. The effect on adolescents was quite different from that at other ages, which correlated with the unique symptoms of many psychiatric disorders during adolescence.
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Affiliation(s)
- Junran Cao
- Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, VA 22911, United States
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D'Agati E, Casarelli L, Pitzianti M, Pasini A. Neuroleptic treatments and overflow movements in schizophrenia: are they independent? Psychiatry Res 2012; 200:970-6. [PMID: 22901438 DOI: 10.1016/j.psychres.2012.07.049] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2011] [Revised: 06/11/2012] [Accepted: 07/27/2012] [Indexed: 11/26/2022]
Abstract
Neurological soft signs (NSS) are minor neurological abnormalities that can be revealed by a clinical examination focused on sensory and motor information processing. NSS include overflow movements (OMs), which are defined as involuntary movements that may accompany the production of voluntary movements. OM is generally considered to be a characteristic feature of schizophrenia. White matter abnormalities might be involved in the pathogenesis of OMs. Dopamine receptors play a role in oligodendrocytes development. There is a direct link between antipsychotic agents that bind to dopamine receptors on oligodendrocytes and the development of oligodendrocytes and myelin formation. In this paper, we review the current knowledge of the effects of antipsychotic agents on NSS in schizophrenic patients. As a result of this critical review we hypothesize that the neuroleptic actions described in this paper could explain why antipsychotic agents have no effect on the resolution of NSS in patients with schizophrenia.
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Affiliation(s)
- Elisa D'Agati
- Unit of Child Neurology and Psychiatry, Department of Neuroscience, University of Rome Tor Vergata, Via Alberico 2 n. 35, 00193 Roma, Italy
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Ramadan E, Basselin M, Taha AY, Cheon Y, Chang L, Chen M, Rapoport SI. Chronic valproate treatment blocks D2-like receptor-mediated brain signaling via arachidonic acid in rats. Neuropharmacology 2011; 61:1256-64. [PMID: 21839100 PMCID: PMC3190603 DOI: 10.1016/j.neuropharm.2011.07.025] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2011] [Revised: 07/12/2011] [Accepted: 07/17/2011] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND OBJECTIVE Hyperdopaminergic signaling and an upregulated brain arachidonic acid (AA) cascade may contribute to bipolar disorder (BD). Lithium and carbamazepine, FDA-approved for the treatment of BD, attenuate brain dopaminergic D(2)-like (D(2), D(3), and D(4)) receptor signaling involving AA when given chronically to awake rats. We hypothesized that valproate (VPA), with mood-stabilizing properties, would also reduce D(2)-like-mediated signaling via AA. METHODS An acute dose of quinpirole (1 mg/kg) or saline was administered to unanesthetized rats that had been treated for 30 days with a therapeutically relevant dose of VPA (200 mg/kg/day) or vehicle. Regional brain AA incorporation coefficients, k*, and incorporation rates, J(in), markers of AA signaling and metabolism, were measured by quantitative autoradiography after intravenous [1-(14)C]AA infusion. Whole brain concentrations of prostaglandin (PG)E(2) and thromboxane (TX)B(2) also were measured. RESULTS Quinpirole compared to saline significantly increased k* in 40 of 83 brain regions, and increased brain concentrations of PGE(2) in chronic vehicle-treated rats. VPA treatment by itself reduced concentrations of plasma unesterified AA and whole brain PGE(2) and TXB(2), and blocked the quinpirole-induced increments in k* and PGE(2). CONCLUSION These results further provide evidence that mood stabilizers downregulate brain dopaminergic D(2)-like receptor signaling involving AA.
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Affiliation(s)
- Epolia Ramadan
- Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
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Peroxisome proliferator-activated receptor γ agonists accelerate oligodendrocyte maturation and influence mitochondrial functions and oscillatory Ca(2+) waves. J Neuropathol Exp Neurol 2011; 70:900-12. [PMID: 21937914 DOI: 10.1097/nen.0b013e3182309ab1] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
We have previously shown that natural (15-deoxy-Δ-prostaglandin J2) and synthetic (pioglitazone) agonists of peroxisome proliferator-activated receptor γ (PPAR-γ) strengthen the intrinsic cellular mechanisms protecting oligodendrocyte (OL) progenitors (OPs) from oxidative insults and promote their differentiation. Here, we demonstrate that repeated administrations of PPAR-γ agonists to OP cultures accelerate their differentiation to OLs, as indicated by increased numbers of O4- and O1-positive cells that show increased myelin basic protein expression, elaborated cholesterol-enrichedmembranes and have increased peroxisomes. Moreover, PPAR-γ agonist-treated OLs show increased activity of the mitochondrial respiratory chain Complex IV and an increased ability to respond to environmental signals, such as adenosine diphosphate (ADP), with oscillatory Ca waves; the latter closely correlated with the presence of mitochondria and were inhibited by the mitochondrial respiratory chain Complex I inhibitor rotenone. Because Ca oscillations and mitochondrial respiratory chain activity play crucial roles in OL differentiation, these findings suggest that PPAR-γ agonists could protect OLs and promote myelination through several mechanisms, including those involving mitochondrial functions. Our studies support the therapeutic potential of PPAR-γ agonists in brain diseases in which mitochondrial alteration, oxidative stress, and demyelination occur and point to the need for a better understanding of the role of PPAR-γ and its agonists in OL biology.
