Gene expression alterations in the medial prefrontal cortex and blood cells in a mouse model of depression during menopause

Abstract

AimsThe prevalence of major depressive disorder (MDD) is higher in women than in men, and this may be due to the decline in estrogen levels that occurs during the menopausal transition. We studied the biological alterations in the medial prefrontal cortex (mPFC), which is a region that is highly implicated in the neurobiology of MDD, and the blood cells (BCs) of ovariectomized (OVX) mice subjected to chronic mild stress (CMS), which represents a mouse model of depression during menopause.Main methodsThe mPFC and the BCs were obtained from the same individuals. Gene expression levels were analyzed by microarray. The data were used for the Ingenuity Pathway Analysis and the Gene Ontology analysis.Key findingsThe gene expression alterations (GEAs) induced by OVX were mainly associated with ribosomal and mitochondrial functions in both the mPFC and the BCs. Rapamycin-insensitive companion of mTOR (RICTOR) was identified as a possible upstream regulator of the OVX-induced GEAs in both tissues. The CMS-induced GEAs were associated with retinoic acid receptor signaling, inflammatory cytokines and post-synaptic density in the mPFC, but not in the BCs.SignificanceOVX and CMS independently affect biological pathways in the mPFC, which is involved in the development of the depression-like phenotype. Because a subset of the OVX-induced GEAs in the mPFC also occurred in the BCs, the GEAs in the BCs might be a useful probe to predict biological pathways in the corresponding brain tissue under specific conditions such as OVX in females.

Translational Identification of Transcriptional Signatures of Major Depression and Antidepressant Response

“…The majority of rodent studies involving behavioral analyses used male rodents, despite a higher prevalence of MDD in women. Future investigations will require the inclusion of both sexes in animal testing (Hodes et al, 2017 ), but it is interesting to note that in a mouse model of depression during menopause, Miyata et al ( 2016b ) also found that the gene expression alterations induced by ovariectomy were mainly associated with ribosomal and mitochondrial functions in both the medial prefrontal cortex and the blood, strengthening the results we discussed above. We also only addressed the response to antidepressant treatment with a single drug, fluoxetine, while other drugs with different selectivity for neurotransmitters other than serotonin are frequently used in the clinic (Bagot et al, 2017 ).…”

“…Daskalakis et al ( 2014 ) demonstrated convergent signaling pathways between the blood and the brain (amygdala and hippocampus) associated with trauma-related individual differences in a rat model of posttraumatic stress disorder. Apart from a recent study comparing gene expression alterations in the medial prefrontal cortex and blood cells of ovariectomized mice subjected to chronic mild stress (Miyata et al, 2016b ), to our knowledge, our study is the first to report central and peripheral transcriptional signatures associated with response to antidepressant treatment in an animal model of major depression.…”

“…Recently, translational studies have been conducted to trigger the discovery of protein-coding transcriptional markers that would play a role in the balance between susceptibility and resilience to acute and chronic signals involved in depressive symptoms (Pajer et al, 2012 ; Malki et al, 2015 ; Bagot et al, 2016 ; Miyata et al, 2016a , b ). In a series of experiments, Redei et al ( 2014 ) used genetic models of depression and chronic stress on different strains of rats to separately profile transcriptional signatures of depression in the brain and the blood, and test whether a subset of transcripts that differentiated depressed-like rats from non-depressed-like rats would also differentiate human patients with early-onset MDD from those without any disorder.…”

Translational identification of transcriptional signatures of major depression and antidepressant response

“…The majority of rodent studies involving behavioral analyses used male rodents, despite a higher prevalence of MDD in women. Future investigations will require the inclusion of both sexes in animal testing (Hodes et al, 2017), but it is interesting to note that in a mouse model of depression during menopause, Miyata et al (2016b) also found that the gene expression alterations induced by ovariectomy were mainly associated with ribosomal and mitochondrial functions in both the medial prefrontal cortex and the blood, strengthening the results we discussed above. We also only addressed the response to antidepressant treatment with a single drug, fluoxetine, while other drugs with different selectivity for neurotransmitters other than serotonin are frequently used in the clinic (Bagot et al, 2017).…”

“…Daskalakis et al (2014) demonstrated convergent signaling pathways between the blood and the brain (amygdala and hippocampus) associated with trauma-related individual differences in a rat model of posttraumatic stress disorder. Apart from a recent study comparing gene expression alterations in the medial prefrontal cortex and blood cells of ovariectomized mice subjected to chronic mild stress (Miyata et al, 2016b), to our knowledge, our study is the first to report central and peripheral transcriptional signatures associated with response to antidepressant treatment in an animal model of major depression.…”