Abstract
Background: Accumulations of stressful life events result in the onset of major depressive disorder (MDD). Comprehensive genomic analysis is required to elucidate pathophysiological changes and identify applicable biomarkers. Methods: Transcriptomic analysis was performed on different brain parts of a chronic mild stress (CMS)-induced MDD mouse model followed by systemic analysis. QPCR and ELISA were utilized for validation in mice and patients. Results: The highest numbers of genes with significant changes induced by CMS were 505 in the amygdala followed by 272 in the hippocampus (twofold changes; FDR, p < 0.05). Enrichment analysis indicated that the core-enriched genes in CMS-treated mice were positively enriched for IFN-γ response genes in the amygdala, and hedgehog signaling in the hippocampus. Transthyretin (TTR) was severely reduced in CMS-treated mice. In patients with diagnosed MDD, serum concentrations of TTR were reduced by 48.7% compared to controls (p = 0.0102). Paired samples from patients with MDD demonstrated a further 66.3% increase in TTR at remission compared to the acute phase (p = 0.0339). Conclusions: This study provides comprehensive information on molecular networks related to MDD as a basis for further investigation and identifies TTR for MDD monitoring and management. A clinical trial with bigger patient cohort should be conducted to validate this translational study.
Highlights
We provided comprehensive genomic information related to major depressive disorder (MDD), and identified transthyretin (TTR) as a gene significantly downregulated in most brain areas as well as in the peripheral blood of chronic mild stress (CMS)-treated mice
To evaluate the induction efficacy of CMS, body weight monitoring and behavioral tests, including the running wheel test (RWT), forced swimming test (FST), and tail suspension test (TST), were performed before and each week after CMS treatments according to the schedule (Figure 2)
Was found to significantly reduce motor activities according to a RWT performed in CMS mice (n = 6) compared to control mice (n = 6; Figure 2b)
Summary
Major depressive disorder (MDD) is a potentially life-threatening disorder with a complicated etiology that imposes a major public health and economic problem worldwide. According to a World Health Organization (WHO) report, it may become a leading cause of disability by the end of 2030 [1]. Patients with MDD exhibit a diverse range of symptoms, including psychomotor retardation, agitation, reduced motivation, depressed mood, and suicidality [2,3]. An epidemiological survey conducted on the working population highlighted the correlations between both chronic psychosocial stress and depression with heart disease, high blood pressure, and high blood glucose [4].
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