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

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.

摘要 唐氏综合症(DS)是导致智力残疾的最常见的染色体原因，其结果是 21号染色体基因的三倍体。患有精神障碍的人表现出认知缺陷和早期 阿尔茨海默病(AD)的发展。Ts65Dn小鼠是DS的一个典型的小鼠模型。 这个模型有神经解剖学的变化，表明6个月大的AD和恶化的行为 赤字在6到11个月之间。除了D的认知异常外，共病还包括 由自主神经系统调节的心血管改变。的具体目标1 Parent Awards将比较WT和Ts65Dn小鼠的心血管状况和血管生理学 3、6和12个月龄。自主音调将在手术中定义并通过心率测量 可变性。这一补充应用程序计划在这些小鼠身上检查行为测量。 巴恩斯迷宫、新物体识别、开阔场地和高架加迷宫将在 针对每个年龄段的心血管实验。这些拟议的调查涉及《消除种族歧视国际公约》专题 有趣的是，唐氏综合征患者患阿尔茨海默病的风险显著增加。 列在NOT-AG-20-3中。Ts65Dn在早期发育中存在认知缺陷，然后采取一些措施， 例如空间学习和记忆，在以后的几个月里会恶化。这些恶化的行为措施是 在Ts65Dn中被认为代表行为和外向AD或其他痴呆症的表现。在……里面 在这一补充中，我们计划将行为测试与心率变异性测量相关联。低高 频率心率变异性表明副交感神经张力较低。在一些人体研究中，较低的 高频心率变异性(较低的副交感神经张力)对应于认知障碍。 我们之前已经发表过Ts65Dn也具有较低的高频心率变异性(较低 副交感神经音调)在9个月龄。由于表明AD的行为变化存在于6-6岁之间 在Ts65Dn的11个月中，我们假设心率变异性的变化将相关，甚至先于 他的行为。这项补充计划调查心率变异性是否可以用作非侵入性 用来确定AD前驱期的标志物。