Epigenetic and cellular mechanisms of age-related memory updating impairments

Project Summary/Abstract Nearly 7 million Americans suffer from Alzheimer’s disease (AD), and this number is only projected to rise as the US population continues to age at an unprecedented rate. Aging remains the single greatest risk factor for the development of AD, but how aging affects the molecular mechanisms underlying memory remains incompletely understood. For instance, aging is often accompanied by memory inflexibility—the inability to update previously formed memories to reflect new information—but minimal research has examined the molecular and cellular mechanisms of memory updating and less still has looked at how these mechanisms change with age. This proposal will use a newly developed memory updating paradigm called the Objects in Updated Locations (OUL) task to probe the epigenetic and cellular mechanisms underlying age-related memory updating deficits in mice. In this proposal, we investigate a specific epigenetic mechanism, the activity of histone deacetylase 3 (HDAC3), in age-related memory updating deficits. HDAC3 is an epigenetic inhibitor of gene expression that is abundant in the aged hippocampus and plays a well-characterized role in the formation of new memories. However, the role of HDAC3 in memory updating is unexplored. We hypothesize that HDAC3 is repressing the expression of genes necessary for proper memory updating in the aged hippocampus and thereby preventing allocation of the update information to the same neurons used to encode the original memory. In Aim 1, I will investigate how neuronal ensemble dynamics during memory updating change with age and whether this process is affected by HDAC3 inhibition in old mice. In Aim 2, I will use RNA-sequencing to identify which genes are dysregulated by HDAC3 during memory updating in the aged hippocampus. Together, these aims will identify important epigenetic and cellular mechanisms underlying the effects of age on memory updating. These results will provide a critical conceptual advance in our understanding of age-related memory deficits and are a necessary step in developing therapeutics to prevent or treat disorders of memory such as AD.