Effects of Chronic Stress on Prefrontal Cortex Transcriptome in Mice Displaying Different Genetic Backgrounds

There is increasing evidence that depression derives from the impact of environmental pressure on genetically susceptible individuals. We analyzed the effects of chronic mild stress (CMS) on prefrontal cortex transcriptome of two strains of mice bred for high (HA)and low (LA) swim stress-induced analgesia that differ in basal transcriptomic profiles and depression-like behaviors. We found that CMS affected 96 and 92 genes in HA and LA mice, respectively. Among genes with the same expression pattern in both strains after CMS, we observed robust upregulation of Ttr gene coding transthyretin involved in amyloidosis, seizures, stroke-like episodes, or dementia. Strain-specific HA transcriptome affected by CMS was associated with deregulation of genes involved in insulin secretion (Acvr1c, Nnat, and Pfkm), neuropeptide hormone activity (Nts and Trh), and dopamine receptor mediated signaling pathway (Clic6, Drd1a, and Ppp1r1b). LA transcriptome affected by CMS was associated with genes involved in behavioral response to stimulus (Fcer1g, Rasd2, S100a8, S100a9, Crhr1, Grm5, and Prkcc), immune effector processes (Fcer1g, Mpo, and Igh-VJ558), diacylglycerol binding (Rasgrp1, Dgke, Dgkg, and Prkcc), and long-term depression (Crhr1, Grm5, and Prkcc) and/or coding elements of dendrites (Crmp1, Cntnap4, and Prkcc) and myelin proteins (Gpm6a, Mal, and Mog). The results indicate significant contribution of genetic background to differences in stress response gene expression in the mouse prefrontal cortex. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12031-012-9850-1) contains supplementary material, which is available to authorized users

Stress susceptibility-specific phenotype associated with different hippocampal transcriptomic responses to chronic tricyclic antidepressant treatment in mice

BACKGROUND: The effects of chronic treatment with tricyclic antidepressant (desipramine, DMI) on the hippocampal transcriptome in mice displaying high and low swim stress-induced analgesia (HA and LA lines) were studied. These mice displayed different depression-like behavioral responses to DMI: stress-sensitive HA animals responded to DMI, while LA animals did not. RESULTS: To investigate the effects of DMI treatment on gene expression profiling, whole-genome Illumina Expression BeadChip arrays and qPCR were used. Total RNA isolated from hippocampi was used. Expression profiling was then performed and data were analyzed bioinformatically to assess the influence of stress susceptibility-specific phenotypes on hippocampal transcriptomic responses to chronic DMI. DMI treatment affected the expression of 71 genes in HA mice and 41 genes in LA mice. We observed the upregulation of Igf2 and the genes involved in neurogenesis (HA: Sema3f, Ntng1, Gbx2, Efna5, and Rora; LA: Otx2, Rarb, and Drd1a) in both mouse lines. In HA mice, we observed the upregulation of genes involved in neurotransmitter transport, the termination of GABA and glycine activity (Slc6a11, Slc6a9), glutamate uptake (Slc17a6), and the downregulation of neuropeptide Y (Npy) and corticotropin releasing hormone-binding protein (Crhbp). In LA mice, we also observed the upregulation of other genes involved in neuroprotection (Ttr, Igfbp2, Prlr) and the downregulation of genes involved in calcium signaling and ion binding (Adcy1, Cckbr, Myl4, Slu7, Scrp1, Zfp330). CONCLUSIONS: Several antidepressant treatment responses are similar in individuals with different sensitivities to stress, including the upregulation of Igf2 and the genes involved in neurogenesis. However, the findings also reveal that many responses to antidepressant treatments, involving the action of individual genes engaged in neurogenesis, neurotransmitter transport and neuroprotection, depend on constitutive hippocampal transcriptomic profiles and might be genotype dependent. The results suggest that, when and if this becomes feasible, antidepressant treatment should take into consideration individual sensitivity to stress

The Effect of Acute and Chronic Social Stress on the Hippocampal Transcriptome in Mice

<div><p>Psychogenic stress contributes to the formation of brain pathology. Using gene expression microarrays, we analyzed the hippocampal transcriptome of mice subjected to acute and chronic social stress of different duration. The longest period of social stress altered the expression of the highest number of genes and most of the stress-induced changes in transcription were reversible after 5 days of rest. Chronic stress affected genes involved in the functioning of the vascular system (<i>Alas2</i>, <i>Hbb-b1</i>, <i>Hba-a2</i>, <i>Hba-a1</i>), injury response (<i>Vwf</i>, <i>Mgp</i>, <i>Cfh</i>, <i>Fbln5</i>, <i>Col3a1</i>, <i>Ctgf</i>) and inflammation (<i>S100a8</i>, <i>S100a9</i>, <i>Ctla2a</i>, <i>Ctla2b</i>, <i>Lcn2</i>, <i>Lrg1</i>, <i>Rsad2</i>, <i>Isg20</i>). The results suggest that stress may affect brain functions through the stress-induced dysfunction of the vascular system. An important issue raised in our work is also the risk of the contamination of brain tissue samples with choroid plexus. Such contamination would result in a consistent up- or down-regulation of genes, such as <i>Ttr</i>, <i>Igf2</i>, <i>Igfbp2</i>, <i>Prlr</i>, <i>Enpp2</i>, <i>Sostdc1</i>, <i>1500015O10RIK</i> (<i>Ecrg4</i>), <i>Kl</i>, <i>Clic6</i>, <i>Kcne2</i>, <i>F5</i>, <i>Slc4a5</i>, and <i>Aqp1</i>. Our study suggests that some of the previously reported, supposedly specific changes in hippocampal gene expression, may be a result of the inclusion of choroid plexus in the hippocampal samples.</p></div

Summary of microarray data.

<p>A—total number of significantly regulated genes. B—Venn diagram showing differences and similarities in gene expression between different stress regimes. Each colored ellipse represents one treatment group. Numbers of genes common between treatment groups are depicted on intersections between ellipses.</p

A—expression pattern of genes belonging to clusters 10. B—examples of anatomical patterns of gene expression obtained from the Allen Mouse Brain Atlas.

<p>d.- days.</p

A—expression pattern of genes belonging to cluster 7. B—anatomical pattern of <i>Prlr</i> gene expression obtained from the Allen Mouse Brain Atlas.

<p>d.- days. Only part of the cluster is presented. For a full list of genes see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0142195#pone.0142195.s003" target="_blank">S2 Table</a>.</p

The design of the experiment.

<p>Broken lines mark days when a group was not stressed. Solid lines mark days when the group was stressed. The last stress episode was performed 24 h before decapitation.</p