㪘㩷㪤㫆㫃㪼㪺㫌㫃㪸㫉㩷㪪㫀㪾㫅㪸㫋㫌㫉㪼㩷㫆㪽㩷㪛㪼㫇㫉㪼㫊㫊㫀㫆㫅㩷㫀㫅㩷㫋㪿㪼㩷㪘㫄㫐㪾㪻㪸㫃㪸㩷㪄㪄㩷㪪㫀㪹㫀㫃㫃㪼㩷㪼㫋㩷㪸㫃㪅㩷㪈㪍㪍㩷㩿㪐㪀㪑㩷㪈㪇㪈㪈㩷㪄㪄㩷㪘㫄㩷㪡㩷㪧㫊㫐㪺㪿㫀㪸㫋㪅㪅㪅 㪈㪆㪊㩷䊕䊷䉳Am J Psychiatry 2009; 166:1011-1024(published online July 15, 2009; doi: 10.1176/appi.ajp.2009.08121760)© 2009 American Psychiatric Association

A Molecular Signature of Depression
in the Amygdala
Etienne Sibille, Ph.D., Yingjie Wang, M.S., Jennifer
Joeyen-Waldorf, B.S., Chris Gaiteri, B.S., Alexandre
Surget, Ph.D., Sunghee Oh, B.S., Catherine Belzung,Ph.D., George C. Tseng, Ph.D., and David A. Lewis,
M.D.
OBJECTIVE: Major depressive disorder is aheterogeneous illness with a mostly uncharacterized
pathology. Recent gene array attempts to identify themolecular underpinnings of the illness in humanpostmortem subjects have not yielded a consensus. Theauthors hypothesized that controlling several sources ofclinical and technical variability and supporting theiranalysis with array results from a parallel study in theunpredictable chronic mild stress (UCMS) rodent modelof depression would facilitate identification of themolecular pathology of major depression. METHOD:
Large-scale gene expression was monitored in
postmortem tissue from the anterior cingulate cortex andamygdala in paired male subjects with familial major
depression and matched control subjects without major
depression (N=14–16 pairs). Area dissections andanalytical approaches were optimized. Results from themajor depression group were compared with those fromthe UCMS study and confirmed by quantitative㪿㫋㫋㫇㪑㪆㪆㪸㫁㫇㪅㫇㫊㫐㪺㪿㫀㪸㫋㫉㫐㫆㫅㫃㫀㫅㪼㪅㫆㫉㪾㪆㪺㪾㫀㪆㪺㫆㫅㫋㪼㫅㫋㪆㪸㪹㫊㫋㫉㪸㪺㫋㪆㪈㪍㪍㪆㪐㪆㪈㪇㪈㪈

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Neurophysiology
Depression
Genetics
Related Article㪉㪇㪈㪇㪆㪇㪌㪆㪇㪏㪘㩷㪤㫆㫃㪼㪺㫌㫃㪸㫉㩷㪪㫀㪾㫅㪸㫋㫌㫉㪼㩷㫆㪽㩷㪛㪼㫇㫉㪼㫊㫊㫀㫆㫅㩷㫀㫅㩷㫋㪿㪼㩷㪘㫄㫐㪾㪻㪸㫃㪸㩷㪄㪄㩷㪪㫀㪹㫀㫃㫃㪼㩷㪼㫋㩷㪸㫃㪅㩷㪈㪍㪍㩷㩿㪐㪀㪑㩷㪈㪇㪈㪈㩷㪄㪄㩷㪘㫄㩷㪡㩷㪧㫊㫐㪺㪿㫀㪸㫋㪅㪅㪅 㪉㪆㪊㩷䊕䊷䉳polymerase chain reaction and Western blot. Gene coexpression network analysis wasperformed on transcripts with conserved major depression-UCMS effects. RESULTS:
Significant and bidirectional predictions of altered gene expression were identified in amygdala
between major depression and the UCMS model of depression. These effects were detected at
the group level and also identified a subgroup of depressed subjects with a more homogeneous
molecular pathology. This phylogenetically conserved "molecular signature" of major
depression was reversed by antidepressants in mice, identified two distinct oligodendrocyte andneuronal phenotypes, and participated in highly cohesive and interactive gene coexpression
networks. CONCLUSIONS: These studies demonstrate that the biological liability to major
depression is reflected in a persistent molecular pathology that affects the amygdala, andsupport the hypothesis of maladaptive changes in this brain region as a putative primarypathology in major depression.

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