Epigenetic and cellular mechanisms of age-related impairments in memory updating

About This Grant

Project Summary Alzheimer’s disease (AD) currently affects 5.8 million Americans and 13.8 million people over the age of 65 are expected to develop the disease by 2030. Aging is the single greatest risk factor for developing AD, something that is a growing concern as the US population continues to age at an unprecedented rate. Both normal aging and AD are accompanied by cognitive decline, yet our understanding of the cellular and molecular mechanisms underlying this process is incomplete and remains a critical unsolved challenge. One aspect of cognition that is especially vulnerable to aging is memory updating, the ability to modify existing memories with new information. To address this, we have developed a paradigm called the Objects in Updated Locations (OUL) task to investigate the mechanisms that support memory updating in young and old rodents. Using OUL, our preliminary research found that age-related impairments in memory updating may stem from disrupted co- allocation, or overlap, between the neuronal ensembles supporting the original and updated memories. Our preliminary work further suggests that the repressive histone deacetylase 3 (HDAC3), an epigenetic inhibitor of gene expression, might contribute to age-related updating impairments; blocking HDAC3 improves memory updating in old mice. Here, we hypothesize that abnormal HDAC3-mediated epigenetic repression in the old hippocampus disrupts proper co-allocation of the OUL update, preventing successful memory updating in old mice. We will test this hypothesis in two specific aims. In Aim 1, we will investigate how inhibiting HDAC3 systemically or within the dorsal hippocampus affects both memory updating and hippocampal co-allocation in young (3-m.o.) and old (18-m.o.) mice. In Aim 2, we will determine the extent to which activating or inhibiting neurons in the original memory ensemble can overcome age- and HDAC3-mediated effects on memory updating and co-allocation. Together, these aims will identify important epigenetic and cellular mechanisms underlying the effects of age on memory updating. More broadly, this work will identify basic biological mechanisms that underlie age-related impairments in memory updating, a critically understudied aspect of the aging process. Thus, this work represents an important step toward developing therapeutics to treat or prevent cognitive decline in both normal aging and AD.