Postnatal Development of Cortical Receptors and White Matter Tracts

描述(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还不成熟，并在出生后经历广泛的变化。这些包括神经递质受体水平的灰质变化和髓鞘形成过程中广泛的白质变化，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，因此对出生后发育的完整描述需要解剖学背景，理想的情况是高空间分辨率。成熟过程中的区域差异被认为在正常发育里程碑的时间选择上发挥了重要作用，并被假设为定义了关键的脆弱时间段，在此期间脑损伤可能导致特定模式的缺陷。NIMH国家咨询精神健康委员会工作组的一份报告已将出生后大脑发育的关键时期确定为加快精神疾病翻译研究的高度优先领域。人类对神经递质受体的发育研究在采样的时间点和区域以及所描述的受体类型的数量方面是有限的，考虑到很难获得合适的死后人体组织和活体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已经存在，但只提供了广泛的解剖学概括。同样，使用磁共振(MR)成像的活体人类髓鞘形成研究分辨率有限，通常基于快速采集，潜在地将髓鞘与其他信号混淆，并且由于髓鞘形成导致白质内单个束的位置发生变化，这一事实变得复杂。虽然没有同样的基本限制，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采样不足，而且还没有对多种神经递质受体的全面研究。我们建议在一个模型系统中，在显微分辨率下，在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种不同神经递质受体亚型的浓度。这些将放在显微解剖特征的背景下(灰质和白质中使用3D偏振光成像以超高(60-100 5m)分辨率定义的束的细胞构筑)。这些显微研究将得到相同标本的体内成像的补充，包括结构、高角度分辨率扩散(HARDI)和3特斯拉的静息状态功能磁共振(MR)成像。在7特斯拉的15个发育时间点对90个倾斜的半球进行尸检MR扫描，将提供更精细的时间样本，并允许更详细地描述个体髓鞘(使用定量MR T2松弛测量法评估)和白质束定位(使用HARDI评估)的变异性。所有结果都将纳入一个用户友好的、基于地图集的在线资源，并与其他在线人类和非人类灵长类发育资源建立链接。

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.