Heart and vascular responses across the lifespan in Ts65Dn mice, a model of Down syndrome

Ts65Dn 小鼠（唐氏综合症模型）整个生命周期中心脏和血管的反应

• 批准号: 10289050
• 负责人: Lara Roberts Deruisseau
• 金额: $ 23.82万
• 依托单位: SYRACUSE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10289050
• 关键词: Address; Adult; Age-Months; Alzheimer' s Disease; Alzheimer' s disease risk; Autonomic nervous system; Award; Behavior; Behavioral; Birth; Blood Vessels; Cardiovascular alteration; Cardiovascular system; Chromosome 21; Cognitive; Cognitive deficits; Dementia; Development; Developmental Disabilities; Down Syndrome; Frequencies; Genes; Heart Abnormalities; Heart Rate; Human; Impaired cognition; Intellectual functioning disability; Investigation; Learning; Longevity; Measures; Mediating; Memory; Modeling; Mus; National Institute of Child Health and Human Development; Parents; Persons; Phase; Physiology; Public Health; Publishing; Work; age group; behavior measurement; behavior test; blood pressure reduction; comorbidity; experimental study; heart rate variability; interest; mouse Ts65Dn; mouse model; novel; object recognition; response; Address; Adult; Age-Months; Alzheimer' s Disease; Alzheimer' s disease risk; Autonomic nervous system; Award; Behavior; Behavioral; Birth; Blood Vessels; Cardiovascular alteration; Cardiovascular system; Chromosome 21; Cognitive; Cognitive deficits; Dementia; Development; Developmental Disabilities; Down Syndrome; Frequencies; Genes; Heart Abnormalities; Heart Rate; Human; Impaired cognition; Intellectual functioning disability; Investigation; Learning; Longevity; Measures; Mediating; Memory; Modeling; Mus; National Institute of Child Health and Human Development; Parents; Persons; Phase; Physiology; Public Health; Publishing; Work; age group; behavior measurement; behavior test; blood pressure reduction; comorbidity; experimental study; heart rate variability; interest; mouse Ts65Dn; mouse model; novel; object recognition; response

ABSTRACT Down Syndrome (Ds) is the most common chromosomal cause of intellectual disability and results from triplication of chromosome 21 genes. Persons with Ds demonstrate cognitive deficits and early development of Alzheimer’s disease (AD). A well-characterized mouse model of Ds is the Ts65Dn mouse. This model has neuroanatomical changes indicative of AD by 6 months of age and worsening behavioral deficits between 6 and 11 months. In addition to cognitive abnormalities in Ds, co-morbidities include cardiovascular alterations that are mediated by the autonomic nervous system. Specific Aim 1 of the parent award will compare the cardiovascular profile and vascular physiology of WT and Ts65Dn mice at 3, 6 and 12 months of age. Autonomic tone will be operationally defined and measured by heart rate variability. This supplemental application plans to examine behavioral measures in these same mice. Barnes maze, novel object recognition, open field, and elevated plus maze will be performed prior to the cardiovascular experiments for each age group. These proposed investigations address the NICHD topic of interest “The significantly increased risk of Alzheimer’s disease in adults with Down syndrome” listed in NOT-AG-20-3. Ts65Dn has cognitive deficits in early development and then some measures, such as spatial learning and memory, worsen in later months. These worsening behavioral measures are considered to represent the presentation of behavior and outwards AD or other dementia in Ts65Dn. In this supplement, we plan to correlate behavioral tests with heart rate variability measures. Lower high frequency heart rate variability is indicative of lower parasympathetic tone. In some human studies, lower high frequency heart rate variability (lower parasympathetic tone) corresponds to cognitive impairment. We have previously published that Ts65Dn also has lower high frequency heart rate variability (lower parasympathetic tone) at 9 months of age. Since behavioral changes indicative of AD present between 6- 11 months in Ts65Dn, we hypothesize that heart rate variability changes will correlate, or even precede the behavior. This supplement plans to investigate if heart rate variability could be used as a non-invasive marker to determine the prodromal phase of AD.

抽象的 唐氏综合症（DS）是智力障碍的最常见染色体原因，来自 染色体21个基因的三分一式化。 DS的人表现出认知缺陷和早期 阿尔茨海默氏病（AD）的发展。 TS65DN鼠标的特征良好的小鼠模型是TS65DN小鼠。 该模型具有神经解剖学的变化，指示AD到6个月大，行为恶化 缺陷在6到11个月之间。除了DS的认知异常外，合并症还包括 由自主神经系统介导的心血管改变。特定目标1 家长奖将比较WT和TS65DN小鼠的心血管概况和血管生理学 3、6和12个月大。自主语调将在操作上定义和通过心率来衡量 可变性。这种补充应用计划研究这些相同小鼠的行为措施。 Barnes Maze，新颖的物体识别，开放场和高架迷宫将在之前进行 每个年龄段的心血管实验。这些建议的调查涉及NICHD主题 感兴趣的“唐氏综合症成年人的阿尔茨海默氏病的风险显着增加” 在NOT-AG-20-3中列出。 TS65DN在早期发展中具有认知缺陷，然后是一些测量， 不幸的是，在后来的几个月中，例如空间学习和记忆。这些令人担忧的行为措施是 被认为代表TS65DN中行为和外向AD或其他痴呆症的表现。 这种补充，我们计划将行为测试与心率变异性指标相关联。较低 频率心率变异性表示副交感神经较低。在一些人类研究中，较低 高频心率的变异性（降低副交感神经语调）对应于认知障碍。 我们以前已经发表过，TS65DN的高频心率变异性也较低（较低 副交感神经）在9个月大时。由于行为变化表明AD存在于6-之间 在TS65DN中11个月，我们假设心率的变化将相关，甚至在 行为。这种补充计划调查是否可以将心率变异性用作非侵入性 标记以确定AD的前驱相。