Gene regulation in the frontal cortex of rats exposed to the chronic mild stress paradigm, an animal model of human depression

Abstract

In the present study, we have coupled the chronic mild stress (CMS) protocol with Affymetrix microarray technology to screen the rat genome for gene changes in the frontal cortex. The aim of our work was to assess whether the CMS protocol could be a useful experimental model to provide insights into the molecular basis of depression. Under our experimental conditions, 59 transcripts changed by more than +/-1.5-fold between naïve and anhedonic rats and showed significantly altered expression levels (P < 0.05). Among these, 18 were upregulated (fold change range +1.509 to +3.161) and 41 were downregulated (fold change range -1.505 to -2.659). To confirm the data obtained with microarrays, we used real-time reverse transcription polymerase chain reaction (RT-PCR). The results confirmed the downregulation of Itga6, Camk2a, Plcb1, Cart, Gad1, Homer1 and Th and the upregulation of Egr2 and Ptgs2 observed in the DNA microarray analysis. Moreover, the fold change data of the nine validated transcripts from microarray analysis and real-time polymerase chain reaction showed a good correlation (r = 0.863, 7 d.f., P < 0.01; slope = 0.976). It is of great interest that prostaglandin-endoperoxide synthase 2, tyrosine hydroxylase, Cart, Homer1 and glutamate decarboxylase have already been implicated in affective disorders by different approaches in previous reports. In conclusion, our findings indicate that the CMS paradigm is a useful preclinical model with which to investigate the molecular basis of anhedonia and to help in the discovery of novel targets for antidepressant drugs.

Replication of Epigenetic Postpartum Depression Biomarkers and Variation with Hormone Levels

“…Of those 12 loci consistently affected by HP1BP3 knockdown in both of the above studies, three may have implications for mood. ITGA6 is downregulated in a chronic mild stress-based depression paradigm in rodents (Orsetti et al, 2008), EIF4B is implicated in mTOR signaling of relevance for depression (Jernigan et al, 2011), and GLO1 is implicated in BDNF signaling (Karpova et al, 2014), a downstream consequence of estrogen signaling in the hippocampus. Murine knockout of HP1BP3 leads to growth retardation (Garfinkel et al, 2015), further suggesting a possible role for modulation of trophic factors in the context of the brain.…”

Increase in Cortical Pyramidal Cell Excitability Accompanies Depression-Like Behavior in Mice: A Transcranial Magnetic Stimulation Study

“…In particular, Homer1 has been implicated in the etiology of major depression by a recent genome-wide association study (Rietschel et al, 2010). Orsetti et al (2008) reported downregulation of Homer1 mRNA in rats under CMS without pinpointing Homer1a. Overall, Homer1a is likely to modify BK channel properties to support the third possibility.…”

Sex-specific differences in the dynamics of cocaine- and amphetamine-regulated transcript and nesfatin-1 expressions in the midbrain of depressed suicide victims vs. controls

“…The possible significance of CART in stress-related psychopathologies derives from the facts that a) CART mRNA is downregulated in the frontal cortex of rats subjected to a chronic mildstress (Orsetti et al, 2008); b) CART-immunoreactivity is increased in the periaqueductal grey in a genetic rat model for depression (Flinders-Sensitive-Line-FSL; (Wiehager et al, 2009); and c) CARTimmunoreactivity is reduced in various brain areas of socially isolated and olfactory bulbectomized rats (Dandekar et al, 2008). Furthermore, a study of an Italian family with high levels of anxiety and MDD has indicated an association between these disorders and a point mutation in the CART gene (Miraglia del Giudice et al, 2006).…”