Age and Cognition in a Mouse Model of Down Syndrome

唐氏综合症小鼠模型的年龄和认知

• 批准号: 7390386
• 负责人: Galen R Wenger
• 金额: $ 24.65万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-15 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7390386
• 关键词: Address; Adult; Age; Age-Months; Alzheimer' s Disease; Animal Model; Animal Testing; Animals; Appendix; Area; Attention; Behavior; Behavioral; Brain; Chromosomes, Human, Pair 16; Chromosomes, Human, Pair 21; Cognition; Cognitive deficits; Collaborations; Communicable Diseases; Condition; Control Animal; Daily; Development; Disease; Down Syndrome; Endocrine System Diseases; Heart Diseases; Hereditary Disease; Human; Impaired cognition; Incidence; Individual; Knowledge; Laboratories; Learning; Life; Longevity; Longitudinal Studies; Masks; Memory; Modeling; Motivation; Motor; Mus; Names; Nootropic Agents; Numbers; Operant Conditioning; Pathogenesis; Performance; Phenotype; Positioning Attribute; Procedures; Proteins; Psyche structure; Publishing; Reinforcement Schedule; Relative (related person); Reporting; Research Personnel; Short-Term Memory; Testing; Time; Treatment Protocols; Trisomy; Work; age related; cognitive function; design; human disease; improved; mouse Ts65Dn; mouse model; neurochemistry; programs; research study; success

DESCRIPTION (provided by applicant): Animal models of human diseases have been of tremendous value in understanding mechanisms of disease and in design of effective treatment protocols. In spite of the success of this approach in certain areas, there has been limited success in development of animal models of diminished mental capacity, especially diminished mental capacity with age. One such model, Ts65Dn, which was developed by Davisson at The Jackson Laboratory, is considered to be the best animal model of human Down syndrome. Although aspects of this model have been studied and parallels to the human condition have been drawn, potential age-related cognitive losses have not been explored. For instance, there are reports of decreased cognitive function in Ts65Dn mice, but most report on a single time period during the first half of the expected life span and most losses are neither robust nor consistently found in all studies. To more fully explore the diminished mental capacity of this model, a longitudinal study over the entire life span of the animal, as we propose here, is needed to determine the extent of additional cognitive loss as this animal model ages. Operant conditioning procedures are uniquely suited for this type of longitudinal study since behavior can be maintained and repeatedly tested in individual subjects for months to years. Recently our group, in collaboration with Dr. Davisson's group, showed a clear deficit in learning in Ts65Dn mice responding under a repeated acquisition of behavioral chains schedule of reinforcement. Specific aims 1-3 will examine the repeated learning, working memory, sustained attention, and the effect of putative cognitive enhancers on the performance of Ts65Dn and littermate controls from 3 to 24 months of age. In specific aim 4, Dr. Griffin's group will analyze the brains of Ts65Dn and littermate control animals to determine the expression of specific proteins that have been implicated in neuropathological changes and in the pathogenesis of age-related decline in cognition in humans and in experimental animals. To our knowledge, the current proposal represents the first attempt to study the behavioral phenotype of the Ts65Dn mouse using operant conditioning procedures, especially over the life span and in conjunction with neuropathological and age-related changes.

描述（由申请人提供）：人类疾病的动物模型对于理解疾病机制和设计有效的治疗方案具有巨大的价值。尽管这种方法在某些领域取得了成功，但在开发智力下降的动物模型方面取得的成功有限，尤其是随着年龄的增长而下降的智力。其中一种模型 Ts65Dn 由杰克逊实验室的戴维森开发，被认为是人类唐氏综合症的最佳动物模型。尽管已经对该模型的各个方面进行了研究，并得出了与人类状况的相似之处，但尚未探讨与年龄相关的潜在认知损失。例如，有报道称 Ts65Dn 小鼠的认知功能下降，但大多数报告都在预期寿命前半段的单个时间段内发生，而且大多数损失在所有研究中既不稳健，也不一致。为了更全面地探索该模型的智力下降，正如我们在此提出的那样，需要对动物的整个生命周期进行纵向研究，以确定随着该动物模型年龄的增长，额外的认知损失程度。操作性条件反射程序特别适合这种类型的纵向研究，因为可以在个体受试者中维持和重复测试数月至数年的行为。最近，我们的团队与 Davisson 博士的团队合作，在重复获得行为链强化计划的情况下，发现 Ts65Dn 小鼠在学习方面存在明显缺陷。具体目标 1-3 将检查重复学习、工作记忆、持续注意力以及假定的认知增强剂对 3 至 24 个月龄 Ts65Dn 和同窝对照动物表现的影响。在具体目标 4 中，Griffin 博士的团队将分析 Ts65Dn 和同窝对照动物的大脑，以确定与人类和实验动物的神经病理变化以及与年龄相关的认知能力下降的发病机制有关的特定蛋白质的表达。据我们所知，目前的提案代表了首次尝试使用操作性调节程序来研究 Ts65Dn 小鼠的行为表型，特别是在整个生命周期以及与神经病理学和年龄相关的变化相结合。