Forebrain Development in Down Syndrome and in Ts65Dn model mice

唐氏综合症和 Ts65Dn 模型小鼠的前脑发育

• 批准号: 7895007
• 负责人: Tarik F Haydar
• 金额: $ 53.34万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7895007
• 关键词: Address; Adolescent; Affect; Animal Model; Appearance; Area; Autopsy; Back; Behavioral; Brain; Breeding; Cell Count; Cell Cycle; Cell Cycle Kinetics; Cerebellum; Cerebral cortex; Cognitive; Cognitive deficits; Congenital Abnormality; Data; Defect; Development; Dorsal; Down Syndrome; Embryo; Embryonic Development; Equilibrium; Etiology; Forebrain Development; Future; Gene Expression; Generations; Genes; Genetic; Goals; Hippocampus (Brain); Human; Impaired cognition; Interneurons; Lead; Measures; Medial; Mental Retardation; Molecular; Molecular Probes; Morphogenesis; Motor; Mus; Neocortex; Neuraxis; Neurons; Outcomes Research; Perinatal; Phenotype; Physiological; Prevention; Process; Production; Prosencephalon; Relative (related person); Resources; Role; Sensory; Staging; Synapses; Techniques; Telencephalon; Testing; Thalamic structure; Transcription factor genes; Trisomy; barrel cortex; base; cognitive function; embryo tissue; inhibitory neuron; migration; morphometry; mouse Ts65Dn; mouse model; neocortical; neurogenesis; postnatal; prenatal; prevent; research study; spatiotemporal; synaptogenesis; treatment strategy

Trisomy 21 results in the constellation of phenotypes collectively termed Down syndrome (DS) and is one of the most prevalent congenital birth defects. Motor and sensory deficits and often severe mental retardation are among the many debilitating sequelae of DS. Although the precise causes of cognitive impairment in DS are not known, these abnormalities are thought to be due to altered brain development as changes in cell number and volume are found in neocortex, hippocampus and cerebellum in the perinatal and juvenile postmortem brain. A comprehensive understanding of the . etiology of the DS cognitive phenotype therefore requires examination of early prenatal development, but this analysis has never been conducted as it is hampered by challenges obtaining staged human embryonic tissue and by breeding difficulties in mouse models of DS. We have addressed this problem by generating a breeding colony of the Ts65Dn mouse model of DS and have used this resource to determine the effect of trisomy on embryonic development of the cerebral cortex and hippocampus. We have uncovered substantial over-production of inhibitory neurons in the Ts65Dn cerebral cortex and hippocampus which may lead to increased inhibitory drive and abnormal morphogenesis of these forebrain regions. These two areas are known to be affected in the DS brain. Using cellular, molecular and electrophysiological techniques, we wi II determine how altered development in Ts65Dn leads to functional changes in the maturing neuronal circuits in the neocortex and hippocampus. These experiments will define the underlying developmental causative factors of cognitive impairment in DS at both the cellular and physiological levels and are therefore important for the future development of prevention or treatment strategies.

21三体导致统称为Down的一系列表型 综合征（DS），是最常见的先天性出生缺陷之一。运动和感觉缺陷， 通常严重的智力迟钝是DS的许多使人衰弱的后遗症之一。虽然精确的 DS中认知障碍的原因尚不清楚，这些异常被认为是由于改变了 大脑发育是在新皮层、海马和海马中发现的细胞数量和体积的变化。 小脑在围产期和青少年死后的大脑。全面了解 .因此，DS认知表型的病因学需要检查早期产前检查， 发展，但由于受到挑战的阻碍，这项分析从未进行过 获得分阶段的人类胚胎组织，以及在DS小鼠模型中繁殖困难。 我们已经通过产生DS的Ts65Dn小鼠模型的繁殖群体来解决这个问题 并利用这一资源来确定三体对大脑胚胎发育的影响， 皮质和海马体。我们已经发现了大量的过度生产的抑制性神经元在 Ts65Dn在大脑皮层和海马中的作用，可能导致抑制性驱动增加和异常 这些前脑区域的形态发生。已知这两个区域在DS大脑中受到影响。 利用细胞、分子和电生理学技术，我们将确定 在Ts65Dn中的表达导致新皮层中成熟神经元回路的功能变化， 海马体。这些实验将确定认知障碍的潜在发展原因。 DS在细胞和生理水平上的损伤，因此对未来很重要 制定预防或治疗策略。

项目成果

Down Syndrome Developmental Brain Transcriptome Reveals Defective Oligodendrocyte Differentiation and Myelination.

• DOI: 10.1016/j.neuron.2016.01.042
• 发表时间: 2016-03-16
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Olmos-Serrano JL;Kang HJ;Tyler WA;Silbereis JC;Cheng F;Zhu Y;Pletikos M;Jankovic-Rapan L;Cramer NP;Galdzicki Z;Goodliffe J;Peters A;Sethares C;Delalle I;Golden JA;Haydar TF;Sestan N
• 通讯作者: Sestan N

Longitudinal measures of cognition in the Ts65Dn mouse: Refining windows and defining modalities for therapeutic intervention in Down syndrome.

Ts65Dn 小鼠认知的纵向测量：细化窗口并定义唐氏综合症治疗干预的方式。

• DOI: 10.1016/j.expneurol.2016.02.005
• 发表时间: 2016
• 期刊: Experimental neurology
• 影响因子: 5.3
• 作者: Olmos-Serrano,JLuis;Tyler,WilliamA;Cabral,HowardJ;Haydar,TarikF
• 通讯作者: Haydar,TarikF