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The transcription factor erythroid 2-related factor 2 (Nrf2) and brain-derived neurotrophic factor (BDNF) play a key role in depression. However, the molecular mechanisms underlying the crosstalk between Nrf2 and BDNF in depression remain unclear. We examined whether Nrf2 regulates the transcription of Bdnf by binding to its exon I promoter. Furthermore, the role of Nrf2 and BDNF in the brain regions from mice with depression-like phenotypes was examined. Nrf2 regulated the transcription of Bdnf by binding to its exon I promoter. Activation of Nrf2 by sulforaphane (SFN) showed fast-acting antidepressant-like effects in mice by activating BDNF as well as by inhibiting the expression of its transcriptional repressors (HDAC2, mSin3A, and MeCP2) and revising abnormal synaptic transmission. In contrast, SFN did not affect the protein expression of BDNF and its transcriptional repressor proteins in the medial prefrontal cortex (mPFC) and hippocampus, nor did it reduce depression-like behaviors and abnormal synaptic transmission in Nrf2 knockout mice. In the mouse model of chronic social defeat stress (CSDS), protein levels of Nrf2 and BDNF in the mPFC and hippocampus were lower than those of control and CSDS-resilient mice. In contrast, the protein levels of BDNF transcriptional repressors in the CSDS-susceptible mice were higher than those of control and CSDS-resilient mice. These data suggest that Nrf2 activation increases the expression of Bdnf and decreases the expression of its transcriptional repressors, which result in fast-acting antidepressant-like actions. Furthermore, abnormalities in crosstalk between Nrf2 and BDNF may contribute to the resilience versus susceptibility of mice against CSDS.

Subthreshold depression (StD) is a prevalent condition associated with social morbidity and increased service utilization, as well as a high risk of developing into a major depressive disorder (MDD). The lack of well-defined diagnostic criteria for StD has limited research on this disorder, with very few brain-imaging studies examining the neurobiology of StD. Yet, identifying the neural pathology of StD has the potential to elucidate risk factors and prognostic markers for major depression and is crucial for developing tailored treatments for patients at mild stages of depression. We investigated resting-state functional connectivity (rs-FC) of the cognitive control network (CCN), known to be dysregulated in MDD, using the bilateral dorsolateral prefrontal cortex (DLPFC) as a seed, focusing on two cohorts of StD subjects (young and middle aged) as well as matched controls. Irrespective of age, we found a significant rs-FC decrease in the CCN of the StD subjects, compared with matched controls, particularly between the DLPFC and the brain regions associated with the representation of self and other mental states (temporo-parietal junction (TPJ) and precuneus), as well as salience detection and orienting (insula). The functional connectivity between the DLPFC and the left TPJ was also associated with depressive symptom scores measured by the Center for Epidemiologic Studies Depression Scale. This finding may shed light on the neural pathology of StD, leading to better understanding of mild stages of depression, its diagnosis and the development of new treatments.