Hawk, Joshua Davis

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2011 - 20122
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  • Publication
    Investigation of the Role of Histone Acetylation in Hippocampus-Dependent Memory Formation
    (2011-05-16) Hawk, Joshua Davis
    New experiences are encoded in a fragile short-term form of memory, but with time these memories can be converted into a stable long-term form of memory through a process known as memory consolidation. Whereas post-translational modification of existing proteins may be sufficient for short-term memory, creation of a long-term memory requires de novo gene expression after learning. The ability to express genes is regulated by association of DNA with histone proteins into a chromatin complex. Chapter 1 reviews the transcriptional mechanisms involved in the memory formation, including the contribution of chromatin modification by acetylation of histone proteins. Mutating the histone acetyltransferase CREB-binding protein (CBP) impairs long-term memory formation, and pharmacologically blocking histone deacetylases (HDAC) enhances long-term memory formation. Memory enhancement by HDAC inhibitors requires the interaction between the transcription factor CREB and CBP, suggesting that these two processes converge at functionally relevant target genes. As reviewed in Chapter 2, the Nr4a family of CREB target genes are potentially involved in memory formation, and the expression of Nr4a genes is enhanced when memory is improved by HDAC inhibitor treatment. In Chapter 3, I combined genetic and pharmacological approaches to discover that impeding NR4A signaling impairs memory formation and blocks the ability of HDAC inhibitors to enhance memory. These studies were performed with the now well-established approach of using broad-spectrum HDAC inhibitors to enhance memory in the aversive contextual fear-conditioning task. In Chapter 4, I found that long-term memory for another hippocampus-dependent task, object location memory, is enhanced by the class I-selective HDAC inhibitor MS-275. This study provides a new behavioral paradigm for studying the mechanisms by which HDAC inhibitors enhances memory, refines the relevant list of HDACs targeted for memory enhancement, and demonstrates the utility of MS-275 as a pharmacological tool in this field. In Chapter 5, I examined the genetic targets of CBP that require the interaction domain between CREB and CBP using mice with a triple point mutation that blocks this interaction (CBPkix/kix). Using an unbiased microarray strategy, I found that several learning-induced genes have impaired expression in CBPkix/kix mice, including a member of the Nr4a gene family.
  • 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 J
    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.