Epigenetic Alterations of the Developing Brain in Animal Models of Schizophrenia

描述（由申请人提供）：基因转录的表观遗传调控，特别是当与dna甲基化模式（甲基组）的变化相关时，是神经精神疾病长期环境影响的合理机制。例如，药理学或环境诱导的甲基组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，导致系统成熟时出现功能和行为改变。我们和其他人已经证明，在大脑抑制神经元成熟期间，氧化应激机制的激活会导致动物成年后永久性的神经化学变化和类似精神分裂症的行为。然而，氧化应激导致大脑成熟过程中断的机制尚不清楚。众所周知，氧化应激和炎症介质会导致癌症的表观遗传改变，在大脑成熟的关键时期，这些机制的激活可能会产生深远的影响。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，由于甲基组的改变，影响神经发育，因此可能是精神分裂症综合征和其他精神障碍的根源。我们将在受到两种发育操作的小鼠出生后额叶皮质发育过程中验证这一假设，已知这两种操作会导致成年早期精神分裂症样的行为和神经化学改变。将开发三个具体目标：目标1将使用MethylC-Seq在小鼠出生后大脑发育过程中在组织和脑细胞类型水平上生成甲基化胞嘧啶（甲基组）的全基因组单碱基分辨率图，并通过RNA-Seq（转录组）确定甲基化变化在转录水平上的后果。Aim 2将确定精神分裂症两种非重叠神经发育模型在额叶皮层两种主要神经元群中诱导的甲基组和转录组变化，并将在两个发育时间点产生所有抑制性亚型的转录组数据。目的3将确定治疗诱导的甲基组和转录组变化是否可以在外周血细胞（中性粒细胞）中观察到。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额叶皮质甲基组在出生后发育至成年期间的完整图谱。此外，它将在神经元和外周组织水平上描述导致成年期精神分裂症样行为的两种发育操作所产生的甲基组变化和转录后果。通过将数据公开，它将作为甲基组和转录组数据库的标准参考，可以参考与已知和未知发育起源有关的神经精神疾病。

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.