All ETDs from UAB

Advisory Committee Chair

Farah D Lubin

Advisory Committee Members

Trygve O Tollefsbol

Asim K Bej

Document Type

Thesis

Date of Award

2012

Degree Name by School

Master of Science (MS) College of Arts and Sciences

Abstract

It is hypothesized that age-related memory deficits arise in part due to altered gene transcription within the hippocampus. These aberrations in gene transcription can lead to alterations in the induction of synaptic plasticity and subsequently interrupt the process of memory formation. Histone methylation-mediated chromatin remodeling mechanisms have recently emerged as crucial regulators of gene transcription in the hippocampus during memory formation. In the present study, we examined the contributions of histone methylation to cognitive deficits and transcriptional aberrations in the hippocampus throughout aging. We found that aging is associated with reduced histone acetylation and an increase in tri-methylation of histone H3 lysine 4 (H3K4me3), a mark associated with activation of gene transcription. Reproducing these age-related changes in H3K4me3 in hippocampal area CA1 of mature adults impaired long-term memory by uncoupling H3K4me3 during memory consolidation. This molecular uncoupling of H3K4me3 was also found to contribute to aberrant expression of the memory-permissive gene bdnf within area CA1 of aged adults. Furthermore, environmental enrichment recoupled H3K4me3 at the bdnf gene promoter to restore bdnf transcription in response to learning and reversed age-associated cognitive decline to restore long-term memory. Together, these data implicate histone methylation in the formation and reversal of long-term memory deficits with aging and demonstrate histone methylation as a molecular mechanism by which environmental enrichment may serve to restore learning and memory processes in the aged brain.

Share

COinS