Functional Connectivity Across Development in a Mouse Model of Rett Syndrome

雷特综合征小鼠模型发育过程中的功能连接

• 批准号: 10189731
• 负责人: Rachel M Rahn
• 金额: $ 0.82万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2021-08-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10189731
• 关键词: Address; Adolescence; Adult; Affect; Age; Animal Model; Architecture; Area; Back; Behavior; Behavioral; Behavioral Model; Biological; Biological Assay; Brain; Calcium; Childhood; Collection; Confounding Factors (Epidemiology); Coupling; Data; Development; Disease; Disease model; Environment; Fluorescence; Functional disorder; Gene Expression; Genetic; Genotype; Hemoglobin; Heterogeneity; Human; Image; Individual; Individual Differences; Infant; Intellectual functioning disability; Knockout Mice; Light; Link; Magnetic Resonance Imaging; Measures; Methyl-CpG-Binding Protein 2; Microscopic; Modeling; Motor; Mus; Neurodevelopmental Disorder; Neurologic; Neurons; Noise; Optics; Participant; Patients; Pattern; Phenotype; Population; Population Heterogeneity; Process; Proteins; Recovery; Research Personnel; Resolution; Rett Syndrome; Severities; Signal Transduction; Symptoms; System; Testing; Visual; Work; association cortex; autism spectrum disorder; behavioral phenotyping; comparative; connectome; emerging adult; fluorescence imaging; hemodynamics; imaging system; infancy; mouse model; network architecture; neural circuit; neuroimaging; neurovascular coupling; optical imaging; relating to nervous system; research study; respiratory; serial imaging; tool; trait

PROJECT SUMMARY Intellectual and developmental disabilities (IDDs) are a collection of disorders that are characterized by abnormalities in individuals' developmental trajectory, but the underlying biological correlates are not always well-understood. Functional connectivity (FC) as measured by magnetic resonance imaging (fcMRI) provides a powerful and noninvasive tool to probe the systems-level features of IDDs and resample an individual at multiple developmental timepoints. However, for all of the human functional neuroimaging studies of development, they have not yet established a functional connectome across age nor its links to behavior. How FC changes across development from infancy to adulthood, and whether FC mirrors abnormal developmental behavior trajectories in IDDs, remain questions. Rett Syndrome (RTT) is an IDD with a known genetic cause and manifests motor and respiratory deficits as well as certain behaviors seen in IDDs such as autism spectrum disorder. However, RTT's complete effect on neural circuits and processes is still not well-understood, in part because the brain architecture and connectivity have not been comprehensively evaluated at the systems level. Tracing the FC and behavioral phenotype of RTT across development could establish a presence or lack of coupling between FC and behavior. Use of an animal model better controls for the potentially confounding genetic and environmental heterogeneity present in human studies. This proposal will therefore track FC across development in mice, using optical intrinsic signal imaging measures of functional connectivity (fcOIS) to circumvent fcMRI's signal-to-noise challenges in mice. FC networks in human infants have been previously shown to vary in their development, with somatomotor areas showing more connectivity than association cortex in infancy. Because of this difference between developmental extremes but the lack of data regarding the developmental progression between them, I will longitudinally image mice at 5 developmental timepoints from P15 to early adulthood and establish a baseline pattern of FC in neurologically typical mice using calcium imaging. To establish sensitivity to IDD-related traits, I will characterize FC patterns in the Rett Syndrome model Mecp2lox-stop and explore inter-individual differences in the population. Finally, to probe beyond these correlative questions, I will examine how the rescue of the Mecp2 model's gene expression in GABAergic neurons affects its FC phenotype, and I will evaluate the relationship between the model's behavioral phenotypes after rescue and its FC measures. Ultimately, the results of this study will shed light on the nuances of longitudinal network architecture development and the interactions between genotype, FC, and behavior that are incompletely characterized in RTT and other IDDs.

项目摘要 智力和发育障碍（IDDs）是一系列疾病，其特征是 个体发育轨迹的异常，但潜在的生物学相关性并不总是 很好理解通过磁共振成像（fcMRI）测量的功能连接性（FC）提供了一个 一个强大的非侵入性工具，用于探测IDD的系统级特征，并在多个 发展时间点。然而，对于所有人类发育的功能性神经成像研究， 还没有建立一个跨年龄的功能性连接体，也没有建立它与行为的联系。FC如何在 从婴儿期到成年期的发育，以及FC是否反映了异常的发育行为轨迹 在缺碘症方面，仍然存在问题。Rett综合征（RTT）是一种具有已知遗传原因的IDD， 呼吸缺陷以及在IDDs中看到的某些行为，如自闭症谱系障碍。然而，RTT 对神经回路和过程的完整影响仍然没有得到很好的理解，部分原因是大脑结构 和连通性尚未在系统一级进行全面评估。跟踪FC和行为 跨发育的RTT表型可以确定FC和行为之间存在或缺乏耦合。 使用动物模型可以更好地控制潜在的混淆遗传和环境异质性 存在于人类研究中。因此，该提案将使用光学固有特性在小鼠中跟踪FC的整个发育过程。 功能连接的信号成像测量（fcOIS），以规避fcMRI的信噪比挑战， 小鼠人类婴儿中的FC网络先前已被证明在其发育过程中存在差异， 在婴儿期，大脑皮层的连接性比联合皮层更强。由于这种差异， 发展的极端，但缺乏数据，关于他们之间的发展进程，我会 在从P15到成年早期的5个发育时间点对小鼠进行纵向成像，并建立基线 使用钙成像的神经学典型小鼠中的FC模式。为了建立对IDD相关性状的敏感性，我 将表征Rett综合征模型Mecp 2lox-stop中的FC模式，并探索 人口。最后，为了超越这些相关的问题，我将研究如何拯救Mecp 2 模型的GABA能神经元的基因表达影响其FC表型，我将评估这种关系 拯救后模型的行为表型与其FC测量之间的关系。最终， 这项研究将揭示纵向网络架构发展的细微差别以及 在RTT和其他IDDs中不完全表征的基因型、FC和行为之间。