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Brain Development in the Fmr1 KO Mouse Model of Fragile X Syndrome

机译：易碎X综合征的Fmr1 KO小鼠模型中的大脑发育。

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摘要

Fragile X syndrome (FXS) is the most commonly inherited form of intellectual disability resulting from silencing of FMR1 gene and consequential absence of fragile X mental retardation protein. FXS is commonly studied in Fmr1 KO mouse, which displays similar behavioral and neurological deficits as FXS patients. Many studies have investigated immature Fmr1 KO brain, but little is known about alterations in brain maturation processes, including developmental changes in metabolites, white and gray matter morphology and brain network function. Alterations in metabolites from 1H-magnetic resonance spectroscopy between Fmr1 KO and WT mice revealed included myo-inositol at postnatal-day 30 (PND 30), and taurine at PND 18, 21, and 30. Next, developmental alterations in myelin and white matter were examined in fixed Fmr1 KO mouse brains compared to WT at PND 18, 21, 30 and 60 with histological staining of myelin and MRI techniques to measure volume and magnetization transfer ratio, which is sensitive to myelin proteins and lipids. Fmr1 KO mice revealed decreased myelin density and MTR at PND 18, increased at PND 30 and decreased at PND 60, suggesting altered pattern of myelin formation in Fmr1 KO mouse. Diffusion tensor imaging was used to study microstructural properties of white matter to provide insight into myelin and axon properties in fixed Fmr1 KO brains at PND 18, 21, 30 and 60. Decreased mean, axial and radial diffusivity was found at PND 21 and 30 in Fmr1 KO brains, suggesting alterations in myelin compaction and axonal organization. Finally, alterations in functional connectivity in Fmr1 KO mouse were studied using resting-state functional-MRI. The longitudinal results showed decreased functional connectivity in the auditory and somatomotor networks in Fmr1 KO brain compared to WT at PND 30 and not different by PND 60, suggesting a delay in development of the resting state networks in Fmr1 KO mice. The work in this thesis characterized metabolic, structural, and functional alterations in developing Fmr1 KO mouse brain.
机译：脆性X综合征（FXS）是由于FMR1基因沉默和因此而缺乏脆性X智力低下蛋白而导致的智力障碍的最普遍遗传形式。 FXS通常在Fmr1 KO小鼠中进行研究，该小鼠表现出与FXS患者相似的行为和神经功能缺陷。许多研究已经调查了未成熟的Fmr1 KO大脑，但对大脑成熟过程的改变知之甚少，包括代谢物，白质和灰质形态以及脑网络功能的发育变化。 Fmr1 KO和WT小鼠在1H磁共振波谱中的代谢产物变化包括出生后30天（PND 30）的肌醇，以及PND 18、21和30时的牛磺酸。接下来，髓磷脂和白质的发育变化。用髓磷脂的组织学染色和MRI技术在固定的Fmr1 KO小鼠大脑中与PND 18、21、30和60处的WT进行了比较，以MRI技术测量体积和磁化传递比，这对髓磷脂蛋白和脂质敏感。 Fmr1 KO小鼠显示在PND 18时髓磷脂密度和MTR降低，在PND 30时升高，在PND 60时降低，表明Fmr1 KO小鼠中髓鞘形成模式改变。使用扩散张量成像研究白质的微结构特性，以深入了解PND 18、21、30和60时固定Fmr1 KO脑中的髓鞘和轴突特性。发现PND 21和30时平均，轴向和径向扩散率降低Fmr1 KO的大脑，表明髓鞘压实和轴突组织发生改变。最后，使用静止状态功能MRI研究了Fmr1 KO小鼠功能连接的改变。纵向结果显示，与PND 30时的WT相比，Fmr1 KO大脑的听觉和躯体运动网络的功能连通性降低，而PND 60则没有差异，这表明Fmr1 KO小鼠静息状态网络的发育有所延迟。本论文的工作特点是在发育中的Fmr1 KO小鼠大脑中代谢，结构和功能的改变。

著录项

  • 作者

    Shi, Da.;

  • 作者单位

    University of Maryland, Baltimore.;

  • 授予单位 University of Maryland, Baltimore.;
  • 学科 Neurosciences.
  • 学位 Ph.D.
  • 年度 2017
  • 页码 287 p.
  • 总页数 287
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 地球物理学;
  • 关键词

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