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.

Grant Number: 5F31AG087533-02
NIH Institute/Center: NIH
Principal Investigator: Chad Brunswick