Diurnal control of memory allocation by the circadian gene Per1

昼夜节律基因 Per1 对内存分配的昼夜控制

• 批准号: 10515899
• 负责人: JANINE LYNN KWAPIS
• 金额: $ 31.01万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10515899
• 关键词: Affect; Aging; Alzheimer' s Disease; Animals; Behavior; Biological Process; Body Temperature; Brain; Brain region; CREB1 gene; CRISPR/Cas technology; Cells; Characteristics; Circadian Dysregulation; Circadian Rhythms; Clustered Regularly Interspaced Short Palindromic Repeats; Cognition; Cyclic AMP-Responsive DNA-Binding Protein; Data; Dorsal; Event; Feeding behaviors; Genes; Genetic Transcription; Hippocampus (Brain); Human; Impairment; Individual; Learning; Longevity; Measures; Mediating; Memory; Memory Loss; Memory impairment; Molecular; Monitor; Mus; Neurons; Performance; Periodicity; Phosphorylation; Physiological; Positioning Attribute; Process; Proteins; Regulation; Repression; Rodent; Role; Simplexvirus; Sleep; Testing; Therapeutic Intervention; Virus; Work; age related; aging brain; aging hippocampus; base; circadian; circadian pacemaker; circadian regulation; experimental study; human old age (65+); improved; knock-down; long term memory; memory consolidation; mimetics; new therapeutic target; normal aging; novel; overexpression; relating to nervous system; spatial memory; suprachiasmatic nucleus; targeted treatment; transcription factor

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.

项目摘要/摘要： 人类和其他动物受到内部生物钟的控制，该生物钟调节生物周期 非病理性衰老和阿尔茨海默病都是一天 24 小时内的过程，包括记忆。 伴随着记忆力和昼夜节律的损害，但这些年龄之间的联系 目前尚不清楚相关的缺陷，最近的研究表明昼夜节律基因Period1（Per1）可能充当。 生物钟和记忆之间的分子界面，因为 Per1 支持背侧的记忆形成 海马体除了在大脑的中央时钟——视交叉上核中发挥的作用之外，还有大量文献记载。 此外，在老年小鼠中，海马 Per1 受到异常抑制，导致与年龄相关的损伤 初步数据表明，Per1 是由白天的学习诱发的，此时记忆力较差。 健壮，但不是由夜间学习引起的，此时记忆力很差，这表明 Per1 可能会调节记忆 此外，Per1 还调节 CREB（一种转录因子）的活性。 对于确定哪些单个神经元参与编码给定记忆至关重要（这一过程称为 该提案旨在了解 Per1 如何对海马体进行昼夜节律控制。 记忆的形成并确定这个过程在旧大脑中是如何改变的。具体来说，我们捕捉到了这一点。 Per1 调节表达活跃 CREB ​​的海马神经元的比例，因此分配给 因此，夜间或老年时 Per1 的减少可能会限制全天 24 小时的记忆。 分配给内存的单元数量，会损害内存形成。为了充分检验这一假设，我们提出。 三个目标 在目标 1 中，我们将测试 Per1 是否控制海马记忆分配的昼夜节律振荡。 在这里，我们将用 HSV- 在白天和晚上双向操纵 Per1 表达。 CRISPR 技术并使用行为和基于 Arc FISH 的神经整体监测来确定 在目标 2 中，我们将结合我们的双向 CRISPR- 基于 Per1 的病毒操作可以阻断（磷酸化死亡的 CREBS133A）或增强（磷酸化死亡） 模拟CREBS133D）CREB磷酸化以确定Per1是否通过调节来控制内存分配 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振荡。 然后，我们将测试 6 岁、12 岁、18 岁和 24 岁小鼠的整个生命周期的分配变化。 Per1 的抑制会扰乱 CREB ​​介导的内存分配，最终扰乱昼夜节律调节 总的来说，我们的结果将决定生物钟如何与记忆相互作用。 分子水平以及这一过程的破坏如何导致与年龄相关的记忆衰退。 我们对与年龄相关的记忆衰退的理解在概念上取得了重大进展，并可能确定 改善老年认知的治疗干预的潜在目标。