Diurnal control of memory allocation by the circadian gene Per1

项目摘要/摘要： 人类和其他动物受体内生物钟的支配，该生物钟调节着生物体的循环 过程，包括记忆，跨越24小时。非病理性衰老和阿尔茨海默病都是 伴随着记忆力和昼夜节律性的损害，但这些年龄之间的联系- 相关赤字目前尚不清楚。最近的研究表明，昼夜节律基因PER1可能起着 生物钟和记忆之间的分子接口，因为PER1支持背部记忆的形成 海马体除了在大脑的中央时钟--视交叉上核--中所扮演的角色之外，还有一个众所周知的角色。 此外，在老年小鼠中，海马区PER1被异常抑制，导致与年龄相关的损伤 空间记忆。初步数据表明，PER1是由白天的学习诱导的，当时记忆是 健壮，但不是在记忆力较差的晚上学习诱导的，这表明PER1可能调节记忆 形成跨越24小时的一天。此外，PER1还调节CREB的活性，CREB是一种转录因子，是 对于确定哪些单个神经元参与编码给定的记忆(这一过程称为 “内存分配”)。这项建议旨在了解PER1如何对海马区进行昼夜节律控制 记忆的形成，并决定这一过程在旧大脑中是如何改变的。具体地说，我们假设 PER1调节海马神经元表达活性CREB的比例，因此被分配到 24小时内的记忆。因此，发生在夜间或老年的PER1降低可能会限制 分配给记忆的细胞的数量，损害记忆的形成。为了充分检验这一假设，我们建议 三个目标。在目标1中，我们将测试PER1是否控制了海马区记忆分配的昼夜振荡 在幼鼠身上。在这里，我们将双向操纵PER1在白天和夜间的表达-HSV- CRISPR技术，并使用基于行为和Arc FISH的神经集成监测来确定 对内存性能和内存分配的影响。在目标2中，我们将结合我们的双向CRISPR- 基于病毒的PER1操纵，阻断(磷酸化死亡的CREBS133A)或增强(磷酸化- 模拟CREBS133D)CREB磷酸化以确定PER1是否通过调节来控制内存分配 CREB活性。最后，在目标3中，我们将首先确定记忆和记忆中的昼夜节律 在6个月、12个月、18个月和24个月的生命周期中，分配情况会发生变化。老鼠。然后，我们将测试与年龄相关的 对PER1的抑制扰乱了CREB介导的记忆分配，最终扰乱了 老年小鼠的记忆。总而言之，我们的结果将决定生物钟如何与记忆在 分子水平以及这一过程的中断如何导致与年龄相关的记忆衰退。这些结果 代表着我们对年龄相关记忆衰退的理解在概念上的重大进步，并可能发现 治疗干预改善老年认知的潜在靶点。

Project Summary/Abstract: Humans and other animals are governed by an internal circadian clock that regulates the cycling of biological processes, including memory, across the 24h day. Both non-pathological aging and Alzheimer’s disease are accompanied by impairments in both memory and circadian rhythmicity, but the connection between these age- related deficits is currently unclear. Recent work suggests that the circadian gene Period1 (Per1) may serve as a molecular interface between the circadian clock and memory, as Per1 supports memory formation in the dorsal hippocampus in addition to its well-documented role in the brain’s central clock, the suprachiasmatic nucleus. Further, in old mice, hippocampal Per1 is abnormally repressed, contributing to age-related impairments in spatial memory. Preliminary data indicates that Per1 is induced by learning during the day, when memory is robust, but is not induced by learning at night, when memory is poor, suggesting that Per1 may modulate memory formation across the 24h day. Additionally, Per1 regulates the activity of CREB, a transcription factor that is critical for determining which individual neurons participate in encoding a given memory (a process termed “memory allocation”). This proposal aims to understand how Per1 exerts circadian control over hippocampal memory formation and determine how this process is changed in the old brain. Specifically, we hypothesize that Per1 regulates the proportion of hippocampal neurons that express active CREB and are therefore allocated to memory across the 24h day. Accordingly, reductions in Per1 that occur either at night or in old age may restrict the number of cells allocated to memory, impairing memory formation. To fully test this hypothesis, we propose three aims. In Aim 1, we will test whether Per1 controls circadian oscillations in hippocampal memory allocation in young mice. Here, we will bidirectionally manipulate Per1 expression during the day and night with HSV- CRISPR technology and use both behavior and Arc FISH-based neural ensemble monitoring to determine the effects on both memory performance and memory allocation. In Aim 2, we will combine our bidirectional CRISPR- based Per1 manipulations with viruses that either block (phospho-dead CREBS133A) or enhance (phospho- mimetic CREBS133D) CREB phosphorylation to determine whether Per1 controls memory allocation by regulating CREB activity. Finally, in Aim 3, we will first determine how circadian oscillations in both memory and memory allocation change across the lifespan in 6-, 12-, 18-, and 24-m.o. mice. Then, we will test whether age-related repression of Per1 disrupts CREB-mediated memory allocation, ultimately disrupting the circadian regulation of memory in old mice. Together, our results will determine how the circadian clock interfaces with memory at a molecular level and how disruption of this process contributes to age-related memory decline. These results represent a significant conceptual advance in our understanding of age-related memory decline and may identify potential targets for therapeutic intervention to improve cognition in old age.