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White matter abnormalities in adults with 22q11 deletion syndrome with and without schizophrenia. Schizophr Res 2011; 132:75-83. [PMID: 21831603 DOI: 10.1016/j.schres.2011.07.017] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2010] [Revised: 07/12/2011] [Accepted: 07/15/2011] [Indexed: 11/23/2022]
Abstract
Dysfunction of cerebral white matter (WM) is a potential factor underlying the neurobiology of schizophrenia. People with 22q11 deletion syndrome have altered brain morphology and increased risk for schizophrenia, therefore decreased WM integrity may be related to schizophrenia in 22q11DS. We measured fractional anisotropy (FA) and WM volume in 27 adults with 22q11DS with schizophrenia (n=12, 22q11DS SCZ+) and without schizophrenia (n=15, 22q11DS SCZ-), 12 individuals with idiopathic schizophrenia and 31 age-matched healthy controls. We found widespread decreased WM volume in posterior and temporal brain areas and decreased FA in areas of the frontal cortex in the whole 22q11DS group compared to healthy controls. In 22q11DS SCZ+ compromised WM integrity included inferior frontal areas of parietal and occipital lobe. Idiopathic schizophrenia patients showed decreased FA in inferior frontal and insular regions compared to healthy controls. We found no WM alterations in 22q11DS SCZ+ vs. 22q11DS SCZ-. However, there was a negative correlation between FA and PANSS scores (Positive and Negative Symptom Scale) in the whole 22q11DS group in the inferior frontal, cingulate, insular and temporal areas. This is the first study to investigate WM integrity in adults with 22q11DS. Our results suggest that pervasive WM dysfunction is intrinsic to 22q11DS and that psychotic development in adults with 22q11DS involves similar brain areas as seen in schizophrenia in the general population.
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32
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Loftis JM. Sertoli cell therapy: a novel possible treatment strategy for treatment-resistant major depressive disorder. Med Hypotheses 2011; 77:35-42. [PMID: 21454019 DOI: 10.1016/j.mehy.2011.03.017] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2010] [Revised: 03/03/2011] [Accepted: 03/07/2011] [Indexed: 12/27/2022]
Abstract
By the year 2020, depression will be the 2nd most common health problem in the world. Current medications to treat depression are effective in less than 50% of patients. There is the need for novel treatments for depression to address the high rates of resistance to current treatment and the chronic residual symptoms in many patients treated for depression. The heterogeneity of major depressive disorder suggests that multiple neurocircuits and neurochemicals are involved in its pathogenesis thus, finding an alternative to neurotransmitter agonist- or antagonist-based treatments offers an important new approach. Cellular therapy is an emerging treatment strategy for multiple diseases, including depression. Based upon their in vivo function as "nurse cells" within the testis and the documented viability, efficacy, and safety of Sertoli cells transplanted into multiple tissues, including brain, the potential for these cells to provide a neuroprotective, anti-inflammatory, and trophic environment for neurons should be considered. It is proposed that the combination of self-protective, immunoregulatory and trophic properties of Sertoli cells may confer a unique potential for depression treatment and avoid many of the risks and challenges associated with stem cell therapies. At the very least, studies of the effects of Sertoli cell transplantation will add substantially to our understanding of the cellular and molecular processes that underlie depression.
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Affiliation(s)
- J M Loftis
- Research & Development Service, Portland VA Medical Center, 3710 SW U.S. Veterans Hospital Rd., Portland, OR 97239, USA.
