Feature Finding Title
Featured Finding Figure

Major depressive disorder (MDD) is a heterogeneous illness with a mostly uncharacterized pathology. Recent gene array attempts to identify the molecular underpinnings of the illness in human postmortem subjects have not yielded a consensus. Thus, we hypothesized that controlling several sources of clinical and technical variability, and supporting our analysis with array results from a parallel study in the unpredictable chronic mild stress (UCMS) rodent model of depression would facilitate identification of the molecular pathology of MDD. Large-scale gene expression was monitored in anterior cingulate cortex (ACC) and amygdala (AMY) in matched pairs of male familial MDD and control subjects. Area dissections and analytical approaches were optimized. MDD results were compared to UCMS results, and confirmed by quantitative PCR and Western blot. Gene coexpression network analysis was performed on transcripts with conserved MDD-UCMS effects. Significant and bi-directional predictions of altered gene expression were identified in AMY between MDD and the UCMS model of depression (Panel A). These effects were detected at the group level, and also identified a subgroup of depressed subjects with a more homogeneous molecular pathology (Panel B). This phylogenetically-conserved “molecular signature” of MDD was reversed by antidepressants in mice, identified two distinct oligodendrocyte and neuronal phenotypes, and participated in highly cohesive and interactive gene coexpression networks. These studies demonstrate that the biological liability to MDD is reflected in a persistent molecular pathology that affects the AMY, and supports the hypothesis of maladaptive changes in this brain region as a putative primary pathology in MDD.

Sibille E, Wang Y, Joeyen-Waldorf J, Gaiteri C, Surget A, Oh S, Belzung C, Tseng G, Lewis DA: A molecular signature of depression in the amygdala. Am J Psychiatry 166: 1011-1024, 2009.

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David A. Lewis, M.D. | Department of Psychiatry | University of Pittsburgh
3811 O'Hara Street, Biomedical Science Tower W1654
Pittsburgh, Pennsylvania 15213-2593
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