The role of HDAC3 in age-related impairments in memory updating

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Project Summary/Abstract: Alzheimer’s disease currently affects 5.8 million Americans and 13.8 million people over the age of 65 are expected to develop the disease by 2030. Even more individuals will experience normal age-related cognitive decline, including mild cognitive impairments and memory deficits. Understanding the molecular mechanisms that underlie these impairments is a key step toward developing treatments to prevent or reverse memory decline in both normal aging and Alzheimer’s disease. One hallmark of age-related cognitive decline is an impairment in memory updating, the ability to modify existing memories with new information. Memories do not persist in a fixed, unalterable state, but instead must be capable of being updated in response to new, relevant experiences. Indeed, most memories are updates to existing memories, rather than brand new associations. Despite its fundamental importance, little is known about the mechanisms that support memory updating and even less is understood about how these mechanisms are altered with age. To address this, we have developed a novel paradigm called the Objects in Updated Locations (OUL) task that is ideal for studying memory updating in both young and old rodents. In this proposal, we will examine the role of a key epigenetic mechanism, histone deacetylase 3 (HDAC3), in regulating gene expression during memory updating in the young and old brain. HDAC3 is a powerful enzyme that promotes a repressive chromatin structure to limit gene expression. Deletion or disruption of HDAC3 in the young brain transforms a subthreshold learning event into one that produces robust memory. Further, deleting HDAC3 in the dorsal hippocampus of old mice ameliorates age-related impairments in spatial memory formation. To date, no studies have tested the role of HDAC3 in memory updating or age- related impairments in memory updating. Here, we hypothesize that aberrant HDAC3 function in the old brain contributes to a repressive chromatin structure that disrupts the gene expression necessary for memory updating. In support of this hypothesis, our preliminary data show that pharmacological HDAC3 inhibition can ameliorate age-related memory updating impairments. To fully test this hypothesis, we propose two aims. In Aim 1, we will test the role of HDAC3 in age-related impairments in memory updating using a combination of pharmacological and viral CRISPR-based inhibition of HDAC3 selectively during a memory update. In Aim 2, we will use next generation sequencing including chromatin immunoprecipitation (ChIP) sequencing and RNA sequencing to identify the molecular mechanisms that underlie memory updating and determine how HDAC3 contributes to age-related impairments in this process. Our results will elucidate the mechanisms that support memory updating and identify HDAC3 as a critical regulator of memory updating in the young and old brain. 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.