Adult Neurogenesis and Executive Function

认知缺陷是与自闭症和精神分裂症相关的主要致残障碍。因为 这种缺陷的潜在遗传和细胞机制仍然知之甚少，以机制为基础 治疗选择不存在，限制了患者有效地融入社会。以前的临床工作 已经表明，工作记忆和认知灵活性等执行功能开始落后于 自闭症和精神分裂症患者从青春期到成年期。然而，精确的基因， 发生这种情况的解剖学和细胞底物仍然知之甚少。我们已经确定了 人类染色体22q11.2上的两个基因编码拷贝数变异(CNV)，是高血压的高危因素 自闭症和精神分裂症，这些疾病的剂量变化会损害工作记忆的发育成熟。 我们发表的研究表明，小鼠从青春期到青春期的工作记忆容量在发育过程中会扩大到 成年期以及儿茶酚-O-甲基转移酶(COMT)活性的结构性升高会损害 小鼠在成年期的工作记忆，但不是青春期。在上一个资助期内，我们有 进一步研究发现，COMT和转录因子TBX1在成人中的过度表达 海马区的神经前体细胞重现了这种与年龄相关的工作记忆缺陷 容量。拟议项目的目标是测试我们的总体假设，即 CNV编码基因通过缺陷成人损害执行功能的发育成熟 海马区的神经发生。为了验证这一假设，我们开发了实验工具来调节CNV- 在特定发育时间点，成年神经前体细胞在海马区的编码基因。 此外，我们还建立了一个筛查系统，以识别其他与自闭症和精神分裂症有关的患者 剂量变化影响成人神经发生和执行功能的CNV基因。我们的实验 读数包括执行功能和成人神经发生。在完成建议的研究后，这些 技术创新实验将首次建立一种共同的细胞机制，通过这种机制 自闭症和精神分裂症相关基因的不同剂量会损害儿童的发育成熟 执行职能。发育时间窗、神经解剖区域(S)和细胞的识别 执行功能成熟所需的亚型将对我们理解执行功能 执行功能的发展机制及其脱轨轨迹。这项提议可能会导致 更好地了解发育的一个重要方面的神经生物学基础 神经精神障碍。

Cognitive deficits are major disabling impairments associated with autism and schizophrenia. Because the underlying genetic and cellular mechanisms of such deficits are still poorly understood, mechanism-based therapeutic options do not exist, limiting the effective integration of patients into society. Previous clinical work has shown that executive functions such as working memory and cognitive flexibility start to lag behind from adolescence to adulthood in individuals with autism and schizophrenia. However, the precise genetic, anatomical and cellular substrates through which this occurs are still poorly understood. We have identified two genes encoded in copy number variants (CNVs) at human chromosome 22q11.2, a high-risk factor for autism and schizophrenia, for which dose alterations impair the developmental maturation of working memory. Our published work shows that mice developmentally expand working memory capacity from adolescence to adulthood and that constitutively elevated activity of catechol-O-methyl-transferase (COMT) impairs the working memory of mice during adulthood, but not adolescence. During the previous funding period, we have further found that over-expression of COMT and the transcription factor TBX1, another 22q11.2 gene, in adult neural progenitor cells of the hippocampus recapitulates this age-dependent deficit in working memory capacity. The objective of the proposed project is to test our overarching hypothesis that dose alterations of CNV-encoded genes impair the developmental maturation of executive function through defective adult neurogenesis in the hippocampus. To test this hypothesis, we developed experimental tools to regulate CNV- encoded genes in adult neural progenitor cells in the hippocampus at specific developmental time points. Moreover, we have established a screening system to identify other autism- and schizophrenia-associated CNV genes whose dose alterations affect adult neurogenesis and executive function. Our experimental readouts include executive function and adult neurogenesis. Upon completion of the proposed studies, these technically innovative experiments will, for the first time, establish a common cellular mechanism through which altered doses of autism- and schizophrenia-associated genes impair the developmental maturation of executive function. Identification of the developmental time window, neuroanatomical region(s), and cellular subtypes necessary for maturation of executive function will have a major impact on our understanding of the developmental mechanisms of executive function and its derailed trajectories. This proposal could lead to a better understanding of the neurobiological substrates for an important dimensional aspect of developmental neuropsychiatric disorders.