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

描述（由申请人提供）：最近的估计表明，活到55岁的人中，十分之一的男性和六分之一的女性将被诊断患有阿尔茨海默病（AD）。这种疾病以显著的认知能力下降和神经病理为特征，导致个人、家庭和社会丧失独立性和严重的心理和经济负担。早期识别阿尔茨海默病对于改善疾病预后至关重要，因为中晚期疾病伴随着明显的神经元丧失和其他病理，这对有效治疗构成了重大障碍。此外，目前缺乏既能早期识别阿尔茨海默病，又能在啮齿动物模型（绝大多数神经生物学数据来自啮齿动物模型）和患有阿尔茨海默病的人类模型之间很好地转换的行为分析。海马体是阿尔茨海默氏症患者早期和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。海马体功能的一个独特方面最近才在阿尔茨海默病的背景下进行了测试，这是基于该系统在将以前学到的信息应用于新问题和新情况（称为“迁移学习”）的能力中发挥重要作用的证据。海马体受损的人和轻度海马体萎缩的老年人（但在标准神经心理学评估中仍表现良好）的迁移学习能力受损。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2年内发展为阿尔茨海默病的人。最近，我们成功地开发了一种人类任务的小鼠模拟物，并在广泛使用的AD小鼠模型中发现迁移学习对年龄相关的AD相关病理也很敏感。当前提案的总体主题是利用我们最近开发的小鼠迁移学习任务扩展我们对迁移学习的理解，最终目标是识别与阿尔茨海默病病理相关的早期认知变化，并在已建立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早期发现阿尔茨海默病的新途径，并为患有或有患阿尔茨海默病风险的个体提供更好的治疗策略。目的1将评估双侧海马病变对迁移任务的影响，以确定海马是否确实对迁移学习至关重要。目的2将扩展我们的初步数据，并在广泛使用的AD小鼠模型中，在生命周期的多个时间点上描述与水迷宫性能相关的转移任务性能。此外，Aim 2将研究该小鼠模型中的迁移学习缺陷与海马突触完整性标志物之间的关系。Aim 3将为使用小鼠迁移学习作为临床前模型来测试AD治疗方法提供基础，并确定在AD样病理发病时开始的治疗方案是否可以阻止或减少AD小鼠模型中认知缺陷的进展。

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.