Janine L. Kwapis, PhD - US grants

? DESCRIPTION (provided by applicant): Normal aging is accompanied by cognitive impairments, most notably disruptions in memory formation and updating, the ability to incorporate new information into existing memory. As lifespans increase and the United States population continues to age, it is increasingly important that treatments are developed to prevent or prolong age-related cognitive decline. Thus, it is a major goal of aging research to characterize the molecular mechanisms that contribute to memory failure in aging individuals. In this proposal, we will examine the role of histone deacetylase 3 (HDAC3) in regulating gene expression during memory formation in the aging rodent. HDAC3 is a powerful enzyme that generates a repressive chromatin structure that typically inhibits gene expression. We hypothesize that in the aging brain, HDAC3 contributes to an unusually restrictive chromatin structure that suppresses normal gene expression, synaptic plasticity, and long-term memory in the aging brain. The preliminary data presented in this proposal demonstrates that 18- month-old mice show severe impairments in hippocampus-dependent memory formation, and long-term potentiation (LTP), a cellular mechanism thought to underlie memory formation. Genetic deletion of Hdac3 in these mice, however, ameliorates age-related impairments in both processes, suggesting that HDAC3 may limit memory formation and synaptic plasticity in aging mice. Additionally, using a novel memory update paradigm, we present preliminary data showing that aging mice also show severe impairments in updating existing memories with new information. This new updating paradigm allows us to independently assess the strength of both the original memory and the updated information in a single test session, something that is not possible with most other memory models. As most memories are not de novo associations but, instead, are additions or alterations (updates) to existing memory, it is critically important to understand how memory updating works and why it is impaired with aging. The overall goal of this proposal is to identify the role of HDAC3 in age-related impairments in synaptic plasticity, memory formation, and memory updating. The focus of Aim 1 is to identify the role of HDAC3 activity in age-related impairments in long-term memory formation and updating using both viral and pharmacological manipulations of HDAC3 activity. Aim 2 proposes to test the role of HDAC3 in age-related impairments in LTP. Finally, in Aim 3, we will explore the mechanism by which HDAC3 limits memory updating throughout the lifespan using next-generation sequencing methods (including RNA-seq and ChIP-seq) following memory formation in mice ranging from 3 to 24 months old. The results from these experiments will elucidate the role of HDAC3 in memory formation and updating failures in the aging brain. Understanding how HDAC3 contributes to age-related memory failure is both a significant conceptual advance and a potentially therapeutic advance that could be leveraged to combat age-related cognitive decline.

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.