Postnatal mechanisms of cognitive development in mice

摘要 认知缺陷是与神经发育障碍相关的主要致残障碍。目前 由于对遗传和细胞机制的了解有限，现有的药物疗效不佳。 这些赤字背后的原因。我们的项目通过探索以下机制基础来满足这一未得到满足的需求 认知缺陷。拷贝数变异体(CNV)，例如22q11.2的1.5Mb半合子缺失，以及变异体 一些单基因，如22q11.2基因tbx1的杂合变异，已经与高风险相关。 这是人类认知缺陷的一个重要特征，也是一个很有希望的机械切入点。就像许多社交、记忆和 带有这些基因变异的个体的认知缺陷在童年(即出生后)表现出来 出生和成年前)，我们之前的工作集中在胚胎后细胞事件上。我们向大家展示了 出生后早期神经干细胞中的TBX1杂合性是导致社会交往缺陷的原因之一 出生后海马伞中髓鞘的改变可能是认知受损的潜在细胞底物。 速度。这项拟议的项目将检验主要的假设，即出生后髓鞘形成的改变是由于 神经发育障碍相关基因的剂量变化会对认知速度产生负面影响。至 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 Tbx1杂合子小鼠模型：Ng2Creer、Tbx1Flox/+和Tbx1/+ NesCreERT2；Tbx1flx/+小鼠。为了评估Tbx1和22q11.2CNV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 少突胶质细胞或少突胶质细胞条件杂合性TBX1缺失的速度 小鼠神经元谱系及TBX1缺陷对认知速度的相对贡献 与全球22q11.2半合度相比。我们将利用啮齿动物的任务来实现空间记忆、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 在22q11.2半合子携带者中。目标2将确定白质完整性改变的区域，评估 受影响脑区的轴突髓鞘形成，并评估髓鞘缺陷通路的传导速度 分别使用扩散张量成像(DTI)-MRI、电子显微镜和电生理记录， 在三种小鼠模型中。目的3将评估Tbx1‘S靶基因在体内的功能作用。 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 体内和体外的少突胶质细胞发生和髓鞘生成。目前的提议将揭示出生后的新奇 与认知功能的不同维度相关的细胞机制，提高了我们对 22q11.2严重影响认知维度改变的细胞机制 半合子，Tbx1和Tbx1‘S非22q11.2靶基因，这将为 治疗方案的发展。

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.