Non-REM (NREM) on synapse plasticity and beta amyloid (aB) accumulation in mice: impact on aging and Alzheimer's

项目摘要/摘要 该项目的目标是1)了解NREM睡眠连续性和衰老的多方面相互作用 关于突触和记忆功能，以及2)作为促进和发展我的独立性的平台 通过将我在突触可塑性和睡眠方面的专业知识与衰老领域的培训相结合进行研究， 神经退行性变和光遗传学。有强有力的支持认为，NREM的连续性在 突触可塑性和记忆功能。此外，在老龄化的人类中，NREM的连续性越来越受到干扰。 然而，NREM介导的突触可塑性如何与衰老引起的认知衰退相互作用尚不清楚。 我使用一种新的蛋白质组突触分析方法的初步结果表明，衰老会减少 皮质突触密度和睡眠通过突触细化和睡眠调节电路水平的结构可塑性 单个突触水平的动态平衡下调，其中突触的平均大小和受体组成是 减少了。有趣的是，我的分析还揭示了Aβ积累和睡眠之间的相关性，在这一点上， 觉醒似乎提高了特定突触亚群中Aβ的水平，而睡眠则调节了 Synaptic Aβ。总之，这些数据表明，睡眠期间的突触和电路优化发生在许多 级别。在电路层面上，新的突触被产生，这加强了先前的连接，并 存储器，并为新存储器的形成提供了肥沃的新衬底。在单一突触水平上，睡眠 动态平衡压力促使突触缩小，以移除不必要的突触连接。 最后，在代谢水平上，积聚的因子，如Aβ，被从代谢活跃的突触中清除。我 假设衰老可能以不同的方式扰乱睡眠的这些方面。突触密度降低 到目前为止在老年小鼠大脑皮质中所看到的，表明电路水平突触的产生可能是 在老年动物中被抑制，而NREM动态平衡下调保持不变。这种不平衡可能 导致突触密度逐渐下降，并暗示在老年人中新的记忆形成 可能会更困难，但留存不应受到影响。然而，人们对老龄化的影响知之甚少。 大脑的突触情况，以及这种影响是否会影响睡眠的突触功能。的目标是 本项目旨在提供以下方面的数据：1)揭示突触景观中的全球分子变化 并揭示了NREM睡眠是如何与这些变化相互作用的。2)特定的突触和 神经元参与A-β突触的聚集和释放。3)NREM中涉及的分子因子 介导的β突触清除；4)突触分子变化与功能获得和 幼年和老年成年小鼠的记忆保持。这项研究的数据将是第一个系统级别的数据 描述突触在衰老和睡眠过程中的分子变化。此外，这项研究的结果可能 显著影响我们对睡眠干预治疗正常及认知功能减退的认识 病理性衰老。拟议的研究和培训将针对一个为期5年的初级教员级别的职位。

Project Summary/Abstract The goals of this project are 1) to understand the multifaceted interaction of NREM sleep continuity and aging on synapse and memory function, and 2) to serve as a platform to facilitate and develop my independent research by combining my expertise in synapse plasticity and sleep with training in the fields of aging, neurodegeneration and optogenetics. There is strong support that NREM continuity plays a critical role in synaptic plasticity and memory function. Moreover, NREM continuity is increasing disrupted in aging humans. However, it is unknown how NREM mediated synaptic plasticity interact with aging induced cognitive decline. My preliminary results, using a novel proteomic synapses analysis method, suggest that aging decreases cortical synapse density, and sleep mediates circuit level structural plasticity through synapse elaboration and single synapse level homeostatic downscaling, where the average synapse size and receptor composition is reduced. Interestingly, my analysis also revealed a correlation between Aβ accumulation and sleep, in which, wake appears to elevate levels of Aβ in specific subsets of synapses, while sleep mediates a reduction of synaptic Aβ. Together, the data suggest that synapse and circuit optimization during sleep occurs on many levels. On the circuit level new synapses are generated, which strengthens previous connections and memories, and provides fertile new substrate for new memory formation. On the single synapse level, sleep homeostatic pressure drives the downscaling of synapses to remove unnecessary synaptic connections. Finally, on a metabolic level, built-up factors, such as Aβ, are cleared from metabolically active synapses. I hypothesize that aging likely disrupts these aspects of sleep differentially. The decreased synapse density I have seen thus far in aged mice cortex, would suggest that circuit level synapse generation could be suppressed in older animals, while NREM homeostatic downscaling remained intact. This imbalance could lead to a gradual decrease in synapse density, and imply that in aged adults new memory formation would likely be more difficult, but retention should not be affected. However, little is known about how aging impacts the synaptic landscape of the brain and whether that impact affects the synaptic function of sleep. The aims of this project are to provide data in: 1) revealing the global molecular changes in the synaptic landscape mediated by aging, and reveal how NREM sleep interacts with these changes. 2) The specific synapses and neurons involved in Aβ synapse accumulation and release. 3) The molecular actors involved in NREM mediated Aβ synapse clearance; and 4) Correlating synapse molecular changes with functional acquisition and retention of memories in young and old adult mice. The data from this research will be a first system level description of molecular changes in synapses during aging and sleep. Moreover, results of this study could significantly impact our understanding of sleep intervention in the treatment of cognitive decline in normal and pathological aging. The proposed research and training will be for a junior faculty level position lasting 5 years.