Nestler Group

Project Summary

Depression is a common, chronic, and debilitating syndrome, which involves dysregulation throughout the brain’s limbic circuitry. Our laboratory has focused on stable changes in gene expression within this circuitry that control life-long vulnerability to different forms of stress and the induction of depression-related behavioral abnormalities in mouse models. We concentrate on transcriptional pathways, deduced from large RNA-sequencing datasets of RNAs that show altered expression in several limbic brain regions of mice as a consequence of stress exposures across the life cycle. Parallel work examines transcriptional mechanisms in homologous regions in the brains of depressed humans examined postmortem. A major interest in the animal and human studies are sex differences in stress responses, given the >2-fold greater prevalence of depression in females.

Current studies are exploring the detailed mechanisms by which specific transcriptional abnormalities identified in mouse models and human depression contribute to a depression-like state. We are particularly interested in how stress causes life-long changes in gene expression and hypothesize that such changes are mediated via so-called “chromatin scars.” We are approaching this question by studying a range of chromatin mechanisms genome-wide, including post-translational modifications of histones, DNA methylation, nucleosome positioning, and the 3-dimensional structure of chromatin. These studies are identifying the most prominent molecular abnormalities induced in limbic brain regions by chronic stress and depression. We are also studying how such molecular derangements alter the functioning of individual cell types within these brain regions and their larger circuits, thus linking transcriptional and chromatin regulation to neural and behavioral plasticity associated with depression. Another major interest is understanding mechanisms of natural resilience, that is, the transcriptional and chromatin mechanisms that make certain individuals more resistant to the deleterious effects of chronic stress.

This work establishes transcriptional and chromatin regulation as important mechanisms underlying the ways in which a history of stress causes lasting changes in targeted limbic brain regions which result in depression-related behavioral abnormalities in vulnerable individuals. The long-term goal is to use these insights to develop improved diagnostic tests and treatments for depression and related syndromes.