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Gene expression patterns in the hippocampus and amygdala of endogenous depression and chronic stress models.

Andrus BM, Blizinsky K, Vedell PT, Dennis K, Shukla PK, Schaffer DJ, Radulovic J, Churchill GA, Redei EE - Mol. Psychiatry (2010)

Bottom Line: No significant difference was observed in the expression of monoaminergic transmission-related genes in either model.Taken together, these results posit that although chronic stress may induce depressive behavior, its molecular underpinnings differ from those of endogenous depression in animals and possibly in humans, suggesting the need for different treatments.The identification of novel endogenous depression-related and chronic stress response genes suggests that unexplored molecular mechanisms could be targeted for the development of novel therapeutic agents.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.

ABSTRACT
The etiology of depression is still poorly understood, but two major causative hypotheses have been put forth: the monoamine deficiency and the stress hypotheses of depression. We evaluate these hypotheses using animal models of endogenous depression and chronic stress. The endogenously depressed rat and its control strain were developed by bidirectional selective breeding from the Wistar-Kyoto (WKY) rat, an accepted model of major depressive disorder (MDD). The WKY More Immobile (WMI) substrain shows high immobility/despair-like behavior in the forced swim test (FST), while the control substrain, WKY Less Immobile (WLI), shows no depressive behavior in the FST. Chronic stress responses were investigated by using Brown Norway, Fischer 344, Lewis and WKY, genetically and behaviorally distinct strains of rats. Animals were either not stressed (NS) or exposed to chronic restraint stress (CRS). Genome-wide microarray analyses identified differentially expressed genes in hippocampi and amygdalae of the endogenous depression and the chronic stress models. No significant difference was observed in the expression of monoaminergic transmission-related genes in either model. Furthermore, very few genes showed overlapping changes in the WMI vs WLI and CRS vs NS comparisons, strongly suggesting divergence between endogenous depressive behavior- and chronic stress-related molecular mechanisms. Taken together, these results posit that although chronic stress may induce depressive behavior, its molecular underpinnings differ from those of endogenous depression in animals and possibly in humans, suggesting the need for different treatments. The identification of novel endogenous depression-related and chronic stress response genes suggests that unexplored molecular mechanisms could be targeted for the development of novel therapeutic agents.

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Related in: MedlinePlus

An across-experiment, gene-to-gene mapping was created for 10 112 gene symbols. Scatter plots are shown for observed effects obtained from the chronic restraint stress-no stress (CRS-NS) microarray experiment (vertical axis) and the Wistar–Kyoto More Immobile-WKY Less Immobile (WMI-WLI) microarray experiment (horizontal axis) by applying the linear models of Equation (1) and (2). The statistics are differences in condition effects, α2g−α1g, for the amygdala (a) and hippocampus (b), and differences in brain region-related effects, γ2g−γ1g (c).
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fig2: An across-experiment, gene-to-gene mapping was created for 10 112 gene symbols. Scatter plots are shown for observed effects obtained from the chronic restraint stress-no stress (CRS-NS) microarray experiment (vertical axis) and the Wistar–Kyoto More Immobile-WKY Less Immobile (WMI-WLI) microarray experiment (horizontal axis) by applying the linear models of Equation (1) and (2). The statistics are differences in condition effects, α2g−α1g, for the amygdala (a) and hippocampus (b), and differences in brain region-related effects, γ2g−γ1g (c).

Mentions: Expression differences in both models were relatively small (Figures 2a and b). If there is an underlying relationship between expression differences in response to CRS and endogenous depressive behavior for many genes, we should see significant positive correlation between the differences in gene expression across the two experiments. In particular, the differences between WMI and WLI model effects and differences between CRS and NS model effects ((α2g−α1g) in equation (1)) should show positive correlation. The Spearman's correlation (ρ) for these comparisons of differences were not significantly different than zero in either tissue (ρ=−0.12, amygdala; ρ=−0.02, hippocampus; Figures 2a and b). This lack of observed correlation could be explained by the different platforms or by the chronologies of the experiments. To address this concern, equation (2), which combined data of both brain regions and estimates the tissue effects, was employed. The tissue (interbrain region) effects showed significant positive correlation between experiments (ρ=0.48, P<0.001; Figure 2c). We also measured correlation for the subset of genes for which the magnitude of tissue effects were comparable to the CRS-NS and WMI-WLI effects, specifically those having a magnitude below 0.4 on both platforms. Within this subset, we still found significant positive correlation (ρ=0.31, P<0.001). We conclude that we should have observed correlation between the CRS-NS and WMI-WLI effects if it were present despite the platform differences. This suggests that, on a global scale, the effects of chronic stress and endogenous depression on the amygdalar and hippocampal transcriptome are dissimilar.


