Ultrasound and MR Imaging of Mouse Brain Development.

小鼠大脑发育的超声和磁共振成像。

• 批准号: 8664143
• 负责人: Daniel H Turnbull
• 金额: $ 19.62万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-11 至 2014-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8664143
• 关键词: Address; Affect; Alleles; Animals; Auditory; Autistic Disorder; Behavior; Behavioral; Biological Assay; Brain; Brain Diseases; Brain Stem; Cell Nucleus; Cells; Cerebellum; Congenital cerebellar hypoplasia; Dandy-Walker Syndrome; Data; Defect; Detection; Development; Diffusion Magnetic Resonance Imaging; Disease; Embryonic Development; Forms Controls; Funding; Genes; Genetic; Genetically Engineered Mouse; Histology; Human; Image; Imaging Techniques; Imaging technology; Inferior Colliculus; Knockout Mice; Label; Laboratories; Life; Link; Longitudinal Studies; Magnetic Resonance; Magnetic Resonance Imaging; Manganese; Maps; Methods; Midbrain structure; Molecular; Monitor; Mus; Mutant Strains Mice; Mutation; Neonatal; Neurodevelopmental Disorder; Pathway interactions; Pattern; Phenotype; Prosencephalon; Protocols documentation; Reporter; Reporter Genes; Research; SLC11A2 gene; Schizophrenia; Signal Transduction; Specific qualifier value; Staging; Structure; Syndrome; Techniques; Testing; Ultrasonography; Validation; Viral Vector; autism spectrum disorder; base; brain morphology; developmental disease; divalent metal; hindbrain; imaging modality; in vivo; innovation; longitudinal analysis; molecular imaging; mouse model; mutant; neural circuit; neuroimaging; novel; postnatal; relating to nervous system; tool; uptake

Genetically-engineered mice are currently being developed for in vivo studies of brain development and a wide range of neurodevelopmental diseases. Indeed, defined mutant mice have been critical for identifying the affected genetic pathways and addressing the underlying cellular and molecular basis of developmental brain diseases. Lacking in these efforts have been effective in vivo imaging methods that can be used to study mouse models of neurodevelopmental disorders, especially during early postnatal stages when disease is first manifested, and the greatest changes in brain structure and function are likely to occur. A major challenge is therefore to develop and validate in vivo imaging techniques that can detect and monitor early changes in brain structure and function in the developing mouse brain. We have established quantitative, in vivo manganese (Mn)-enhanced MRI (MEMRI) approaches for analyzing the early postnatal mouse brain, showing that MEMRI provides an exquisitely sensitive method for revealing multiple nuclei and axonal tracts in the early postnatal mouse brain. Results from our laboratory and others have already proven the utility of MEMRI for assessing neural activity and connectivity. These new findings now point to the potential of MEMRI for in vivo detection and quantitative analysis of functional circuits in the developing mouse brain. We have also discovered that the Divalent Metal Transporter, DMT1 can be utilized as an effective reporter gene for MEMRI. We now propose to develop and test a combination of DMT1 expression with MEMRI to provide a precise in vivo approach to analyze functional connectivity in the mouse brain, starting from critical neonatal stages when the circuitry is first established. We will test this new imaging technology in mice with mutations in the mid-hindbrain (MHB) genes engrailed (En1 and En2) and Fgf17, which have morphological and functional cerebellum and midbrain phenotypes. Recent evidence also suggests that both En and Fgf17 mutant mice have defects in MHB circuitry. We will therefore use DMT1-MEMRI to study MHB circuitry in these mice during the critical postnatal period of brain development. The specific aims of the project are: 1) Determine the normal stage-dependent MEMRI intensities in defined nuclei in wildtype (WT), En and Fgf17 mutant mice; 2) Utilize DMT1 to genetically label defined nuclei for MEMRI analysis of midbrain and cerebellar circuits; and 3) Analyze differences in functional circuitry between WT, En and Fgf17 mouse mutants using DMT1-MEMRI. This research has high potential to establish an innovative, genetically-controlled form of MEMRI for in vivo analysis of circuits in the developing mouse brain, providing critical new tools for analyzing mouse models of a wide variety of neurodevelopmental disorders, including cerebellum hypoplasia syndromes (e.g., Joubert and Dandy-Walker syndromes), autism spectrum disorders, and schizophrenia.

目前正在开发基因工程小鼠，用于大脑发育和各种神经发育疾病的体内研究。事实上，明确的突变小鼠对于识别受影响的遗传途径和解决发育性脑疾病的潜在细胞和分子基础至关重要。这些努力缺乏可用于研究神经发育障碍小鼠模型的有效体内成像方法，特别是在疾病首次出现的产后早期，大脑结构和功能可能发生最大的变化。因此，一个主要挑战是开发和验证体内成像技术，该技术可以检测和监测发育中小鼠大脑的大脑结构和功能的早期变化。我们建立了定量体内锰 (Mn) 增强 MRI (MEMRI) 方法来分析出生后早期小鼠大脑，表明 MEMRI 为揭示出生后早期小鼠大脑中的多个核和轴突束提供了一种极其灵敏的方法。我们实验室和其他实验室的结果已经证明了 MEMRI 在评估神经活动和连接性方面的实用性。这些新发现表明 MEMRI 在体内检测和定量分析发育中的小鼠大脑功能回路方面具有潜力。我们还发现二价金属转运蛋白DMT1可以作为MEMRI的有效报告基因。我们现在建议开发和测试 DMT1 表达与 MEMRI 的组合，以提供一种精确的体内方法来分析小鼠大脑的功能连接，从电路首次建立的关键新生儿阶段开始。我们将在中后脑 (MHB) 基因 engrailed（En1 和 En2）和 Fgf17 发生突变的小鼠中测试这种新的成像技术，这些小鼠具有小脑和中脑的形态和功能表型。最近的证据还表明，En 和 Fgf17 突变小鼠的 MHB 电路均存在缺陷。因此，我们将使用 DMT1-MEMRI 来研究这些小鼠在出生后大脑发育的关键时期的 MHB 回路。该项目的具体目标是： 1) 确定野生型（WT）、En 和 Fgf17 突变小鼠的特定细胞核中正常的阶段依赖性 MEMRI 强度； 2) 利用DMT1对确定的细胞核进行基因标记，用于中脑和小脑回路的MEMRI分析； 3) 使用 DMT1-MEMRI 分析 WT、En 和 Fgf17 小鼠突变体之间功能电路的差异。这项研究很有可能建立一种创新的、基因控制的 MEMRI，用于对发育中的小鼠大脑回路进行体内分析，为分析各种神经发育障碍的小鼠模型提供关键的新工具，包括小脑发育不全综合征（例如 Joubert 和 Dandy-Walker 综合征）、自闭症谱系障碍和 精神分裂症。