NR4A nuclear receptors support memory enhancement by histone deacetylase inhibitors
Joshua D. Hawk, Angie L. Bookout, Shane G. Poplawski, Morgan Bridi, Allison J. Rao, Michael E. Sulewski, Brian T. Kroener, David J. Manglesdorf, Ted Abel
Joshua D. Hawk, Angie L. Bookout, Shane G. Poplawski, Morgan Bridi, Allison J. Rao, Michael E. Sulewski, Brian T. Kroener, David J. Manglesdorf, Ted Abel
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Research Article Neuroscience

NR4A nuclear receptors support memory enhancement by histone deacetylase inhibitors

Abstract

The formation of a long-lasting memory requires a transcription-dependent consolidation period that converts a short-term memory into a long-term memory. Nuclear receptors compose a class of transcription factors that regulate diverse biological processes, and several nuclear receptors have been implicated in memory formation. Here, we examined the potential contribution of nuclear receptors to memory consolidation by measuring the expression of all 49 murine nuclear receptors after learning. We identified 13 nuclear receptors with increased expression after learning, including all 3 members of the Nr4a subfamily. These CREB-regulated Nr4a genes encode ligand-independent “orphan” nuclear receptors. We found that blocking NR4A activity in memory-supporting brain regions impaired long-term memory but did not impact short-term memory in mice. Further, expression of Nr4a genes increased following the memory-enhancing effects of histone deacetylase (HDAC) inhibitors. Blocking NR4A signaling interfered with the ability of HDAC inhibitors to enhance memory. These results demonstrate that the Nr4a gene family contributes to memory formation and is a promising target for improving cognitive function.

Authors

Joshua D. Hawk, Angie L. Bookout, Shane G. Poplawski, Morgan Bridi, Allison J. Rao, Michael E. Sulewski, Brian T. Kroener, David J. Manglesdorf, Ted Abel

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Figure 1

The formation of contextual fear memories induces expression of NR genes in the hippocampus.

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The formation of contextual fear memories induces expression of NR genes...
(A) Contextual fear conditioning produces a long-lasting memory for the training context and the association of this context with a mild foot-shock. RNA was collected from whole hippocampi at multiple time points after training to survey the impact of training on NR gene expression using a standard ΔΔCT approach. (B) High-throughput qPCR data are illustrated for the 13 NR genes with statistically significant changes in gene expression during the first 2 hours after training, the window in which the majority of changes were observed. (C) The data from this screen indicate that 13 NRs have increased expression in the hippocampus within the first 2 hours after training (red), whereas 13 NRs are not appreciably expressed in the hippocampus (black). The remaining 23 NRs (blue) show no evidence of altered hippocampal expression in the first 2 hours after training. Expression changes are illustrated within clusters defined by anatomical expression profiling (IA, IB, IC, IIA, IIB, IIC) in a diagram modified with permission from Cell; ref. 17. (D) Nr4a1 expression is potently induced in the first hour after learning (P < 0.001). (E) Nr4a2 expression increases after fear conditioning (P = 0.033). (F) Nr4a3 expression increases after fear conditioning (P = 0.004). HC, home cage. Error bars represent SEM. *P < 0.05. See also Supplemental Figure 1.