Aging is accompanied by cognitive deficits, including impairments in long-term memory formation. Understanding the molecular mechanisms that support preserved cognitive function in aged animals is a critical step toward identifying novel therapeutic targets that could improve memory in aging individuals. One potential mechanism is thefamily of genes, a group of CREB-dependent nuclear orphan receptors that have previously been shown to be important for hippocampal memory formation. Here, using a cross-species approach, we tested the role ofandin age-related memory impairments. Using a rat model designed to identify individual differences in age-related memory impairments, we first identifiedas a key gene that fails to be induced by learning in cognitively impaired male aged rats. Next, using a mouse model that allows for genetic manipulations, we determined that histone deacetylase 3 (HDAC3) negatively regulatesin the aged male and female hippocampus. Finally, we show that overexpression of,, or both transcripts in the male mouse dorsal hippocampus can ameliorate age-related impairments in object location memory. Together, our results suggest thatmay be a key mechanism that promotes preserved cognitive function in old age, with HDAC3-mediated repression ofcontributing to age-related cognitive decline. More broadly, these results indicate that therapeutic strategies to promotegene expression or function may be an effective strategy to improve cognitive function in old age.Aging is accompanied by memory impairments, although there is a great deal of variability in the severity of these impairments. Identifying molecular mechanisms that promote preserved memory or participate in cognitive reserve in old age is important to develop strategies that promote healthy cognitive aging. Here, we show that learning-induced expression of the CREB-regulated nuclear receptor geneis selectively impaired in aged rats with memory impairments. Further, we show thatis regulated by histone deacetylase HDAC3 in the aged mouse hippocampus. Finally, we demonstrate that hippocampal overexpression of eitheror its family member,, can ameliorate age-related memory impairments. This suggests that promotingexpression may be a novel strategy to improve memory in aging individuals. Nr4a Nr4a1Nr4a2Nr4a2Nr4a2Nr4a1Nr4a2Nr4a2Nr4a2Nr4a Nr4a2Nr4a2Nr4a2Nr4a1Nr4a SIGNIFICANCE STATEMENT
