The epigenetics of stress and addiction: A role for individual differences.

摘要

Stress is a ubiquitous aspect of everyday life. As such, there exists a great deal of variability in the individual response to stress, particularly as a functional cause of depression. The aim of this dissertation is to investigate the mechanisms behind individual differences in response to stressful events in the attempt to explain differing levels of vulnerability to depression and drug addiction following exposure to stress. To accomplish this goal, we examine variations in the stress response using a rodent model of individual differences based on novelty-seeking behavior. Outbred rats can be classified as either High Responders (HR) or Low Responders (LR) depending on their locomotor activity in a novel environment. Previous studies have demonstrated that HR and LR rats differ in key components of the stress response pathway and would thus make a good model of individual differences in response to stress.;Of the many types of stressors that one might encounter in their daily activities, the most commonly experienced is social stress. We therefore utilized a rodent model of social stress termed social defeat to investigate whether exposure to social stress might induce depressive-like behaviors. We then examined histone modifications as a potential mechanism behind such behavioral alterations. Our results found that repeated social defeat induces a number of depressive-like behaviors in Sprague-Dawley rats that are correlated with short-term changes in histone acetylation in the hippocampus and the amygdala.;We then focused on individual differences in response to social defeat and in histone modifications. We found that HR rats are more susceptible to the effects of social stress, as evidenced by the expression of depressive-like behaviors following exposure to social defeat. Additionally, HR rats differ from LR rats in the levels of hippocampal histone acetylation in both basal conditions and following exposure to social defeat. We investigated potential genes that may be responsible for our observed changes in acetylation. We found basal changes in cyclic-AMP response element binding (CREB) Binding Protein (CBP) mRNA between HR and LR rats. These results indicate a role for epigenetic mechanisms as a potential mechanism for individual differences in responses to stress.;We then explored individual susceptibilities in acute versus repeated social defeat exposure. We found that while both HR and LR rats exhibit long-term memories to repeated social defeat, only HR rats display long-term memories of an acute social defeat exposure. We examined histone acetylation levels following an acute exposure to social defeat, and found changes in the timing of acetylation patterns between HR and LR rats in the hippocampus and amygdala. These findings again highlight the importance of considering individual differences in stress responses and uncover the HR/LR model as a potential model for posttraumatic stress disorder.;Finally, in a collaborative study, we investigated the role of methionine in depression and drug addiction. We found that systemic injection of methionine, a methyl donor, blocked behavioral sensitization to cocaine and resulted in decreased cocaine self-administration in male Sprague-Dawley rats. We propose several follow-up studies for investigating the role of DNA methylation further, including investigation of specific DNA methyltransferases, such as DNMT3A, and their target genes. This particular enzyme has also been implicated in the pro-depressant behaviors following exposure to social defeat, providing a common mechanism for the fields of depression and addiction.