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

• 批准号: 8039920
• 负责人: Christopher D Kroenke
• 金额: $ 25.51万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-15 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8039920
• 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

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. PUBLIC HEALTH RELEVANCE: Magnetic resonance imaging (MRI) can be used to detect brain anatomical abnormalities in individuals affected by a diverse array of neurodevelopmental disorders, but it is not capable of characterizing these abnormalities in detail. We therefore propose to combine MRI experiments with traditional cellular-anatomical measurements on an animal model of neurodevelopmental disorders to provide a framework for interpreting MRI findings. We will also use this experimental strategy to expand the capabilities of MRI to studies of earlier stages of brain development.

描述（由申请人提供）：使用称为扩散张量成像（DTI）的磁共振成像（MRI）技术的研究发现，受遗传（例如雷特综合征、苯丙酮尿症）、环境（例如胎儿酒精谱系障碍、早产）、 或多因素（例如自闭症、精神分裂症）起源。虽然这些结果意味着受影响的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来研究由神经发育障碍引起的 WM 和 FA 中大脑皮层变化的细胞基础。我们选择研究的疾病是新生儿双侧剜除术，因为已知这种操作会诱发晚熟物种（例如啮齿动物和雪貂）视觉皮层的神经连接模式异常。我们选择雪貂是因为它们的大脑 WM 与灰质 (GM) 比率相对较大，这使得应用与人类研究相关的扩散各向异性数据分析程序成为可能。基于对新生儿去核雪貂 WM 和大脑皮层 FA 变化的初步观察，我们假设 WM FA 的变化是由于髓磷脂/神经胶质细胞的异常，或轴突投射的发散/收敛的变化，或两者兼而有之。为了检验这一假设，将对对照和去核成年动物的死后大脑进行 DTI 测量。视觉 WM 的分数各向异性值将与基于甲苯胺蓝的髓鞘形成测量值以及基于逆行示踪剂的轴突收敛/发散测量值进行比较。此外，我们假设皮质 GM FA 的变化反映了神经毡中轴突和树突神经元过程分布的变化。这一假设源于我们最近开发的一个分析模型，该模型将大脑皮层中的扩散各向异性（表示为 FA）与神经毡中轴突和树突神经元过程分布的各向异性（表示为 FAN）联系起来。我们将通过比较从出生后 (P)6 到 P45 五个年龄段的死后雪貂大脑中获取的 FA 测量值与通过应用高尔基体和解剖追踪程序标记在同一组织中的树突和轴突的 FAN 测量值来测试该模型。我们还将描述早期摘除后 FA 和 FAN 之间关系的发展概况。预计结果将证明 DTI 可用于检测大脑皮层神经发育障碍的早期表现，可能在中枢神经系统可塑性丧失之前。拟议的实验将增进我们对 WM 和 GM 扩散各向异性异常背后的细胞变化的理解。这些知识不仅有助于监测发育中的神经投射的完整性，而且有助于制定治疗策略，以抵消神经发育障碍对大脑发育的有害影响。 公共健康相关性：磁共振成像 (MRI) 可用于检测受多种神经发育障碍影响的个体的大脑解剖异常，但它无法详细描述这些异常的特征。因此，我们建议将 MRI 实验与神经发育障碍动物模型的传统细胞解剖测量相结合，为解释 MRI 结果提供一个框架。我们还将利用这一实验策略将 MRI 的功能扩展到大脑发育早期阶段的研究。