Epigenetic Alterations of the Developing Brain in Animal Models of Schizophrenia

精神分裂症动物模型中大脑发育的表观遗传改变

• 批准号: 8464803
• 负责人: M MARGARITA BEHRENS
• 金额: $ 65.43万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-07 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8464803
• 关键词: Adult; Affect; Animal Model; Animals; Astrocytes; Autistic Disorder; Behavior; Behavioral; Bipolar Disorder; Birth; Blood Cells; Brain; Brain Diseases; Consult; Cytosine; DNA Methylation; DNA Methyltransferase Inhibitor; DNA methyltransferase inhibition; Data; Databases; Development; Disease; Early Diagnosis; Epigenetic Process; Foundations; Functional disorder; Gene Activation; Gene Expression Profile; Genetic; Genetic Transcription; Health; Human; In Vitro; Inflammation Mediators; Knowledge; Lead; Life; Literature; Malignant Neoplasms; Maps; Mediating; Mental Depression; Mental disorders; Methylation; Modeling; Modification; Mus; Neurons; Oxidative Stress; Pattern; Peripheral; Population; Process; Proteins; Reference Standards; Regulation; Research; Resolution; Schizophrenia; Symptoms; Syndrome; System; Testing; Therapeutic Intervention; Time; Tissues; Work; age related; base; brain cell; cell type; critical period; emerging adult; epigenomics; excitatory neuron; frontal lobe; genome-wide; in vivo; inhibitory neuron; mental disorder prevention; methylome; mouse development; neurochemistry; neurodevelopment; neuropsychiatry; neutrophil; postnatal; prevent; social; transcriptome sequencing

DESCRIPTION (provided by applicant): Epigenetic regulation of gene transcription, specifically when related to changes in DNA-methylation patterns (methylome), is a plausible mechanism underlying long-term environmental contributions to neuropsychiatric disorders. For example, pharmacological or environmentally-induced methylome alterations may lead to the silencing or aberrant activation of genes involved in the postnatal maturational process of brain circuitry, leading to functional and behavioral alterations appearing when the system reaches maturity. We and others have shown that activation of oxidative stress mechanisms during the period of maturation of brain inhibitory neurons leads to permanent neurochemical changes and schizophrenia-like behavior when animals reach adulthood. However, the mechanisms by which oxidative stress leads to disruption of the brain maturational process are unknown. Oxidative stress and inflammatory mediators are known to lead to epigenetic alterations in cancer, and activation of such mechanisms may have profound consequence during critical periods of brain maturation. Our preliminary findings suggest that activation of oxidative stress mechanisms during early life may produce epigenomic modifications, due to methylome changes, that affect neurodevelopment and thus may underlie the origins of the schizophrenia syndrome and possibly other mental disorders. We will test this hypothesis during postnatal development of frontal cortex of mice subjected to two developmental manipulations, known to lead to schizophrenia-like behavioral and neurochemical alterations in early adulthood. Three specific aims will be developed: Aim 1 will use MethylC-Seq to produce genome-wide, single-base resolution maps of methylated cytosines (methylome) during mouse postnatal brain-development at the tissue and brain cell-type levels, and determine the consequences of methylation changes at the transcriptional level by RNA-Seq (transcriptome). Aim 2 will determine the methylome and transcriptome changes induced by two non-overlapping neurodevelopmental models of schizophrenia in the two major neuronal populations in frontal cortex, and will produce transcriptome data for all inhibitory subtypes at two developmental time points. Aim 3 will determine whether treatment-induced methylome and transcriptome changes can be observed in peripheral blood cells (neutrophils). Health Impact: The proposed studies will produce a complete map of the mouse frontal cortex methylome, at the tissue and cell-type level, during the period of postnatal development until adulthood. Moreover, it will delineate the methylome changes and transcriptional consequences produced by two developmental manipulations that lead to schizophrenia-like behavior in adulthood, at the neuronal and peripheral tissue level. By making the data publically available, it will serve as a standard reference for methylome and transcriptome databases that can be consulted in relation to neuropsychiatric disorders with known and unknown developmental origins.

描述（由申请方提供）：基因转录的表观遗传调控，特别是与DNA甲基化模式（甲基化组）变化相关时，是神经精神疾病长期环境贡献的合理机制。例如，药理学或环境诱导的甲基化改变可能导致参与出生后脑回路成熟过程的基因沉默或异常激活，导致系统达到成熟时出现功能和行为改变。 我们和其他人已经表明，在大脑抑制性神经元成熟期间，氧化应激机制的激活会导致永久性的神经化学变化和动物成年后的精神分裂症样行为。然而，氧化应激导致大脑成熟过程中断的机制尚不清楚。已知氧化应激和炎症介质导致癌症的表观遗传改变，并且这些机制的激活可能在脑成熟的关键时期具有深远的后果。我们的初步研究结果表明，在生命早期氧化应激机制的激活可能会产生表观基因组修饰，由于甲基化的变化，影响神经发育，从而可能是精神分裂症综合征和其他精神疾病的起源。我们将测试这一假设在出生后发育的额叶皮质的小鼠进行两个发展的操作，已知导致精神分裂症样的行为和神经化学变化在成年早期。将开发三个具体目标：目标1将使用MethylC-Seq在组织和脑细胞类型水平上产生小鼠出生后脑发育期间甲基化胞嘧啶（甲基化组）的全基因组单碱基分辨率图谱，并通过RNA-Seq（转录组）确定转录水平上甲基化变化的后果。目的2将确定由两种不重叠的精神分裂症神经发育模型在额叶皮层的两个主要神经元群体中诱导的甲基化组和转录组变化，并将产生两个发育时间点的所有抑制亚型的转录组数据。目的3将确定是否可以在外周血细胞（中性粒细胞）中观察到治疗诱导的甲基化组和转录组变化。健康影响：拟议的研究将在组织和细胞类型水平上绘制出小鼠出生后发育至成年期间额叶皮质甲基化的完整图谱。此外，它将描绘的甲基化的变化和转录的后果所产生的两个发展操纵，导致精神分裂症样行为在成年期，在神经元和外周组织水平。通过使数据可供检索，它将作为甲基化组和转录组数据库的标准参考，可以咨询与已知和未知的发育起源的神经精神疾病。