Stressed Out of Their Minds: The Effects of Chronic Stress on the Hippocampal DNA Methylome in Mice

Abstract

Chronic stress is a well-established risk factor for the development of neurodegenerative diseases. The hippocampus is uniquely susceptible, as evidenced by impaired adult neurogenesis in the dentate gyrus in individuals with high exposure to stress. While accumulating research suggests that repeated stress alters gene expression profiles in pathways for neural proliferation, the underlying mechanisms which drive these changes remain to be elucidated. As an environmentally-sensitive epigenetic modification that regulates gene expression without altering the genetic code, DNA methylation offers a logical lens to investigate the interplay between chronic stress and its biological manifestations on the hippocampus.

I analyzed changes to the hippocampal methylome, relative to controls, of tissue derived from mice subjected to two models of stress: subcutaneous injection of the glucocorticoid stress hormone corticosterone (CORT) and forced chronic restraint stress (CRS). I found that CORT treatment is not associated with differential methylation and thus exogenous administration of stress hormone alone may not sufficiently mimic the chronic stress response in the hippocampus. Conversely, the hippocampus of animals under CRS displayed a significant decrease in methylation. This hypomethylation was observed both globally and in regulatory regions of genes implicated in multiple levels of gene regulation, pathways of neural proliferation, and Alzheimer’s disease. I additionally identified hypomethylation in a constellation of genes which contribute to autophagic cell death of neural progenitor cells. Together, my results present initial evidence that stress-associated changes to DNA methylation may fill the explanatory gap between chronic stress, reduced adult neurogenesis, and neurodegenerative disease.