Postnatal mechanisms of cognitive development in mice

小鼠认知发展的产后机制

• 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
• 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

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.

摘要 认知缺陷是与神经发育障碍相关的主要致残性损伤。目前 由于对遗传和细胞机制的理解有限， 这些赤字的根源。我们的项目通过探索以下机制基础来解决这一未满足的需求： 认知缺陷拷贝数变异（CNVs），如22q11.2的1.5 Mb半合子缺失，以及变异 单个基因的突变，如22q11.2基因Tbx 1的杂合变异，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。许多社交、记忆和 具有这些遗传变异的个体的认知缺陷在儿童期表现出来（即，产后一段时间后， 出生和完全成年之前），我们以前的工作集中在胚胎后细胞事件。我们发现 出生后早期神经干细胞中Tbx 1杂合性导致社会互动的缺陷， 海马伞中出生后髓鞘形成的改变可能是认知功能受损的潜在细胞基质， 速度这个项目将测试总体假设，即出生后髓鞘形成的改变， 与神经发育障碍有关的基因的剂量改变对认知速度产生负面影响。到 允许出生后少突神经发生和出生后神经发生的相对作用的歧义， 为了提高认知速度，我们开发了两种条件性Tbx 1杂合子小鼠模型：Ng 2CreER; Tbx 1flox/+和 nesCreERT 2; Tbxlflox/+小鼠。为了评估Tbx 1和22q11.2 CNV在认知速度中的相对作用， 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 出生后少突胶质细胞干/祖细胞中条件性杂合Tbx 1缺失速度 神经元谱系，并确定Tbx 1缺陷对认知速度的相对贡献 与全球22q11.2半合子相比。我们将使用啮齿类动物的任务来测试空间记忆，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将识别白色物质完整性改变的区域，评估 在受影响的大脑区域的轴突髓鞘形成，并评估髓鞘缺乏途径的传导速度 分别使用扩散张量成像（DTI）-MRI、电子显微镜和电生理记录， 在三个小鼠模型中。目的3：研究TBX 1靶基因在肿瘤细胞中的作用。 突变小鼠的认知功能，并建立与出生后 体内和体外的少突神经发生和髓磷脂产生。目前的建议将揭示新的产后 细胞机制与认知功能的独特维度相关，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、TBX 1和TBX 1的非22q11.2靶基因，这将为Tbx 1和Tbx 1的非22q11.2靶基因的表达提供机制基础。 开发治疗方案。