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Modulation of cell adhesion systems by prenatal nicotine exposure in limbic brain regions of adolescent female rats. Int J Neuropsychopharmacol 2011; 14:157-74. [PMID: 20196919 PMCID: PMC5575906 DOI: 10.1017/s1461145710000179] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
Maternal smoking during pregnancy (MS) has long-lasting neurobehavioural effects on the offspring. Many MS-associated psychiatric disorders begin or change symptomatology during adolescence, a period of continuous development of the central nervous system. However, the underlying molecular mechanisms are largely unknown. Given that cell adhesion molecules (CAMs) modulate various neurotransmitter systems and are associated with many psychiatric disorders, we hypothesize that CAMs are altered by prenatal treatment of nicotine, the major psychoactive component in tobacco, in adolescent brains. Pregnant Sprague-Dawley rats were treated with nicotine (3 mg/kg.d) or saline via osmotic mini-pumps from gestational days 4 to 18. Female offspring at postnatal day 35 were sacrificed, and several limbic brain regions (the caudate putamen, nucleus accumbens, prefrontal cortex, and amygdala) were dissected for evaluation of gene expression using microarray and quantitative RT-PCR techniques. Various CAMs including neurexin, immunoglobulin, cadherin, and adhesion-GPCR superfamilies, and their intracellular signalling pathways were modified by gestational nicotine treatment (GN). Among the CAM-related pathways, GN has stronger effects on cytoskeleton reorganization pathways than on gene transcription pathways. These effects were highly region dependent, with the caudate putamen showing the greatest vulnerability. Given the important roles of CAMs in neuronal development and synaptic plasticity, our findings suggest that alteration of CAMs contributes to the neurobehavioural deficits associated with MS. Further, our study underscores that low doses of nicotine produce substantial and long-lasting changes in the brain, implying that nicotine replacement therapy during pregnancy may carry many of the same risks to the offspring as MS.
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Lövdén M, Bodammer NC, Kühn S, Kaufmann J, Schütze H, Tempelmann C, Heinze HJ, Düzel E, Schmiedek F, Lindenberger U. Experience-dependent plasticity of white-matter microstructure extends into old age. Neuropsychologia 2010; 48:3878-83. [PMID: 20816877 DOI: 10.1016/j.neuropsychologia.2010.08.026] [Citation(s) in RCA: 156] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2010] [Revised: 08/25/2010] [Accepted: 08/27/2010] [Indexed: 01/30/2023]
Abstract
Experience-dependent alterations in the human brain's white-matter microstructure occur in early adulthood, but it is unknown whether such plasticity extends throughout life. We used cognitive training, diffusion-tensor imaging (DTI), and structural MRI to investigate plasticity of the white-matter tracts that connect the left and right hemisphere of the frontal lobes. Over a period of about 180 days, 20 younger adults and 12 older adults trained for a total of one hundred and one 1-h sessions on a set of three working memory, three episodic memory, and six perceptual speed tasks. Control groups were assessed at pre- and post-test. Training affected several DTI metrics and increased the area of the anterior part of the corpus callosum. These alterations were of similar magnitude in younger and older adults. The findings indicate that experience-dependent plasticity of white-matter microstructure extends into old age and that disruptions of structural interhemispheric connectivity in old age, which are pronounced in aging, are modifiable by experience and amenable to treatment.
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Affiliation(s)
- Martin Lövdén
- Center for Lifespan Psychology, Max Planck Institute for Human Development, Berlin, Germany.
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35
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Fossella JA, Guise K, Fan J. Genetics as a tool for the dissociation of mental operations over the course of development. Ann N Y Acad Sci 2010; 1191:110-32. [DOI: 10.1111/j.1749-6632.2010.05439.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Ma L, Hasan KM, Steinberg JL, Narayana PA, Lane SD, Zuniga EA, Kramer LA, Moeller FG. Diffusion tensor imaging in cocaine dependence: regional effects of cocaine on corpus callosum and effect of cocaine administration route. Drug Alcohol Depend 2009; 104:262-7. [PMID: 19595517 PMCID: PMC2728358 DOI: 10.1016/j.drugalcdep.2009.05.020] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2008] [Revised: 05/11/2009] [Accepted: 05/14/2009] [Indexed: 01/09/2023]
Abstract
Recent studies demonstrated that diffusion tensor imaging (DTI) can provide information regarding white matter integrity of the corpus callosum (CC). In this study, DTI parameters were compared between cocaine dependent subjects (CDs) and non-drug using controls (NCs) in midsagittal CC. DTI images were acquired from 19 CDs and 18 age-matched NCs. The midsagittal CC was segmented into: genu, rostral body, anterior midbody, posterior midbody, isthmus, and splenium. Linear mixed models analyses showed that, relative to NCs, CDs had lower fractional anisotropy (FA), higher radial diffusivity (lambda(perpendicular)), and higher mean diffusivity (D(av)) in the isthmus; higher lambda(perpendicular) and D(av) in the rostral body; and lower FA in the splenium. After including mass of lifetime alcohol use in the mixed model analysis of covariance (ANCOVA) as a covariate, significant between group differences in lambda(perpendicular) in the rostral body and isthmus remained. These results suggest that alterations in lambda(perpendicular) in the rostral body and isthmus were mainly due to cocaine use, consistent with previous studies showing that cocaine may alter myelin integrity. Between group differences in FA in the isthmus and splenium, and D(av) in the rostral body and isthmus became non-significant after inclusion of alcohol use as a covariate. This is suggestive of alcohol influencing these values, or may be related to the decreased degrees of freedom for these effects. Consistent with clinical data of greater severity of drug use in smoked versus intranasal cocaine, subjects who smoked cocaine showed lower FA and higher lambda(perpendicular) compared to intranasal CDs.
