Structural determinants of DTI observations in developing cortex and white matter

发育中皮层和白质 DTI 观察结果的结构决定因素

基本信息

批准号：
8627659
负责人：
Christopher D Kroenke
金额：
$ 22.37万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-15 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8627659
关键词：
Affect Age Anatomy Animal Model Animals Anisotropy Autistic Disorder Axon Behavior Bilateral Biological Brain Caspase-1 Cerebral cortex Cerebrum Control Animal Corpus Callosum Data Data Analyses Deformity Dendrites Derivation procedure Development Diffusion Diffusion Magnetic Resonance Imaging Disease Drug Formulations Etiology Experimental Models Ferrets Fetal Alcohol Spectrum Disorder Fiber Genetic Golgi Apparatus Growth Human Image Analysis Imaging Techniques Impairment Individual Injection of therapeutic agent Knowledge Label Link Magnetic Resonance Imaging Measurement Measures Modeling Molecular Monitor Morphology Mustela putorius furo Myelin Nature Neonatal Neuraxis Neurodevelopmental Disorder Neuroglia Neurons Neuropil Pattern Phenylketonurias Premature Birth Procedures Process Relative (related person)Rett Syndrome Rodent Schizophrenia Source Staging Staining method Stains Structure Syndrome Techniques Testing Therapeutic Therapeutic Intervention Tissues Tolonium chloride Tracer Visual Visual Cortex Visual system structure Water base diffusion anisotropy extrastriate visual cortex gray matter human subject in utero in vivo insight mature animal mind control myelination neural patterning postnatal public health relevance relating to nervous system research study stem water diffusion white matter

项目摘要

DESCRIPTION (provided by applicant): Studies using the magnetic resonance imaging (MRI) technique termed diffusion tensor imaging (DTI) have found that fractional anisotropy (FA) is reduced in cerebral white matter (WM) of mature individuals affected by disorders either of genetic (e.g. Rett syndrome, phenylketonuria), environmental (e.g. fetal alcohol spectrum disorder, premature birth), or multifactorial (e.g. autism, schizophrenia) origin. While these results imply that there are neural structural differences between affected individuals and age-matched controls, the nature of these structural differences at the cellular level remains unknown. We propose to develop an experimental model to investigate the cellular bases of both WM and cerebral cortical changes in FA that are induced by neurodevelopmental disorders. The disorder we chose to study is neonatal bilateral enucleation because this manipulation is known to induce abnormal patterns of neural connections in the visual cortex of altricial species such as rodents and ferrets. We chose ferrets because they have a relatively large cerebral WM to gray matter (GM) ratio, which makes it possible to apply diffusion anisotropy data analysis procedures of relevance to human studies. Based on preliminary observations of changes in both WM and cerebral cortex FA in neonatally enucleated ferrets, we hypothesize that changes in WM FA arise from abnormalities of myelin/glia, or changes in the divergence/convergence of axonal projections, or both. To test this hypothesis, DTI measurements will be performed on post-mortem brains of control and enucleated adult animals. Fractional anisotropy values from visual WM will be compared to Toluidine blue-based measurements of myelination, and to retrograde tracer-based measurements of axonal convergence/divergence. In addition, we hypothesize that changes in cortical GM FA reflect changes in the distribution of axonal and dendritic neuronal processes in the neuropil. This hypothesis stems from an analytical model that we recently developed to relate diffusion anisotropy in the cerebral cortex (expressed as FA) to anisotropy in the distribution of axonal and dendritic neuronal processes in the neuropil (expressed as FAN). We will test this model by comparing FA measurements taken from post-mortem ferret brains at five ages spanning postnatal day (P)6 to P45, to measurements of FAN of dendrites and axons labeled in the same tissue by the application of Golgi and anatomical tracing procedures. We will also characterize the developmental profile of the relationship between FA and FAN following early enucleation. The results are expected to demonstrate that DTI can be used to detect early manifestations of neurodevelopmental disorders in cerebral cortex, potentially prior to the loss of central nervous system plasticity. The proposed experiments will advance our understanding of the cellular changes underlying abnormalities in diffusion anisotropy in both WM and GM. This knowledge will not only facilitate monitoring the integrity of developing neural projections, but also the formulation of therapeutic strategies to counteract deleterious effects that neurodevelopmental disorders on brain development.

DESCRIPTION (provided by applicant): Studies using the magnetic resonance imaging (MRI) technique termed diffusion tensor imaging (DTI) have found that fractional anisotropy (FA) is reduced in cerebral white matter (WM) of mature individuals affected by disorders either of genetic (e.g. Rett syndrome, phenylketonuria), environmental (e.g. fetal alcohol spectrum disorder, premature birth),或多因素（例如自闭症，精神分裂症）起源。尽管这些结果表明受影响个体和年龄匹配的对照之间存在神经结构差异，但这些结构差异在细胞水平上的性质仍然未知。我们建议开发一个实验模型，以研究由神经发育疾病诱导的FA中WM和脑皮质变化的细胞碱基。我们选择研究的疾病是新生儿双侧摘除剂，因为已知这种操纵诱导了诸如啮齿动物和雪貂等私人物种的视觉皮层中神经连接的异常模式。我们之所以选择雪貂，是因为它们具有相对较大的脑WM与灰质（GM）的比率，这使得可以将相关性的扩散各向异性数据分析程序应用于人类研究。基于对新生儿in核雪貂中WM和脑皮质FA变化的初步观察，我们假设WM FA的变化是髓磷脂/神经胶质的异常发生的，或者是由异常的变化，或者是轴突预测的差异/融合。为了检验该假设，将对对照和凝聚成年动物的验尸大脑进行DTI测量。视觉WM的分数各向异性值将与基于甲苯胺蓝的基于髓鞘的测量值，以及基于轴突收敛/散射的基于逆行示踪剂的测量值。此外，我们假设皮质GM FA的变化反映了神经皮质中轴突和树突神经元过程的分布的变化。该假设源于我们最近开发的一种分析模型，该模型是为了将脑皮质中的扩散各向异性（称为FA）与各向异性在神经胶质中的轴突和树突神经元过程的分布中（表示为FAN）。我们将通过将跨越后日（P）6年代的后雪貂大脑（P）与P45进行比较，通过将GOLGI和解剖学跟踪程序应用在同一组织中标记的树突和轴突的粉丝进行测量来测试该模型。我们还将表征早期摘除后FA和风扇之间关系的发展概况。预计结果将证明DTI可用于检测脑皮质中神经发育疾病的早期表现，这可能是在中枢神经系统可塑性丧失之前。提出的实验将提高我们对WM和GM扩散各向异性中基础异常的细胞变化的理解。这些知识不仅将有助于监测发展神经预测的完整性，还可以制定治疗策略，以抵消神经发育障碍对脑发育的有害影响。