Saturday, November 23, 2024
11/23/2024
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.
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