CORTICAL ABNORMALITIES IN A MODEL OF DOWN SYNDROME

唐氏综合症模型中的皮质异常

• 批准号: 6182566
• 负责人: PAUL J YAROWSKY
• 金额: $ 7.43万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6182566
• 关键词: Downs syndrome; apoptosis; cell cycle; cell migration; cell proliferation; cerebral cortex; confocal scanning microscopy; developmental neurobiology; histology; laboratory mouse; learning disorders; memory disorders; neurogenesis; neurogenetics; neurons; stereotaxic techniques; synapses; synaptogenesis; trisomy

DESCRIPTION: (adapted from applicant's abstract) The goal of this research program is to investigate the development of the cerebral cortex of the segmental trisomy 16 (Ts65Dn) mouse, a potential animal model of Down syndrome (DS, trisomy 21). Many of the same chromosome 21 genes triplicated in DS are also triplicated in Ts65Dn and therefore, DS and Ts65Dn share a common genetic abnormality. Both DS and Ts65Dn have deficits in spatial learning and memory that are consistent with functional impairment in the frontal cortex. However, there is little information available about the development of the frontal cortex in Ts65Dn. The investigators hypothesize that the spatial learning and memory deficits in Ts65Dn are due to abnormalities in the generation, maturation, and survival of neurons during prenatal neuronogenesis and/or early postnatal neocortical development. The proposed experiments probe the behavior of neuroblasts and young postmitotic neurons in the developing neocortex. During the neuronogenic period, neurons are born and migrate to their final locations and the formation of connections begins. Abnormalities occurring during this period could lead to delayed formation of the pallial layers and cortical connections. During early postnatal life, synapses are formed, interneuronal connections are firmly established, and extra neurons are removed by programmed cell death. Abnormalities during this period could lead to abnormal dendritic organization and synaptogenesis, loss of connections and inappropriate programmed cell death. Defects in neuroblast proliferation, synaptogenesis, connectivity, and programmed cell death during neocortical development could lead to permanent cortical abnormalities responsible for the cognitive deficits in Ts65Dn. Similar defects in human brain development could lead to cognitive deficits in DS.

描述：（根据申请人的摘要改编）这项研究的目标 计划是调查开发的大脑皮层的发展 节段三体16（TS65DN）小鼠，唐氏综合症的潜在动物模型 （DS，三体第21条）。 DS中的许多相同的21个基因中的许多相同的染色体基因是 在TS65DN中也三率，因此，DS和TS65DN共享一个共同的遗传 紊乱 etc。 DS和TS65DN都在空间学习和记忆中都有缺陷 与额叶皮层中功能障碍一致的。然而， 关于额叶开发的信息很少 TS65DN中的皮质。调查人员假设空间学习和 TS65DN中的记忆缺陷是由于一代异常引起的， 产前神经发生和/或早期神经元的成熟和神经元的存活 产后新皮质发育。提出的实验探测了行为 在发育中的新皮层中的神经细胞和年轻的有丝分裂神经元的含量。 在神经发育时期，神经元诞生并迁移到最终 位置和连接的形成开始。异常发生 在此期间，可能导致层层层的形成延迟 皮质连接。在产后早期生活中，会形成突触， 牢固建立了神经元的连接，并去除额外的神经元 通过程序性细胞死亡。在此期间异常可能导致 树突状组织和突触发生异常，连接的丧失和 不适当的程序性细胞死亡。神经细胞增殖的缺陷， 新皮质期间的突触发生，连通性和程序性细胞死亡 发展可能导致永久性皮质异常负责 TS65DN中的认知缺陷。人脑发育中的类似缺陷可能 导致DS的认知缺陷。