Abstract:

Objective To investigate the alterations in hippocampal circFBXW4 expression within a rat model of perinatal depression， as well as its association with depression-related behaviors and the neurodevelopment of offspring. Methods Pregnant Sprague-Dawley （SD） rats were randomly allocated into a control group and an experimental group. The experimental group was exposed to chronic unpredictable mild stress （CUMS）. The behavioral performances of maternal rats and their offspring were assessed using the sucrose preference test （SPT）， open-field test （OFT）， and elevated plus-maze （EPM）. Serum corticosterone levels and circFBXW4 expression in the maternal brain tissue were determined. Hematoxylin-eosin （HE） staining was carried out on the hippocampal tissue of offspring on postnatal day 7. Moreover， Spearman correlation analysis was employed to evaluate the relationship between circFBXW4 and behavioral indicators. Results When compared with the control group， maternal rats in the CUMS group exhibited a decreased sucrose preference index （U = 104.00， P = 0.049）， a reduced central activity time （t = 7.67， P < 0.001） and distance （t = 6.29， P < 0.001） in the OFT， as well as a decreased open-arm time （U = 122.00， P < 0.001）， distance （U = 118.00， P = 0.001）， and entries （U = 119.50， P < 0.001） in the Elevated Plus-Maze （EPM）. Serum corticosterone levels were elevated （t = -3.56， P = 0.001）， and the expression of hippocampal circFBXW4 was reduced （U = 120.00， P = 0.006）， which showed a negative correlation with sucrose preference and OFT indicators. In the offspring， the CUMS group demonstrated a decreased sucrose preference index （U = 181.00， P < 0.001）， a reduced central activity time （U = 196.00， P < 0.001） and distance （t = 4.87， P < 0.001） in the OFT， and a decreased open-arm time （U = 196.00， P < 0.001） and distance （U = 196.00， P < 0.001） in the EPM. The offspring's serum corticosterone levels were increased （t = -2.46， P = 0.040）. Conclusions circFBXW4 was significantly reduced in the perinatal depression model when compared to the control group， and this reduction was closely associated with maternal depression-like behaviors. Maternal depression had long-lasting effects on offspring， which were manifested as anhedonia， decreased exploratory behavior， and hippocampal structural abnormalities. These findings strongly suggest that circFBXW4 may be involved in perinatal depression and exert intergenerational effects， and it has potential as a molecular biomarker.

Key words: perinatal depression, circFBXW4, chronic unpredictable mild stress, offspring neurodevelopment