Dorsal raphe serotonergic neurons mediate depression in a mouse model of loss of control over stress

Abstract Our previous study found that, in a triadic experiment, helplessness exhibited in mice in the loss of control over stress (LOC) group in response to aversive events was more prominent than that seen in the yoked (Yoked) group of mice. However, the mechanisms responsible for such phenomena are poorly understood. Increasing evidence has demonstrated that 5-hydroxytryptamine (5-HT) plays a critical role in emotional behaviours. Therefore, we hypothesized that the serotonergic system might mediate depression induced by the loss of control over stress. Our results showed that the activity level of 5-HT neurons of mice in the LOC group was significantly higher than that of mice in the Yoked and Control groups. Additionally, optogenetic inhibition of 5-HT neuron projections from the dorsal raphe nucleus (DRN) to the ventral hippocampus (VH) significantly reduced escape latency and freezing time, improved escape defect behaviour of mice in the LOC/Yoked group, and downregulated the expression of DRN 5-HT1A autoreceptor (DRN 5-HT1AR) of mice in the LOC group. These results provide compelling evidence that the sensitization of dorsal raphe 5-HT neurons mediates depression in a mouse model of loss of control over stress.