Maternal Depression by Distress (DMD): Behavioral Validation of a Gestational Mouse Model

Antenatal depression is a prevalent neuropsychiatric condition, yet its mechanisms remain difficult to investigate. We developed and validated the Maternal Depression by Distress (DMD) mouse model to test whether chronic peripubertal stress produces behavioral alterations persisting into pregnancy. Female C57BL/6 mice were socially isolated from weaning and subjected to 15 restraint sessions (2 h/day, 5 days ON / 2 days OFF). Behavioral profiling was conducted at pre-gestational baseline and gestational day 16 using the Sucrose Preference Test (SPT), Splash Test, Forced Swim Test (FST), and Elevated Plus Maze (EPM). Prior to mating, DMD females showed anhedonia (t(18) = 2.40, p<0.05, d = −1.08) and reduced self-care in the Splash Test (t(9) = 3.58, p<0.01, d = −2.25), with no differences in body weight, FST immobility, or EPM exploration. At late gestation, DMD dams exhibited anxiety-like behavior, spending more time in the EPM central platform (t(10) = −3.03 p<0.01, d = 1.75) and increasing closed-arm entries (t(10) = −2.31, p<0.05, d = 1.33). They also showed diminished self-care in the Splash Test (t(8) = −2.90, p<0.05) and lower sucrose preference (t(12) = −2.29, p<0.05). In conclusion, the DMD protocol establishes a face-valid preclinical model of gestational distress, providing a robust platform to investigate postpartum trajectories and maternal–fetal neurobiological mechanisms.