O22. Transcriptional Organization of Gene Networks in Human MDD and Their Correlates in Different Mouse Models of Stress
Section snippets
Background
Our capacity to better define the contribution of brain-specific molecular alterations associated with MDD passes through the use of well validated mouse models. However, while these models induce some of the behavioral and clinical features of MDD, the extent by which they reproduce its molecular and transcriptional alterations is still a matter of debate.
Methods
Here, combining differential expression and gene coexpression network analyses, we overlapped human profiles in different brain regions with those from three mouse models of stress including chronic variable stress (CVS), prolonged social isolation (SI) and chronic social defeat stress (CSDS) and capitalized on converging pathways to define molecular and physiological mechanisms underlying the expression of stress susceptibility.
Results
Our results show a major rearrangement of transcriptional patterns in MDD, with limited overlap between males and females. Our interspecies analyses suggest that every model reproduces common but also distinct transcriptional alterations relevant to the disease. We identified key regulators of gene networks underlying MDD and confirmed their impact as mediators of stress susceptibility. For example, downregulation of the female-specific hub gene Dusp6 in mouse prefrontal cortex mimicked stress
Conclusions
Together our findings reveal the extent by which CVS, SI and CSDS mouse models of stress reproduce the transcriptional alterations associated with MDD and highlight functional pathways driving stress susceptibility in a sex-specific fashion, highlighting the importance of studying sex-specific treatments for this disorder.
Supported By
CIHR, FRQS, NARSAD, ULaval-Sentinelle Nord
Keywords
Major Depressive Disorder (MDD), Transcriptomics, Mouse Models, Stress, Sex Differences