Postnatal Development of Cortical Receptors and White Matter Tracts

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是不成熟的，并且在出生后经历了广泛的变化。这些变化包括神经递质受体水平的灰质变化和髓鞘形成的广泛白质变化，这些变化甚至会持续到成年。不同的大脑区域以不同的速度成熟，所以出生后发育的完整特征需要解剖学背景，最好是高空间分辨率。成熟过程中的区域差异被认为在正常发育里程碑的时间上起着重要作用，也被假设为定义了关键的脆弱性时间，在此期间脑损伤可能导致特定的缺陷模式。在NIMH国家咨询精神健康委员会工作组的报告中，产后大脑发育的关键时期被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采样的时间点和区域以及表征的受体类型的数量方面是有限的，鉴于难以获得适当的死后出生的人体组织和体内测量所需的辐射暴露，这种情况不太可能改变。人类死后对髓鞘形成的研究是可用的，但只提供了广泛的解剖学概括。同样，使用磁共振（MR）成像的体内人类髓鞘形成研究分辨率有限，通常基于快速获取，这可能会混淆髓鞘与其他信号，并且由于髓鞘形成导致白质内单个束的位置发生变化，这一事实使其变得复杂。尽管不受相同的基本限制，但现有的非人类灵长类动物对出生后大脑发育的研究在时间和空间上都是不足的，而且对多种神经递质受体的综合研究也不可用。我们建议在一个模型系统中，在显微镜分辨率和六个不同的出生后发育时间点，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。这些将被放置在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米）分辨率定义的灰质和束）。这些显微研究将通过对相同标本的预先体内成像进行补充，包括结构，高角分辨率扩散（HARDI）和静息状态功能磁共振（MR）成像，在3特斯拉。在7特斯拉的15个发育时间点对90个半球进行尸检后磁共振扫描，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松弛测量法评估）和白质束定位（使用HARDI评估）。所有的结果将被整合到一个用户友好的，基于地图集的在线资源与其他在线人类和非人类灵长类动物发展资源的链接。

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.