Epigenetic Mechanisms of Depression
For the general public
The Center's organizing hypothesis is: HA host of chromatin regulatory mechanisms work in concert to mediate the lasting effects of chronic stress and antidepressant treatments on the brain and to control an individual's life-time vulnerability to stress, with some shared but many distinct mechanisms operating in males vs. females.
Increasing evidence, much of it from Center investigators, has demonstrated the significance of modifications of histones, DNA, and numerous classes of chromatin regulatory proteins in depression models, although we are still at relatively early stages of examining all of the many chromatin changes potentially involved. A key question in the field is to know which of hundreds or thousands of chromatin mechanisms should be characterized for their role in depression-related phenomena. Our Center has taken an unbiased approach by generating very large and diverse datasets encompassing several mouse depression models in males and females, antidepressant responsiveness vs. non-responsiveness (to both standard and experimental drugs), multiple limbic brain regions, multiple time points, as well as homologous brain regions of depressed humans—again male and female. By overlaying these datasets, we have identified—as a consolidated Center—those genes (and the brain regions where they act) that exert particularly strong influence over stress susceptibility and depression as well as the opposite—stress resilience. Each Project of the Center focuses on a subset of these genes for further exploration. This underscores the fact that, while each Project is described as an independent undertaking, in reality each is highly integrated, and involves all four Projects.
Such long-lived epigenetic changes are ideal candidates to mediate the ability of an individual's lifetime experiences to determine his or her vulnerability for a stress-related disorder at some discrete point in time. The goal of this Center is to decipher such mechanisms and mine them for translational applications, including both improved treatments and diagnostic tests (so-called biomarkers). More controversial, and still unproven, is whether stress might induce epigenetic modifications in germ cells (sperm or eggs), which then lead to changes in stress vulnerability in offspring, perhaps for multiple generations. Our Center, while not directly studying this question, works collaboratively with other groups to explore the possibilities for trans-generational transmission of stress by epigenetic mechanisms.