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Molecular Mechanisms of Depression and Aging

Major Depression results from a complex polygenic mechanism with contributing environmental factors, but no gene mutations or specific molecular disruptions have been identified as causative factors. To initiate a molecular characterization of depression, we are applying genome-wide investigational strategies to test the hypothesis that the biological liability of the disease is reflected in a persistent molecular pathology in a corticolimbic network of mood regulation. In particular, dysfunctions in the amygdala/cingulate corticolimbic network might specifically cause, or at least correlate with the affective component of depression. Accordingly, we have now identified significant and bi-directional predictions of altered gene expression in the amygdala between human subjects affected with major depression and mice subjected to the unpredictable chronic mild stress model of depression. This phylogenetically-conserved “molecular signature” identifies distinct oligodendrocyte and neuronal phenotypes, and recruits existing cellular pathways, as demonstrated by its inclusion in highly cohesive gene coexpression networks. Based on these (and other) findings, hypotheses for disease mechanisms are being further investigated in the human postmortem brain and tested for causal relationships in genetic mouse models.

Aging leads to a variety of morphological and functional changes in the brain, and is associated with increased risk for specific psychiatric and neurological disorders. However, the mechanisms underlying normal aging likely differ from those associated with pathological conditions and are still poorly understood. We have previously identified robust and life-long progressive changes in expression levels of several hundred genes in the human brain.  Based on the predictive aspect of this “molecular signature” of aging, we are now investigating the contribution of genetic variability to molecular aging in the human brain and its interactions with neurological disease pathways  Finally, to identify genes and pathways that correspond to particular behavioral, cognitive or physiological characteristics of aging, we are investigating behavioral and genomic correlates of aging in the context of targeted genetic manipulations in the mouse.

Trainees in the laboratory have the opportunity to participate in a number of collaborative research projects investigating relationships between genes and behavior, in the context of depression and aging. To achieve these goals, we combine genetic, genomic, molecular biology, behavioral and bioinformatic approaches.

Specific Projects may include: identification of cellular and molecular disturbances in human depression and in parallel animal models of the illness, identification of mechanisms of aging in the central nervous system that are common between mice and humans, characterization of the role of serotonin receptors in aging and mood disorders, genetic and pharmacological modeling in the mouse of aspects of human mood disorders, bioinformatic analysis of gene co-expression and transcription factor networks, regional and cellular characterization of altered gene and protein expression in the mammalian brain (human and mouse).