Date of Award

Spring 2011

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Neuroscience

First Advisor

Ted Abel

Abstract

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.

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