Journal
JOURNAL OF NEUROSCIENCE
Volume 39, Issue 25, Pages 4999-5009Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2799-18.2019
Keywords
aging; epigenetics; HDAC3; memory; Nr4a1; Nr4a2
Categories
Funding
- National Institutes of Health [MH101491, AG051807, AG050787]
- National Institute on Aging [F32 AG052303, K99 AG056596]
- Intramural Research Program of the National Institute on Aging
- NATIONAL INSTITUTE ON AGING [ZIAAG000350] Funding Source: NIH RePORTER
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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 the Nr4a family 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 of Nr4a1 and Nr4a2 in age-related memory impairments. Using a rat model designed to identify individual differences in age-related memory impairments, we first identified Nr4a2 as 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 regulates Nr4a2 in the aged male and female hippocampus. Finally, we show that overexpression of Nr4a1, Nr4a2, or both transcripts in the male mouse dorsal hippocampus can ameliorate age-related impairments in object location memory. Together, our results suggest that Nr4a2 may be a key mechanism that promotes preserved cognitive function in old age, with HDAC3-mediated repression of Nr4a2 contributing to age-related cognitive decline. More broadly, these results indicate that therapeutic strategies to promote Nr4a gene expression or function may be an effective strategy to improve cognitive function in old age.
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