Postnatal Development of Cortical Receptors and White Matter Tracts

皮质受体和白质束的产后发育

• 批准号: 8627210
• 负责人: ROGER P WOODS
• 金额: $ 43.39万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8627210
• 关键词: 3 year old; Address; Adolescent; Adult; Age-Years; Anatomy; Animals; Area; Atlases; Base of the Brain; Behavioral; Biocompatible Materials; Biological Models; Birth; Brain; Brain Injuries; Brain region; Cercopithecus tantalus; Data; Development; Diffusion; Electronics; Formalin; Functional Magnetic Resonance Imaging; Gene Expression; Gene Expression Profiling; Genetic; Growth; Heritability; Human; Image; Individual; Lead; Left; Link; MRI Scans; Macaca; Magnetic Resonance; Magnetic Resonance Imaging; Maps; Measurement; Measures; Mental Health; Mental disorders; Methodology; Microscopic; Modeling; Myelin; National Institute of Mental Health; Nature; Neurotransmitter Receptor; Neurotransmitters; Online Systems; Pattern; Peripheral; Play; Positioning Attribute; Primates; Process; Publishing; RNA; Radiation; Recording of previous events; Relative (related person); Reporting; Resolution; Resources; Rest; Right-On; Role; Sampling; Scanning; Signal Transduction; Single Nucleotide Polymorphism Map; Specimen; Staging; Staining method; Stains; Structure; System; Testing; Time; Tissues; Translational Research; Universities; Water; Work; base; critical period; design; forest; gray matter; human tissue; improved; in vivo; in vivo imaging; mature animal; myelination; nervous system disorder; nonhuman primate; novel; polarized light; postnatal; postnatal human; primate development; receptor; regional difference; ultra high resolution; user-friendly; vervet; white matter; white matter change

DESCRIPTION (provided by applicant): Relative to many mammalian species, the brains of humans and other primates are immature at birth and undergo extensive postnatal changes. These include gray matter changes in neurotransmitter receptor levels and extensive white matter changes in myelination, which continue even into adulthood. Different brain regions mature at different rates, so a complete characterization of postnatal development requires an anatomic context, ideally at high spatial resolution. Regional differences in maturational processes are thought to play a major role in the timing of normal developmental milestones and are also hypothesized to define critical temporal periods of vulnerability during which brain injury may lead to specific patterns of deficits. Critical periods in postnatal brain development has been identified in an NIMH National Advisory Mental Health Council Workgroup report as a high priority area for accelerating translational research in mental illness. Human developmental studies of neurotransmitter receptors are limited in terms of time points and regions sampled and in terms of the number of receptor types characterized, a situation unlikely to change given the difficulties of obtaining suitable post-mortem postnatal human tissues and the radiation exposures required for in vivo measurements. Post-mortem human studies of myelination are available, but provide only broad anatomic generalizations. Likewise, in vivo human myelination studies using magnetic resonance (MR) imaging have limited resolution, are typically based on fast acquisitions that potentially confound myelin with other signals and are complicated by the fact that the positions of individual tracts within white matter change as a result of myelination. Though not subject to the same fundamental limitations, available non-human primate studies of postnatal brain development are nonetheless undersampled both temporally and spatially, and comprehensive studies of multiple neurotransmitter receptors are not available. We propose here in a model system to characterize, at microscopic resolution and at six different postnatal developmental time points, myelination of white matter and the concentrations of 19 different major neurotransmitter receptor subtypes in gray matter. These will be placed in the context of micro-anatomic features (cytoarchitectonics in gray matter and tracts defined at ultrahigh (60-100 5m) resolution in white matter using 3D polarized light imaging). These microscopic studies will be supplemented by antecedent in vivo imaging of the same specimens, including structural, high angular resolution diffusion (HARDI), and resting state functional magnetic resonance (MR) imaging at 3 Tesla. Post-mortem MR scanning of 90 banked hemispheres at fifteen developmental time points at 7 Tesla will provide finer temporal sampling and allow more detailed characterization of individual variability of myelination (evaluated using quantitative MR T2 relaxometry) and white matter tract localization (evaluated using HARDI). All results will be integrated into a user-friendly, atlas- based on-line resource with links to other on-line human and non-human primate developmental resources.

描述（由申请人提供）：相对于许多哺乳动物物种，人类和其他灵长类动物的大脑在出生时并不成熟，并在出生后经历广泛的变化。这些包括灰质神经递质受体水平的变化和白质髓鞘形成的广泛变化，这种变化甚至持续到成年期。不同的大脑区域以不同的速度成熟，因此出生后发育的完整特征需要解剖背景，最好是高空间分辨率。成熟过程的区域差异被认为在正常发育里程碑的时间安排中发挥着重要作用，并且还被假设定义了脆弱的关键时间段，在此期间脑损伤可能导致特定的缺陷模式。 NIMH 国家咨询心理健康委员会工作组报告已将产后大脑发育的关键时期确定为加速精神疾病转化研究的高度优先领域。神经递质受体的人类发育研究在时间点和采样区域以及表征的受体类型数量方面受到限制，鉴于难以获得合适的死后出生后人体组织以及体内测量所需的辐射暴露，这种情况不太可能改变。可以进行髓鞘形成的死后人体研究，但仅提供广泛的解剖学概括。同样，使用磁共振（MR）成像的体内人类髓鞘形成研究的分辨率有限，通常基于快速采集，这可能会将髓鞘质与其他信号混淆，并且由于髓鞘化导致白质内单个纤维束的位置发生变化，这一事实使情况变得复杂。尽管没有受到相同的基本限制，但现有的非人类灵长类动物出生后大脑发育研究在时间和空间上仍然采样不足，并且无法对多种神经递质受体进行全面研究。我们在此提出在一个模型系统中以显微分辨率和六个不同的出生后发育时间点来表征白质的髓鞘形成和灰质中 19 种不同主要神经递质受体亚型的浓度。这些将被置于微观解剖特征的背景下（使用 3D 偏振光成像在白质中以超高（60-100 5m）分辨率定义的灰质和束的细胞结构）。这些显微研究将得到相同样本的先前体内成像的补充，包括结构、高角分辨率扩散 (HARDI) 和 3 特斯拉的静息态功能磁共振 (MR) 成像。在 7 特斯拉的 15 个发育时间点对 90 个存储半球进行死后 MR 扫描，将提供更精细的时间采样，并允许更详细地表征髓鞘形成的个体变异性（使用定量 MR T2 弛豫测量法评估）和白质束定位（使用 HARDI 评估）。所有结果将被整合到一个用户友好的、基于图谱的在线资源中，并链接到其他在线人类和非人类灵长类动物发育资源。