Summary Major depressive disorder (MDD) is a leading cause of disease burden worldwide. While the incidence, symptoms and treatment of MDD all point toward major sex differences, the molecular mechanisms underlying this sexual dimorphism remain largely unknown. Here, combining differential expression and weighted gene coexpression network analyses, we provide a comprehensive characterization of male and female transcriptional profiles associated with MDD across 6 brain regions. We overlap our human profiles with those from a mouse model of chronic variable stress and capitalize on converging pathways to define molecular and physiological mechanisms underlying the expression of stress susceptibility in males and females. Our results show a major rearrangement of transcriptional patterns, with male and female transcriptional profiles sharing very limited overlap, an effect seen in depressed humans and in stressed mice. We identify male and female hub genes and confirm their sex-specific impact as stress-susceptibility mediators. For example, downregulation of the female-specific hub gene DUSP6 in prefrontal cortex mimics stress susceptibility in females only by increasing ERK signaling and pyramidal neuron excitability. Such DUSP6 downregulation also recapitulates the transcriptional remodelling that occurs in PFC of depressed females. Together, our findings reveal dramatic sexual dimorphism at the transcriptional level in MDD and highlight the importance of studying sex-specific treatments for this disorder.

Early life stress increases risk for depression. Here we establish a “two-hit” stress model in mice wherein stress at a specific postnatal period increases susceptibility to adult social defeat stress and causes long-lasting transcriptional alterations that prime the ventral tegmental area (VTA)—a brain reward region—to be in a depression-like state. We identify a role for the developmental transcription factor orthodenticle homeobox 2 (Otx2) as an upstream mediator of these enduring effects. Transient juvenile—but not adult—knockdown of Otx2 in VTA mimics early life stress by increasing stress susceptibility, whereas its overexpression reverses the effects of early life stress. This work establishes a mechanism by which early life stress encodes lifelong susceptibility to stress via long-lasting transcriptional programming in VTA mediated by Otx2.

Summary Depression is a complex, heterogeneous disorder and a leading contributor to the global burden of disease. Most previous research has focused on individual brain regions and genes contributing to depression. However, emerging evidence in humans and animal models suggests that dysregulated circuit function and gene expression across multiple brain regions drive depressive phenotypes. Here we performed RNA-sequencing on 4 brain regions from control animals and those susceptible or resilient to chronic social defeat stress at multiple time points. We employed an integrative network biology approach to identify transcriptional networks and key driver genes that regulate susceptibility to depressive-like symptoms. Further, we validated in vivo several key drivers and their associated transcriptional networks that regulate depression susceptibility and confirmed their functional significance at the levels of gene transcription, synaptic regulation and behavior. Our study reveals novel transcriptional networks that control stress susceptibility and offers fundamentally new leads for antidepressant drug discovery.