Transfer Learning in Mice: Implications for improved diagnosis and treatment of

小鼠迁移学习：改善诊断和治疗的意义

• 批准号: 7917133
• 负责人: Karienn Souza Montgomery
• 金额: $ 3.41万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-16 至 2013-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7917133
• 关键词: Age-associated memory impairment; Alzheimer' s Disease; Behavioral Assay; Bilateral; Biological Assay; Brain; Cognitive; Cognitive deficits; Data; Diagnosis; Disease; Disease Outcome; Early Diagnosis; Early identification; Elderly; Family; Foundations; Goals; Hippocampus (Brain); Human; Impaired cognition; Individual; Learning; Lesion; Life; Longevity; Memory Loss; Mus; Neurobiology; Neurodegenerative Disorders; Pathology; Performance; Play; Pre-Clinical Model; Preclinical Testing; Psychological Transfer; Risk; Rodent Model; Role; Societies; Staging; Structure; Synapses; System; Testing; Transgenic Mice; Translating; Treatment Protocols; Water; Woman; Work; age related; analog; base; cognitive change; cognitive function; comparative; effective therapy; hippocampal atrophy; improved; men; mouse model; neuron loss; neuropathology; neuropsychological; novel; psychologic; public health relevance; research study; treatment strategy

DESCRIPTION (provided by applicant): Recent estimates indicate that one in ten men and one in six women who live to 55 years will be diagnosed with Alzheimer's disease (AD). This disease, characterized by marked cognitive decline and neuropathology, leads to loss of independence and significant psychological and financial burdens for individuals, their families, and society. Early identification of AD is essential for improving disease outcomes as mid- and late-stage disease is accompanied by marked neuronal loss and other pathology which present significant barriers for effective treatments. Moreover, there is a current lack of behavioral assays that both identify AD early and that translate well between rodent models, from which the vast majority of the neurobiological data are derived, and humans, who suffer from the disease. The hippocampus is a brain structure that declines early and precipitously in AD, and tasks that assess hippocampal function are among the best targets for novel cognitive assessments. A unique aspect of hippocampal function only recently tested within the context of AD is based on evidence that this system plays an important role in the ability to apply previously learned information to novel problems and situations (referred to as 'transfer learning'). Transfer learning is impaired in humans with hippocampal damage and elderly individuals with mild hippocampal atrophy (but who still perform well on standard neuropsychological assessments). A small scale study has even shown that transfer learning deficits predict those individuals who will progress into AD over a 2 year window. Recently, we successfully developed a mouse analogue of this human task, and found that transfer learning is also sensitive to age-related AD- associated pathology in a widely-used mouse model of the disease. The overarching theme of the current proposal is to extend our understanding of transfer learning using our recently developed mouse transfer learning task, with the ultimate goal of both identifying early cognitive changes associated with AD pathology and halting the progression of neurobiological and cognitive deficits in a well-established mouse model of the disease. The data obtained from these studies should directly translate into novel avenues for the early detection of, and superior treatment strategies for, individuals with or at risk for developing AD. Aim 1 will evaluate the effects of bilateral hippocampal lesions on the transfer task, to determine whether the hippocampus is indeed critical for transfer learning. Aim 2 will expand upon our Preliminary Data and characterize performance on the transfer task in relation to performance on the water maze at multiple timepoints across the lifespan in a widely used mouse model of AD. In addition, Aim 2 will examine the relationship between transfer learning deficits in this mouse model and markers of synaptic integrity in hippocampus. Aim 3 will provide a foundation for using mouse transfer learning as a preclinical model for testing therapies for AD and determine if treatment regimens started at the onset of AD-like pathology can halt or reduce the progression of cognitive deficits in the AD mouse model. PUBLIC HEALTH RELEVANCE: Alzheimer's disease is an age-related progressive neurodegenerative disorder characterized by a marked loss of memory and other cognitive functions. Work under the proposed experiments will build on exciting results from our lab and others related to a novel cognitive assay (i.e., transfer learning) that may have significant advantages over traditional assessments in that it appears sensitive to early detection of the disease and is highly translational across humans and transgenic mouse models, yielding improved comparative power across species. Results from these studies should directly translate into novel avenues for the early detection of Alzheimer's disease and superior preclinical testing of treatment strategies for individuals with or at risk for developing age-related cognitive decline.

描述(由申请人提供)：最近的估计表明，活到55岁的男性中有十分之一和女性中有六分之一将被诊断为阿尔茨海默病(AD)。这种疾病以明显的认知功能下降和神经病理为特征，导致丧失独立性，给个人、他们的家庭和社会带来沉重的心理和经济负担。早期识别AD对于改善疾病预后至关重要，因为中晚期疾病伴随着显着的神经元丢失和其他病理改变，这对有效的治疗构成了巨大的障碍。此外，目前缺乏既能早期识别AD，又能很好地在啮齿动物模型和人类之间转换的行为分析方法。绝大多数神经生物学数据都来自啮齿动物模型，而人类患有这种疾病。海马体是一种在阿尔茨海默病中早期急剧衰退的大脑结构，评估海马体功能的任务是新认知评估的最佳目标之一。最近才在AD背景下测试的海马体功能的一个独特方面是基于证据表明，该系统在将以前学到的信息应用于新问题和新情况的能力方面发挥着重要作用(称为转移学习)。在患有海马区损伤的人类和患有轻度海马区萎缩的老年人(但他们在标准的神经心理评估中仍然表现良好)，转移学习受到了损害。一项小规模的研究甚至表明，迁移学习缺陷预示着那些将在两年内进展为AD的人。最近，我们成功地开发了一个类似人类任务的小鼠，并在一个广泛使用的小鼠疾病模型中发现，转移学习对年龄相关的AD相关病理也很敏感。目前提案的首要主题是使用我们最近开发的小鼠转移学习任务来扩展我们对转移学习的理解，最终目标是识别与AD病理相关的早期认知变化，并在建立良好的疾病小鼠模型中阻止神经生物学和认知缺陷的进展。从这些研究中获得的数据应该直接转化为新的途径，用于早期发现患有或处于阿尔茨海默病风险的个体，并制定更好的治疗策略。目的1将评估双侧海马损伤对迁移任务的影响，以确定海马区是否确实对迁移学习起关键作用。目标2将扩展我们的初步数据，并描述在广泛使用的阿尔茨海默病小鼠模型中，转移任务的表现与在多个时间点的水迷宫中的表现之间的关系。此外，Aim 2还将研究这种小鼠模型中的迁移学习缺陷与海马区突触完整性标志之间的关系。目的3将为使用小鼠转移学习作为测试AD治疗方法的临床前模型提供基础，并确定在AD样病理开始时开始的治疗方案是否可以阻止或减缓AD小鼠模型中认知障碍的进展。 公共卫生相关性：阿尔茨海默病是一种与年龄相关的进行性神经退行性疾病，其特征是记忆和其他认知功能明显丧失。拟议实验的工作将建立在我们实验室和其他与一种新的认知测试(即转移学习)相关的令人兴奋的结果的基础上，这种测试可能比传统评估具有显著的优势，因为它似乎对疾病的早期发现很敏感，并且在人类和转基因小鼠模型中具有高度的翻译能力，从而提高了跨物种的比较能力。这些研究的结果将直接转化为阿尔茨海默病早期发现的新途径，以及对患有或有患年龄相关性认知能力下降风险的个人的治疗策略进行更好的临床前测试。