Bridi, Morgan
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Publication NR4A Nuclear Receptors Support Memory Enhancement by Histone Deacetylase Inhibitors(2012-10-01) Hawk, Joshua Davis; Poplawski, Shane Gary; Bridi, Morgan; Sulewski, Michael E; Bookout, Angie L; Abel, Ted; Rao, Allison J; Kroener, Brian T; Manglesdorf, David JThe 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.Publication The Regulation of Hippocampal Synaptic Plasticity by Upstream and Downstream Effectors of Histone Acetylation(2015-01-01) Bridi, MorganLong-lasting forms of hippocampal plasticity and hippocampus-dependent memory share a requirement for gene expression. Activity-induced neuronal gene expression is regulated by epigenetic mechanisms such as the post-translational modification of histone proteins. Histone acetylation plays a major role in neuronal function, but our understanding of the upstream mechanisms that regulate recruitment of the HDAC enzymes, and of the genes and proteins downstream of histone acetylation that support plasticity, are poorly understood. In my thesis research I investigated the role of the SIN3A/HDAC complex, a repressive histone-modifying complex, and of the Nr4a nuclear receptors, which are acetylation-regulated and memory-related transcription factors, in hippocampal synaptic plasticity. In Chapter 1, I discussed the mechanisms that support memory formation and the stabilization of synaptic potentiation, described the mechanisms of post-translational histone modification, and reviewed the role of epigenetic histone modification in memory and plasticity as well as in neuronal dysfunction. In Chapter 2, we demonstrated that reducing levels of the co-repressor SIN3A enhanced long-term potentiation and long-term memory, increased expression of Cdk5 and Homer1, and altered signaling through the Group I metabotropic glutamate receptors. In the Appendix, I show additional data that demonstrates increased mGluR5-mediated signaling in hippocampal neurons with loss of SIN3A. In Chapter 3, I found that disrupting the function of the Nr4a family of nuclear receptor transcription factors impaired long-lasting forms of synaptic potentiation and blocked the enhancement of plasticity by pharmacological HDAC inhibition. In Chapter 4 I found that C-DIM compounds, activators of NR4A, enhanced hippocampal potentiation in a manner sensitive to Nr4a disruption; we also found that CREB/CBP interaction regulates activity-induced Nr4a2 promoter acetylation and gene expression. These findings improve our understanding of the role of epigenetic histone modification in synaptic plasticity and memory, and indicate that the NR4A nuclear receptors are exceptional downstream targets for the enhancement of cognitive function and the amelioration of neuronal dysfunction.