Date of Award

2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Pharmacology

First Advisor

Edwin (Ted) Abel

Abstract

Memory consolidation is the process through which short-term memories are stabilized for long-term retention. New gene expression is required for this process to occur successfully. Although gene expression is a necessary component for memory consolidation, the targets and regulation of this gene expression are not well understood. The advent of next-generation sequencing technologies has provided a tremendous resource to probe important questions genome-wide in ways that were previously impossible. In this dissertation, I use next-generation sequencing to investigate the transcriptional targets of learning in the hippocampus. Chapter 1 reviews the previous research on the regulation of gene expression during memory consolidation. Previous work has implicated histone acetylation as an epigenomic modification that regulates long-term memory. In Chapter 2, I use RNA-seq to investigate the gene expression changes that occur 30 minutes after contextual fear conditioning. I use recently developed analysis techniques to improve our ability to detect changes and study alternative splicing genome-wide for the first time after learning. Chapter 3 investigates whether these gene expression changes are specific to contextual fear conditioning or shared with other hippocampus-dependent learning tasks such as object-location memory. I find that the transcriptional targets are similar between training paradigms, but their temporal activation differs. In Chapter 4, we use ChIP-seq, Sono-seq and MNase-seq to determine changes in histone acetylation, chromatin accessibility and nucleosome positioning that occur in response to learning. I find only small changes in H3K9/14ac, but large changes in chromatin accessibility. This may suggest that a multitude of histone modifications act in concert to regulate chromatin accessibility during memory consolidation.

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