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Affiliation(s)
- Liangsuo Ma
- Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center, Houston, TX 77030, USA.
| | - Khader M. Hasan
- Department of Diagnostic and Interventional Imaging, University of Texas Health Science Center, Houston, Texas 77030, USA
| | - Joel L. Steinberg
- Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center, Houston, Texas 77030, USA
| | - Ponnada A. Narayana
- Department of Diagnostic and Interventional Imaging, University of Texas Health Science Center, Houston, Texas 77030, USA
| | - Scott D. Lane
- Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center, Houston, Texas 77030, USA
| | - Edward A. Zuniga
- Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center, Houston, Texas 77030, USA
| | - Larry A. Kramer
- Department of Diagnostic and Interventional Imaging, University of Texas Health Science Center, Houston, Texas 77030, USA
| | - F. Gerard Moeller
- Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center, Houston, Texas 77030, USA
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Brocki K, Clerkin SM, Guise KG, Fan J, Fossella JA. Assessing the molecular genetics of the development of executive attention in children: focus on genetic pathways related to the anterior cingulate cortex and dopamine. Neuroscience 2009; 164:241-6. [PMID: 19344637 DOI: 10.1016/j.neuroscience.2009.01.029] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2008] [Revised: 12/26/2008] [Accepted: 01/14/2009] [Indexed: 11/16/2022]
Abstract
It is well known that children show gradual and protracted improvement in an array of behaviors involved in the conscious control of thought and emotion. Non-invasive neuroimaging in developing populations has revealed many neural correlates of behavior, particularly in the developing cingulate cortex and frontostriatal circuits. These brain regions, themselves, undergo protracted molecular and cellular change in the first two decades of human development and, as such, are ideal regions of interest for cognitive- and imaging-genetic studies that seek to link processes at the biochemical and synaptic levels to brain activity and behavior. We review our research to date that employs both adult and child-friendly versions of the attention network task (ANT) in an effort to begin to describe the role of specific genes in the assembly of a functional attention system. Presently, we constrain our predictions for genetic association studies by focusing on the role of the anterior cingulate cortex (ACC) and of dopamine in the development of executive attention.
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Affiliation(s)
- K Brocki
- Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA
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Bockbrader K, Feng Y. Essential function, sophisticated regulation and pathological impact of the selective RNA-binding protein QKI in CNS myelin development. FUTURE NEUROLOGY 2008; 3:655-668. [PMID: 19727426 DOI: 10.2217/14796708.3.6.655] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The selective RNA-binding protein QKI play a key role in advancing oligodendrocyte-dependent myelination, which is essential for the function and development of the CNS. The emerging evidence that QKI abnormalities are associated with schizophrenia and may underlie myelin impairment in this devastating disease has greatly increased interest in understanding the function of QKI. Despite the discovery of the biochemical basis for QKI-RNA interaction, a comprehensive model is currently missing regarding how QKI regulates its mRNA ligands to promote normal myelinogenesis and how deficiency of the QKI pathway is involved in the pathogenesis of human diseases that affect CNS myelin. In this review, we will focus on the role of QKI in regulating distinct mRNA targets at critical developmental steps to promote oligodendrocyte differentiation and myelin formation. In addition, we will discuss molecular mechanisms that control QKI expression and activity during normal myelinogenesis as well as the pathological impact of QKI deficiency in dysmyelination mutant animals and in human myelin disorders.
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Affiliation(s)
- Katrina Bockbrader
- Department of Pharmacology, Emory University School of Medicine, 1510 Clifton Road, Atlanta, GA 30322, USA, Tel.: +1 404 727 0351, ,
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