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.
Age-related cognitive decline is a significant concern in the United States, as lifespans continue to increase and approximately 20% of the US population is expected to be age 65 or older by the year 2030. Understanding age-related memory impairments and developing new treatment strategies to improve memory and prolong healthy cognitive function are therefore becoming increasingly important as the population ages. This proposal will examine a key epigenetic mechanism that underlies memory formation, histone deacetylase 3 (HDAC3), which may be a critical contributor to age-related memory impairments and has the real potential to unlock novel therapeutic avenues.
| Shu, Guanhua; Kramár, Enikö A; López, Alberto J et al. (2018) Deleting HDAC3 rescues long-term memory impairments induced by disruption of the neuron-specific chromatin remodeling subunit BAF53b. Learn Mem 25:109-114 |
| Kwapis, Janine L; Alaghband, Yasaman; Kramár, Enikö A et al. (2018) Epigenetic regulation of the circadian gene Per1 contributes to age-related changes in hippocampal memory. Nat Commun 9:3323 |
| Kwapis, Janine L; Alaghband, Yasaman; López, Alberto J et al. (2017) Context and Auditory Fear are Differentially Regulated by HDAC3 Activity in the Lateral and Basal Subnuclei of the Amygdala. Neuropsychopharmacology 42:1284-1294 |
