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The Dissociable Involvement of Epigenetic Mechanisms in Hippocampus- and Perirhinal Cortex-mediated Object Memory in Male Rats

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Title: The Dissociable Involvement of Epigenetic Mechanisms in Hippocampus- and Perirhinal Cortex-mediated Object Memory in Male Rats
Author: Mitchnick, Krista
Department: Department of Psychology
Program: Psychology
Advisor: Winters, BoyerWinters, Boyer
Abstract: This thesis investigated the involvement of several epigenetic proteins in hippocampus (HPC)- and perirhinal cortex (PRh)-mediated object recognition. Previous literature has demonstrated the requirement for both DNA methylation and histone acetylation, two prominent epigenetic mechanisms, in HPC-dependent memory, including object recognition, but at the outset of these experiments no one had studied these mechanisms within the PRh, another structure necessary for object recognition. Specifically, we determined the involvement of the DNA methyltransferases DNMT1, DNMT3a, and DNMT3b, which are required for DNA methylation; the GADD45 isoforms GADD45a, GADD45b, and GADD45g, which are involved in DNA demethylation; and three prominent histone acetyltransferases, CBP, p300, and PCAF, which are involved in histone acetylation, in both the HPC and PRh for object-in-place (OiP) memory. The use of the OiP task enabled us to compare the involvement of these mechanisms within these two regions, as successful performance in this paradigm requires the HPC and PRh for processing of object location and object identity, respectively. The role of these factors in short-term (20min) and long-term (24h) OiP memory was assessed using intra-HPC and PRh administration of various compounds that selectively inhibit or activate these proteins. Furthermore, quantitative polymerase chain reaction (qPCR) was used to measure mRNA expression of these factors. Similarly, chromatin immunoprecipitation and methylated DNA immunoprecipitation, followed by qPCR, were used to measure protein and 5mC occupancy, respectively, on specific genomic loci. Our results demonstrate that epigenetic mechanisms are necessary for PRh-mediated memory, but additionally illustrate differential involvement of these epigenetic factors in the HPC and PRh for successful OiP memory. Notably, we determined that DNMT1 and GADD45a, neither of which have been implicated in mnemonic processes, are both necessary in PRh, but not the HPC, for long-term OiP memory. Moreover, our results suggest that GADD45a modulates DNMT1-mediated methylation on two intergenic loci, following learning. Additionally, we have shown that PCAF functionally interacts with ERalpha to support short-term memory in the HPC, but not PRh. These regional dissociations are likely due to the differences in information processing, highlighting the importance of comparing the involvement of epigenetic mechanisms between mnemonic structures.
Date: 2018-05-28

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