All ETDs from UAB

Advisory Committee Chair

J David Sweatt

Advisory Committee Members

Rita Cowell

W Timothy Garvey

Joseph Messina

Trygve Tollefsbol

J David Sweatt

Document Type

Dissertation

Date of Award

2015

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

A preponderance of evidence has established that obesity contributes to memory impairments in mid-age adults. Empirical evidence has revealed that diet-induced obesity contributes to memory impairments in adult rodents. Precisely how obesity disrupts memory remains an open question. Bourgeoning data indicate that molecular epigenetic mechanisms mediate the changes in gene transcription that are necessary for hippocampus-dependent memory consolidation. Epigenetic mechanisms, such as DNA methylation, stably regulate gene expression without affecting the DNA sequence. Moreover, DNA methylation of memory-related genes with in the hippocampus is indispensible for memory formation. There is recent evidence of obesity-induced aberrantions in DNA methylation both peripherally and centrally. These obesity-associated alterations in DNA methylation have yet to be observed within the hippocampus, nor have they been linked to memory impairment. The present body of work sought out to detect, for the first time, dysregulated transcription and DNA methylation of memory related genes within the hippocampus of adult mouse model of diet-induced obesity. Here we report evidence obesity-induced impairments in hippocampus-dependent spatial memory, alterations in the expression of memory-related genes, as well as corresponding alterations in DNA methylation. Of the genes studied, special attention was paid to Sirt1. These findings suggest a novel mechanism by which Sirt1 expression within the hippocampus is reduced in obese mice. To access the sufficiency of high-fat diet-induced reductions in Sirt1 expression to impair memory, Sirt1 was deleted in the forebrain neurons of adult mice. Sirt1 inducible and conditional knockout mice (SICKO) closely recapitulated the hippocampus-dependent deficits in spatial memory exhibited by obese mice, suggesting that high-fat diet mediated reduction of hippocampal Sirt1 could potentially be the critical pathogenic insult responsible for obesity-linked memory impairment. To further test the hypothesis that obesity-linked memory impairment is at least partially mediated by reduced Sirt1 within the hippocampus, obese mice were fed a diet supplemented with the Sirt1-activating molecule resveratrol. Interestingly, resveratrol-fed obese mice exhibited increased hippocampal Sirt1 activity and preserved hippocampus-dependent memory. Thus, the findings presented in this dissertation suggest that the memory impairing effects of diet-induced obesity are potentially mediated by neuroepigenetic dysregulation of Sirt1 expression within the hippocampus.

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