Gene expression patterns in the hippocampus and amygdala of endogenous depression and chronic stress models.

Andrus BM, Blizinsky K, Vedell PT, Dennis K, Shukla PK, Schaffer DJ, Radulovic J, Churchill GA, Redei EE - Mol. Psychiatry (2010)

An across-experiment, gene-to-gene mapping was created for 10 112 gene symbols. Scatter plots are shown for observed effects obtained from the chronic restraint stress-no stress (CRS-NS) microarray experiment (vertical axis) and the Wistar–Kyoto More Immobile-WKY Less Immobile (WMI-WLI) microarray experiment (horizontal axis) by applying the linear models of Equation (1) and (2). The statistics are differences in condition effects, α2g−α1g, for the amygdala (a) and hippocampus (b), and differences in brain region-related effects, γ2g−γ1g (c).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3117129&req=5

fig2: An across-experiment, gene-to-gene mapping was created for 10 112 gene symbols. Scatter plots are shown for observed effects obtained from the chronic restraint stress-no stress (CRS-NS) microarray experiment (vertical axis) and the Wistar–Kyoto More Immobile-WKY Less Immobile (WMI-WLI) microarray experiment (horizontal axis) by applying the linear models of Equation (1) and (2). The statistics are differences in condition effects, α2g−α1g, for the amygdala (a) and hippocampus (b), and differences in brain region-related effects, γ2g−γ1g (c).
Mentions: Expression differences in both models were relatively small (Figures 2a and b). If there is an underlying relationship between expression differences in response to CRS and endogenous depressive behavior for many genes, we should see significant positive correlation between the differences in gene expression across the two experiments. In particular, the differences between WMI and WLI model effects and differences between CRS and NS model effects ((α2g−α1g) in equation (1)) should show positive correlation. The Spearman's correlation (ρ) for these comparisons of differences were not significantly different than zero in either tissue (ρ=−0.12, amygdala; ρ=−0.02, hippocampus; Figures 2a and b). This lack of observed correlation could be explained by the different platforms or by the chronologies of the experiments. To address this concern, equation (2), which combined data of both brain regions and estimates the tissue effects, was employed. The tissue (interbrain region) effects showed significant positive correlation between experiments (ρ=0.48, P<0.001; Figure 2c). We also measured correlation for the subset of genes for which the magnitude of tissue effects were comparable to the CRS-NS and WMI-WLI effects, specifically those having a magnitude below 0.4 on both platforms. Within this subset, we still found significant positive correlation (ρ=0.31, P<0.001). We conclude that we should have observed correlation between the CRS-NS and WMI-WLI effects if it were present despite the platform differences. This suggests that, on a global scale, the effects of chronic stress and endogenous depression on the amygdalar and hippocampal transcriptome are dissimilar.

Bottom Line: No significant difference was observed in the expression of monoaminergic transmission-related genes in either model.Taken together, these results posit that although chronic stress may induce depressive behavior, its molecular underpinnings differ from those of endogenous depression in animals and possibly in humans, suggesting the need for different treatments.The identification of novel endogenous depression-related and chronic stress response genes suggests that unexplored molecular mechanisms could be targeted for the development of novel therapeutic agents.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.

ABSTRACT
The etiology of depression is still poorly understood, but two major causative hypotheses have been put forth: the monoamine deficiency and the stress hypotheses of depression. We evaluate these hypotheses using animal models of endogenous depression and chronic stress. The endogenously depressed rat and its control strain were developed by bidirectional selective breeding from the Wistar-Kyoto (WKY) rat, an accepted model of major depressive disorder (MDD). The WKY More Immobile (WMI) substrain shows high immobility/despair-like behavior in the forced swim test (FST), while the control substrain, WKY Less Immobile (WLI), shows no depressive behavior in the FST. Chronic stress responses were investigated by using Brown Norway, Fischer 344, Lewis and WKY, genetically and behaviorally distinct strains of rats. Animals were either not stressed (NS) or exposed to chronic restraint stress (CRS). Genome-wide microarray analyses identified differentially expressed genes in hippocampi and amygdalae of the endogenous depression and the chronic stress models. No significant difference was observed in the expression of monoaminergic transmission-related genes in either model. Furthermore, very few genes showed overlapping changes in the WMI vs WLI and CRS vs NS comparisons, strongly suggesting divergence between endogenous depressive behavior- and chronic stress-related molecular mechanisms. Taken together, these results posit that although chronic stress may induce depressive behavior, its molecular underpinnings differ from those of endogenous depression in animals and possibly in humans, suggesting the need for different treatments. The identification of novel endogenous depression-related and chronic stress response genes suggests that unexplored molecular mechanisms could be targeted for the development of novel therapeutic agents.

Show MeSH
Related in: MedlinePlus