1. ¹Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA
2. ²Stanford Human Genome Center and the Department of Genetics, Stanford University, Stanford, CA, USA
3. ³Molecular and Behavioral Neuroscience Institute and the Department of Psychiatry, University of Michigan, MI, USA
4. ⁴Department of Psychiatry and Human Behavior, University of California, Irvine, CA, USA
5. ⁵Center for Neuroscience, University of California, Davis, CA, USA

Correspondence: Dr DM Lyons, Psychiatry Neuroscience, Stanford University, 1201 Welch Rd, MSLS P104—Mail Code 5485, Stanford, CA 94305-5485, USA. E-mail: dmlyons@stanford.edu

⁶These authors contributed equally to this work.

⁷Current address: Korea Basic Science Institute, Chuncheon, South Korea.

Received 22 August 2006; Revised 9 August 2007; Accepted 10 August 2007; Published online 25 September 2007.

Abstract

Stressful experiences that consistently increase cortisol levels appear to alter the expression of hundreds of genes in prefrontal limbic brain regions. Here, we investigate this hypothesis in monkeys exposed to intermittent social stress-induced episodes of hypercortisolism or a no-stress control condition. Prefrontal profiles of gene expression compiled from Affymetrix microarray data for monkeys randomized to the no-stress condition were consistent with microarray results published for healthy humans. In monkeys exposed to intermittent social stress, more genes than expected by chance appeared to be differentially expressed in ventromedial prefrontal cortex compared to monkeys not exposed to adult social stress. Most of these stress responsive candidate genes were modestly downregulated, including ubiquitin conjugation enzymes and ligases involved in synaptic plasticity, cell cycle progression and nuclear receptor signaling. Social stress did not affect gene expression beyond that expected by chance in dorsolateral prefrontal cortex or prefrontal white matter. Thirty four of 48 comparisons chosen for verification by quantitative real-time polymerase chain reaction (qPCR) were consistent with the microarray-predicted result. Furthermore, qPCR and microarray data were highly correlated. These results provide new insights on the regulation of gene expression in a prefrontal corticolimbic region involved in the pathophysiology of stress and major depression. Comparisons between these data from monkeys and those for ventromedial prefrontal cortex in humans with a history of major depression may help to distinguish the molecular signature of stress from other confounding factors in human postmortem brain research.