Sex-Dependent Gene Expression Alterations in Social Defeat Stress Model of Major Depression Disorder

Introduction: Major Depression Disorder (MDD) is a prevalent, recurrent, and chronic disorder that represents a leading cause of disability worldwide. Millions are affected with symptoms that go from constant sadness to even suicidal thoughts. In the U.S., major depression and fatal suicide have increased by 57.4% among adolescents and young adults. Myelin and inflammation-related genes have been found to play a role in individuals with MDD. Methods: Adolescent males and females C57BL/6 mice underwent a vicarious defeat stress (VDS) procedure in which a mouse witnessed a conspecific being defeated. VDS and control (CON) mice underwent the Social Interaction (SI) test. The SI test was done in an open field with and without the presence of a social target in which the interaction time between the mouse and the target is recorded and expressed as emotional stress (ES). The prefrontal cortex of adolescent VDS mice and CON, males, and females (N=12 per group) were collected for RNA extraction and reversed-transcribed to cDNA. Gene expression VDS mice and CON of myelin and inflammation- related genes INSRR (Insulin Receptor Related Receptor), IGF2 (Insulin-like Growth Factor 2), CCL2 (Chemokine Ligand 2) BCAS1 (Brain-enriched Myelin-Associated Protein 1), MOBP (Myelin Associated Oligodendrocyte Basic Protein), CDH19 (Cadherin-19), ERMN (ERM-like protein) OPALIN (Oligodendrocyte Myelin Paranodal and Inner Loop Protein), and MBP (Myelin Basic Protein) were quantified by qPCR and compared. Protein expressions of IGF2, MBP, and OPALIN were analyzed and quantified by immunohistochemistry (IHC) for further confirmation of results. Results: In VDS/ES mice, male and female SI was significantly reduced compared to CON. Genes IGF2 and CCL2 showed a significantly higher expression of VDS mice males and females compared to CON. BCAS1 and MOBP genes showed a significantly lower expression in VDS mice males and females compared to CON. In addition, CDH19, ERMN, and OPALIN displayed significantly lower expressions in VDS males compared to CON but not in females. Interestingly, the MBP gene was the only one to show a sex-dependent difference in gene expression, with significantly low expression in VDS males and the opposite in VDS females when compared to CON. Violin plots revealed that the relative gene expression analyzed by gene and by condition, either VDS or CON, using violin plots revealed that in general, females, either CON or VDS were significantly over-expressing the genes of interest, including INSRR, IGF2, CCL2, CDH19, ERMN, OPALIN when compared to males (CON or VDS). Interestingly, MOBP was the only gene in which females showed a significantly lower expression compared to males, either CON or VDS. Conclusion: The present study reveals that myelin-related MOBP, BCAS1, and inflammation-related INSRR and CCL2 genes are altered in the VDS/ES male and female mice with reduced. social interaction as a sign of depressive-like behavior after exposure to emotional stress. Sex-dependent alterations occurred in myeline-related genes in which MBP is the only gene showing opposite gene expression between male and female VDS/ES mice. The other myeline-related genes, CDH19, ERMN, and OPALIN, show altered expression only in males. Whereas the gene IGF2 was over-expressed in both male and female VDS/ES mice, suggesting a neuroprotective function.