Social isolation after chronic unpredictable mild stress perpetuates depressive-like behaviors, memory deficits and social withdrawal via inhibiting ERK/KEAP1/NRF2 signaling

Social withdrawal in patients with depression can aggravate depressive symptoms. However, few studies focus on the behavioral changes of social isolation after CUMS. NRF2 had been reported to be down-regulated after CUMS. But whether NRF2 participates in behavioral changes induced by social isolation after CUMS remains unclear. This study aims to develop a new model combined social isolation with CUMS, and investigate whether such behavioral changes are related to NRF2 signaling.This study included two stages. In Stage 1, rats were subjected to 4-week CUMS and CUMS-susceptible rats were selected. In Stage 2, the CUMS-susceptible rats received 4-week social isolation or social support. Behavioral tests were carried out to observe behavioral changes, including sucrose preference test, forced swimming test, open field test, novel object recognition and social interaction test. QRT-PCR, western blot and immunofluorescence staining detected the ERK/KEAP1/NRF2 signaling.CUMS-susceptible rats exhibited depressive-like behaviors accompanied by the down-regulated ERK/KEAP1/NRF2 signaling in hippocampus. In Stage 2, compared with 4-week social support (group CUMSG), 4-week social isolation (group CUMSI) perpetuated the depressive-like behaviors, memory deficits and social withdrawal in CUMS-susceptible rats, as well as lower levels of p-ERK, NRF2, p-NRF2, HO-1 and NQO1, and the higher levels of KEAP1 in hippocampus.These findings suggested that social isolation after CUMS perpetuated depressive-like behaviors, memory deficits and social withdrawal via inhibiting ERK/KEAP1/NRF2 signaling. This study provided molecular evidence for the effects of post-stress social isolation on mental health, and the antioxidant stress signaling might be a target to rescue these.