The role of sleep in age-related decline in learning and memory

描述(申请人提供)：衰老伴随着记忆力和认知功能的进行性下降。老年人的睡眠质量和效率也会下降。尽管人们普遍认为睡眠在学习和记忆中起着关键作用，但与年龄相关的睡眠中断和记忆缺陷之间的联系仍不清楚。我们之前已经证明，学习诱导的大脑皮层新突触连接的形成代表了与长期记忆存储相关的结构变化。我们的初步数据表明，睡眠促进了幼年成年动物学习后突触的形成和表现的改善。此外，学习诱导的突触形成在老年小鼠的运动皮质中减少。基于这些发现，我们假设与年龄相关的睡眠障碍有助于减少学习依赖型突触的形成和行为改善。在这项应用中，我们将通过在体内对突触结构和功能进行成像、记录和在同一动物中进行行为测试来验证这一假设。该提案有两个具体目标。在第一个目标中，我们将研究睡眠在幼年、中年和老年小鼠学习依赖型突触重塑和行为表现中的作用。这将检验一种假设，即睡眠在促进突触形成和记忆编码方面的好处在老年小鼠中减弱。在第二个目标中，我们将使用体内钙成像来确定任务相关神经元的睡眠依赖重新激活是否在衰老过程中减少，以及这种睡眠重新激活不足是否介导了与学习相关的突触缺陷。这项拟议的项目首次在活着的大脑中单个神经元和突触的水平上探索了睡眠在与年龄相关的衰退中在学习和记忆中的作用。该项目的成功完成将为未来的研究奠定基础，这些研究将探索睡眠异常导致阿尔茨海默病等神经疾病认知功能障碍的机制。

DESCRIPTION (provided by applicant): Aging is accompanied by a progressive decline in memory and cognitive function. Aging people also experience a deterioration of sleep quality and efficiency. Although it is widely acknowledged that sleep has a critical role in learning and memory, the link between age-related sleep disruption and memory deficits remains unclear. We have previously shown that learning-induced formation of new synaptic connections in the cortex represents structural changes correlated with long-term memory storage. Our preliminary data suggests that sleep promotes synapse formation and performance improvement after learning in young adult animals. Moreover, learning-induced synapse formation is reduced in the motor cortex of aged mice. Based on these findings, we hypothesize that age-related sleep impairment contributes to the reduction in learning-dependent synapse formation and behavioral improvement. In this application, we will test this hypothesis by combining in vivo imaging of synapse structure and function, recording and behavioral testing in the same animals. The proposal has two specific aims. In the first aim, we will examine the role of sleep in learning-dependent synapse remodeling and behavioral performance in young, middle-aged and old mice. This will test the hypothesis that the benefit of sleep in promoting synapse formation and memory encoding is diminished in older mice. In the second aim, we will use in vivo calcium imaging to determine whether sleep- dependent reactivation of task-related neurons is reduced in aging and whether such deficiency in sleep reactivation mediates learning-related synaptic deficits. The proposed project explores, for the first time, the role of sleep in age-related declie in learning and memory at the level of individual neurons and synapses in the living brain. Successful completion of the project will lay the foundation for future studies exploring the mechanisms by which sleep abnormalities contribute to cognitive dysfunction in neurological diseases such as Alzheimer's disease.