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Postnatal mechanisms of cognitive development in mice

小鼠认知发展的产后机制

基本信息

批准号：
10539977
负责人：
Noboru Hiroi
金额：
$ 60.75万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-18 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10539977
关键词：
22q11.2 Address Adult Affect Animals Axon Birth Brain region Capital Cell physiology Cells Childhood Cognition Cognitive Cognitive deficits Copy Number Polymorphism Data Development Diffusion Magnetic Resonance Imaging Dimensions Disease Dose Electron Microscopy Electrophysiology (science)Embryo Event Exhibits Fiber Funding Gene Mutation Genes Genetic Goals Heterozygote Hippocampus (Brain)Human Impaired cognition Impairment In Vitro Individual Italy Knowledge Letters Link Magnetic Resonance Imaging Memory impairment Mental disorders Molecular Mus Mutant Strains Mice Mutation Myelin Nature Neonatal Neurodevelopmental Disorder Neurons Nomenclature Oligodendroglia Outcome Pathway interactions Pharmaceutical Preparations Physiological Play Production Progress Reports Proteins Publishing Research Rodent Role Short-Term Memory Signal Transduction Social Interaction Solid Speed Testing Text Therapeutic Variant Work cognitive development cognitive function cognitive task design fimbria flexibility genetic variant granule cell high risk improved in vivo memory acquisition mouse model myelination nerve stem cell neurogenesis novel novel therapeutics oligodendrocyte precursor postnatal postnatal period precursor cell social deficits spatial memory stem stem cells subventricular zone therapeutic development white matter

项目摘要

Abstract Cognitive deficits are major disabling impairments associated with neurodevelopmental disorders. Currently available drugs have poor efficacy due to a limited understanding of the genetic and cellular mechanisms underlying these deficits. Our project addresses this unmet need by exploring the mechanistic underpinnings of cognitive deficits. Copy number variants (CNVs), such as a 1.5 Mb hemizygous deletion of 22q11.2, and variants of single genes, such as heterozygous variants of Tbx1, a 22q11.2 gene, have been associated with a high risk of cognitive deficits in humans and serve as promising mechanistic entry points. As many social, memory, and cognitive deficits in individuals with these genetic variants manifest during childhood (i.e., a postnatal period after birth and before full adulthood), our previous work focused on post-embryonic cellular events. We showed that the heterozygosity of Tbx1 in early postnatal neural stem cells contribute to deficits in social interactions and that altered postnatal myelination in the fimbria may represent a potential cellular substrate for impaired cognitive speed. This proposed project will test the overarching hypothesis that alterations in postnatal myelination due to dose alterations of genes implicated in neurodevelopmental disorders negatively impact cognitive speed. To allow for the disambiguation of the relative roles of postnatal oligodendrogenesis and postnatal neurogenesis in cognitive speed, we developed two conditional Tbx1 heterozygous mouse models: Ng2CreER;Tbx1flox/+ and nesCreERT2;Tbx1flox/+ mice. To evaluate the relative roles played by Tbx1 and 22q11.2 CNV in cognitive speed, we will include a mouse model of 22q11.2 hemizygous deletion. Aim 1 will evaluate the impacts on cognitive speed of conditional heterozygous Tbx1 deletion from postnatal stem/progenitor cells of oligodendrocyte or neuronal lineage in mice and determine the relative contributions to cognitive speed of Tbx1 deficiency compared with global 22q11.2 hemizygosity. We will use rodent tasks for spatial memory, cognitive flexibility, and working memory, as the speed of these cognitive dimensions are negatively impacted from childhood among carriers of 22q11.2 hemizygosity. Aim 2 will identify regions with altered white matter integrity, assess axonal myelination in affected brain regions, and evaluate the conductance speed of myelin-deficient pathways using diffusion tensor imaging (DTI)-MRI, electron microscopy, and electrophysiological recordings, respectively, in the three mouse models. Aim 3 will evaluate the in vivo functional roles of TBX1’s target genes in the cognitive functions in mutant mice and establish the precise cellular processes associated with postnatal oligodendrogenesis and myelin production in vivo and in vitro. The current proposal will reveal novel postnatal cellular mechanisms associated with a distinct dimension of cognitive function, improving our understanding of the cellular mechanisms contributing to altered cognitive dimensions that are severely impacted by 22q11.2 hemizygosity, Tbx1 and TBX1’s non-22q11.2 target genes, which will provide a mechanistic basis for the development of therapeutic options.

抽象的认知缺陷是与神经发育障碍相关的主要致残障碍。现在由于对遗传和细胞机制的了解有限，现有药物疗效不佳这些赤字的背后。我们的项目通过探索以下机制的基础来解决这一未满足的需求认知缺陷。拷贝数变异 (CNV)，例如 22q11.2 的 1.5 Mb 半合子缺失，以及变异单基因的数量，例如 22q11.2 基因 Tbx1 的杂合变体，与高风险相关人类认知缺陷的研究，并作为有希望的机械切入点。正如许多社交、记忆和具有这些遗传变异的个体的认知缺陷在童年时期（即出生后的一段时间）表现出来出生和成年之前），我们之前的工作重点是胚胎后细胞事件。我们证明了出生后早期神经干细胞中 Tbx1 的杂合性会导致社交互动的缺陷菌毛中出生后髓鞘形成的改变可能是认知受损的潜在细胞基质速度。这个拟议的项目将测试一个总体假设，即出生后髓鞘形成的改变是由于与神经发育障碍有关的基因的剂量改变会对认知速度产生负面影响。到允许消除出生后少突胶质细胞发生和出生后神经发生的相对作用的歧义认知速度方面，我们开发了两种条件性 Tbx1 杂合小鼠模型：Ng2CreER；Tbx1flox/+ 和 nesCreERT2；Tbx1flox/+ 小鼠。为了评估 Tbx1 和 22q11.2 CNV 在认知速度中发挥的相对作用，我们将包括 22q11.2 半合子缺失的小鼠模型。目标 1 将评估对认知的影响少突胶质细胞出生后干细胞/祖细胞条件性杂合 Tbx1 缺失的速度或小鼠神经元谱系并确定 Tbx1 缺陷对认知速度的相对贡献与整体 22q11.2 半合子相比。我们将使用啮齿动物任务来提高空间记忆、认知灵活性、和工作记忆，因为这些认知维度的速度从童年起就受到负面影响 22q11.2 半合子携带者。目标 2 将识别白质完整性发生改变的区域，评估受影响大脑区域的轴突髓鞘形成，并评估髓鞘缺乏通路的电导速度分别使用扩散张量成像（DTI）-MRI、电子显微镜和电生理记录，在三个鼠标模型中。目标 3 将评估 TBX1 靶基因在体内功能作用突变小鼠的认知功能并建立与出生后相关的精确细胞过程体内和体外少突胶质细胞发生和髓磷脂产生。目前的提案将揭示新的产后与认知功能的独特维度相关的细胞机制，提高了我们对导致认知维度改变的细胞机制受到 22q11.2 的严重影响半合子性、Tbx1和TBX1的非22q11.2靶基因，这将为制定治疗方案。