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Sleep, Depression Appear to Involve Shared Gene Networks

NEW YORK (GenomeWeb) – A team led by researchers at Northwestern University and the Icahn School of Medicine at Mount Sinai reported today that it has identified a handful of gene networks contributing to sleep as well as depression in mice and humans.

The researchers began by searching for expression quantitative trait loci (eQTL) in hybrid mice with hundreds of documented sleep and affective phenotypes, using array-based SNP profiles and expression patterns across four brain regions. Together with publicly available transcriptomic data for humans with major depressive disorder (MDD), their mouse data highlighted networks of genes impacted by sleep and MDD in opposite directions.

Together, the networks encompassed nearly 500 genes in total and more than 100 genes implicated in sleep. When the team focused in on one of the gene networks — containing genes related to circadian rhythm activity and immediate early genes (IEG) influenced by neuronal activity — it found activity that hinged on a regulatory gene called Arc. The findings appeared online today in Science Advances.

"[B]y integrating our dataset with publicly available transcriptomic datasets, we showed that [acute sleep deprivation] in mice and MDD in humans affected a set of cortical networks in opposite directions and identified Arc as a potential network driver of this relationship, providing a mechanistic basis for the role of sleep/wake in MDD," the authors wrote.

Following from past studies hinting at biological ties between sleep and mood-related behaviors, the researchers set out to characterize the gene networks behind these process, starting in mice.

Using an Affymetrix mouse genotyping array, the team profiled SNP patterns in hybrid C57Bl/6J-129S1/SvImJ mice that had undergone a suite of tests and measurements to assess 283 phenotypic traits related to sleep, cognition, and/or affective behavior.

Along with information from nearly 2,500 informative mouse variants, the researchers assessed brain gene expression patterns in the frontal cortex, hypothalamus, thalamus/midbrain, and hippocampus in 121 of the mice with Affymetrix GeneChip Mouse Genome arrays. With data for 83 to 108 samples per region, they documented expression of 2,300 to more than 2,800 mouse genes, depending on the part of the brain considered.

When the team searched for ties between sleep or affective behavior traits and eQTL-influenced genes in the brain samples, it narrowed in on more than 500 genes that appeared to associate with one or more of the traits in at least one mouse brain region. More than two dozen of the eQTL genes were linked to both sleep and affective traits, including a handful of genes previously suspected of contributing to MDD in humans.

The researchers went on to analyze gene network modules in the brain regions, before folding in 13 cerebral cortex transcriptome datasets for a dozen individuals with MDD — analyses that pointed to shared networks showing distinct expression in MDD and mouse sleep deprivation.

From these and other network analyses, the authors concluded that cortical gene networks altered in both MDD and sleep deprivation "may suggest plausible mechanisms underlying the reduced sleep drive in MDD and the well-known antidepressant effects of acute [sleep deprivation]."

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