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: 8238927
• 负责人: ROGER P WOODS
• 金额: $ 45.84万
• 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/8238927
• 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; 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; 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. PUBLIC HEALTH RELEVANCE: This project will study important changes that take place in the brain between birth and adulthood. The changes to be studied are thought to play an important role in brain function during normal development. Better characterization of these changes and their timing will help to identify critical times during which developmental problems might lead to neurological or psychiatric disorders.

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不成熟，并经历广泛的产后变化。这些变化包括神经递质受体水平的灰质变化和髓鞘形成中广泛的白色物质变化，这些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表征需要解剖背景，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安排中发挥了重要作用，并且还假设定义了脑损伤可能导致特定模式的缺陷的关键时间段。NIMH国家心理健康咨询理事会工作组的报告将出生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取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后人体组织以及体内测量所需的辐射照射，这种情况不太可能改变。对髓鞘形成的死后人类研究是可用的，但只提供了广泛的解剖学概括。同样地，使用磁共振（MR）成像的体内人类髓鞘形成研究具有有限的分辨率，通常基于快速采集，其潜在地将髓鞘与其他信号混淆，并且由于白色物质内的各个束的位置由于髓鞘形成而改变的事实而复杂化。虽然不受相同的基本限制，但现有的非人灵长类动物出生后大脑发育的研究在时间和空间上都是采样不足的，并且没有多种神经递质受体的综合研究。我们建议在这里的一个模型系统的特点，在微观分辨率和在6个不同的出生后发育时间点，髓鞘的白色物质和19个不同的主要神经递质受体亚型的浓度在灰质。这些将被放置在微解剖特征的背景下（使用3D偏振光成像在白色物质中以100（60-100 5 m）分辨率定义的灰质和神经束中的细胞结构）。这些显微镜研究将通过相同标本的先前体内成像进行补充，包括结构、高角分辨率弥散（HARDI）和3特斯拉下的静息状态功能磁共振（MR）成像。在15个发育时间点，在7特斯拉下对90个倾斜半球进行死后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（使用定量MR T2弛豫测定法评估）和白色物质束定位（使用HARDI评估）的个体变异性。所有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的发展资源的链接。 公共卫生相关性：该项目将研究出生和成年之间大脑发生的重要变化。研究的变化被认为在正常发育过程中对大脑功能起着重要作用。更好地描述这些变化及其时间将有助于确定发育问题可能导致神经或精神疾病的关键时期。