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.

Background Previous work has shown that chronic social defeat stress (CSDS) induces increased phasic firing of ventral tegmental area (VTA) dopamine neurons that project to the nucleus accumbens (NAc) selectively in mice that are susceptible to the deleterious effects of the stress. In addition, acute optogenetic phasic stimulation of these neurons promotes susceptibility in animals exposed to acute defeat stress. These findings are paradoxical since increased dopamine (DA) signaling in NAc normally promotes motivation and reward, and the influence of chronic phasic VTA firing in the face of chronic stress remains unknown. Methods We used CSDS with repeated optogenetic activation and pharmacological manipulations of the mesolimbic VTA-NAc pathway to examine the role of brain-derived neurotrophic factor (BDNF) and DA signaling in depressive-like behaviors. BDNF protein expression and DA release were measured in this model. Results Pharmacological blockade of BDNF-TrkB signaling, but not DA signaling, in NAc prevented CSDS-induced behavioral abnormalities. Chronic optogenetic phasic stimulation of the VTA-NAc circuit during CSDS exacerbated the defeat-induced behavioral symptoms, and these aggravated symptoms were also normalized by BDNF-TrkB blockade in NAc. The aggravated behavioral deficits induced by phasic stimulation of the VTA-NAc pathway were also blocked by local knockdown of BDNF in VTA. Conclusions These findings show that BDNF-TrkB signaling, rather than DA signaling, in the VTA-NAc circuit is crucial for facilitating depressive-like outcomes after CSDS, and establish such BDNF-TrkB signaling as a pathological mechanism during periods of chronic stress.

Mitochondrial fission and trafficking to dendritic protrusions have been implicated in dendritic spine development. Here, we show that Wiskott-Aldrich syndrome protein (WASP)-family verprolin homologous protein 1 (WAVE1) controls depolarization-induced mitochondrial movement into dendritic spines and filopodia and regulates spine morphogenesis. Depolarization-induced degradation of the p35 regulatory subunit of cyclin-dependent kinase 5 (Cdk5), with the resultant decreased inhibitory phosphorylation on WAVE1, depend on NMDA receptor activation. Thus, WAVE1 dephosphorylation and activation are likely associated with mitochondrial redistribution and spine morphogenesis.itochondria play a critical role in neuronal development and synaptic function through their ability to supply ATP and regulate Ca 2ϩ homeostasis (1-6). Moreover, mitochondrial abnormalities are associated with many neurological diseases, including neurodegenerative diseases and psychiatric disorders (7,8). Mitochondria are highly dynamic and undergo constant fusion and fission (9, 10). Mitochondria are transported from the cell body to sites of high-energy utilization through axons and dendrites, and they undergo retrograde transport from the nerve terminal toward the cell body (11). Interestingly, neuronal activity increases the ratio of fission versus fusion and increases the percentage of mitochondria in dendritic spines and filopodia (4). Repetitive depolarization induces the formation of dendritic protrusions (filopodia) (12) and spines (4) in hippocampal neurons, and mitochondria are likely to supply ATP and regulate calcium during spine morphogenesis (4). The presence of mitochondria in spines also might play a role in the regulation of synaptic transmission.The molecular mechanisms that mediate activity-dependent mitochondrial distribution in dendritic spines are unknown. Interactions between mitochondria and the cytoskeleton are essential for normal mitochondrial motility and distribution (13). Microtubules are the primary means for long-distance mitochondrial transport, whereas the actin cytoskeleton is required for short-distance mitochondrial movements (14). Wiskott-Aldrich syndrome protein (WASP)-family verprolin homologous protein 1 (WAVE1), through its ability to activate the Arp2/3 complex, is a key regulator of actin polymerization and dendritic spine morphology (15). Here we show that WAVE1 is required for activity-dependent mitochondrial trafficking to dendritic spines and filopodia. Results Localization of WAVE1 in Mitochondria.Previous studies have shown that WAVE1 is present in dendrites, dendritic spines, and axonal growth cones (16-18). Because both WAVE1 (15) and mitochondria (4) are implicated in dendritic spine formation, we examined the localization of WAVE1 and mitochondria in the dendrites of primary-cultured hippocampal neurons. Mitochondria were visualized after the expression of Mito-DsRed (DsRed2 fused to the mitochondrial targeting sequence from subunit VIII of human cytochrome c oxidase) (19). Endogenous WAVE1 wa...