Brain-derived neurotrophic factor in 5-HT neurons regulates susceptibility to depression-related behaviors induced by subchronic unpredictable stress.

Chronic stress is a major risk factor for the development of depression. Brain-derived neurotrophic factor (BDNF) plays an important role in neural functions and exhibits antidepressant effects. However, studies on depression-related behavioral response to BDNF have mainly focused on the limbic system, whereas other regions of the brain still require further exploration. Here, we report that exposure to chronic unpredictable stress (CUS) can induce depression-associated behaviors in mice. CUS could decrease total Bdnf mRNA and protein levels in the dorsal raphe nucleus (DRN), which correlated with depression-related behaviors. A corresponding reduction in exon-specific Bdnf mRNA was observed in the DRN of CUS mice. Bdnf was highly expressed in 5- Hydroxytryptamine (5-HT) neurons from the DRN. Selective deletion of Bdnf in 5-HT neurons alone could not induce anhedonia and behavioral despair in male or female mice, as indicated by the unchanged female urine sniffing time and preference for sucrose/saccharin. However, it could increase the latency to food in female mice, but not in male mice as shown by novelty-suppressed food test. Nevertheless, enhanced stress-induced susceptibility is observed in these male mice as suggested by the decrease in female urine sniffing time, and for female mice by the reduced sucrose preference and increased immobility in forced swim test. Furtherly, total Bdnf mRNA levels in DRN were correlated with depression-related behaviors of female, but not male 5-HT neurons specific Bdnf knockout mice. Our results indicate that BDNF might act on 5-HT neurons to regulate depression-related behaviors and stress vulnerability in a sex-dependent manner.