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

项目总结/摘要 这个项目的目标是1）了解NREM睡眠连续性和衰老的多方面相互作用 对突触和记忆功能，2）作为一个平台，以促进和发展我的独立 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， 神经变性和光遗传学。有强有力的支持，NREM连续性发挥了关键作用， 突触可塑性和记忆功能。此外，NREM连续性在老年人中越来越受到破坏。 然而，它是未知的NREM介导的突触可塑性如何与衰老引起的认知能力下降。 我的初步结果，使用一种新的蛋白质组学突触分析方法， 皮层突触密度，睡眠通过突触加工介导回路水平的结构可塑性， 单突触水平稳态降尺度，其中平均突触大小和受体组成是 降低有趣的是，我的分析还揭示了Aβ积累和睡眠之间的相关性，其中， 觉醒似乎会升高特定突触亚群中的Aβ水平，而睡眠介导A β水平的降低。 突触Aβ总之，这些数据表明，睡眠期间的突触和回路优化发生在许多人身上。 程度.在电路层面上，新的突触产生，这加强了以前的连接， 存储器，并为新的存储器形成提供肥沃的新基质。在单突触层面上，睡眠 稳态压力驱动突触的缩小以去除不必要的突触连接。 最后，在代谢水平上，积累的因子，如Aβ，从代谢活跃的突触中清除。我 假设衰老可能会不同地破坏睡眠的这些方面。突触密度降低 到目前为止，在老年小鼠大脑皮层中发现，这表明回路水平的突触生成可能是 抑制老年动物，而NREM稳态降尺度保持不变。这种不平衡可能 导致突触密度逐渐降低，这意味着在老年人中，新的记忆形成将 可能会更困难，但保留不应受到影响。然而，人们对衰老如何影响 大脑的突触景观以及这种影响是否会影响睡眠的突触功能。的目的 本研究的主要目的是：1）揭示突触整体分子结构的变化 通过老化介导的，并揭示NREM睡眠如何与这些变化相互作用。2)特定的突触和 参与Aβ突触积累和释放的神经元。3)参与NREM的分子参与者 介导的Aβ突触清除;和4）将突触分子变化与功能获得和 年轻和年老的成年小鼠的记忆保留。从这项研究的数据将是第一个系统级 描述衰老和睡眠过程中突触的分子变化。此外，这项研究的结果可能 显著影响我们对睡眠干预治疗认知功能下降的理解， 病理性衰老拟议的研究和培训将是一个初级教师水平的位置持续5年。

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.