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性损伤。因为 这种缺陷的潜在遗传和细胞机制仍然知之甚少， 治疗选择不存在，限制了患者有效融入社会。既往临床工作 已经表明，执行功能，如工作记忆和认知灵活性开始落后于 自闭症和精神分裂症患者的青春期到成年期。然而，精确的基因， 这种情况发生的解剖学和细胞基质仍然知之甚少。我们已经确定 两个基因编码的拷贝数变异（CNVs）在人类染色体22q11.2，一个高风险因素， 自闭症和精神分裂症，剂量改变会损害工作记忆的发育成熟。 我们发表的研究表明，小鼠从青春期到成年期， 成年和组成性升高的儿茶酚-O-甲基-转移酶（COMT）活性损害了 成年期的小鼠的工作记忆，但不是青春期。在上一个财政年度，我们 进一步发现COMT和转录因子TBX 1在成人中的过表达，TBX 1是另一个22q11.2基因， 海马体的神经祖细胞重现了工作记忆中的这种年龄依赖性缺陷 容量拟议项目的目标是测试我们的总体假设，即剂量变化 CNV编码基因通过缺陷性成年人损害执行功能的发育成熟 海马体的神经发生为了验证这一假设，我们开发了调节CNV的实验工具- 在特定的发育时间点，海马中的成年神经祖细胞中的编码基因。 此外，我们还建立了一个筛查系统，以确定其他自闭症和精神分裂症相关的 剂量改变影响成年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。建议的研究完成后， 技术创新实验将首次建立一种共同的细胞机制， 改变剂量的自闭症和精神分裂症相关基因损害发育成熟， 执行功能识别发育时间窗、神经解剖区域和细胞 执行功能成熟所必需的亚型将对我们对执行功能的理解产生重大影响。 执行功能的发展机制及其脱轨轨迹。这一提议可能导致 更好地了解神经生物学基板的一个重要方面的发展 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.