Stage-Specific Effects of Maternal Circadian Rhythm Disruption during Pre-Pregnancy, Pregnancy, and Lactation on Behavioral and Neurobiological Outcomes in Male Rat Offspring

Maternal circadian rhythm disruption (CRD) during reproduction is increasingly recognized as a risk factor for long-term neurobehavioral disturbances in offspring. However, the stage-specific consequences of maternal CRD remain poorly understood.This study investigated the effects of maternal CRD during distinct reproductive phases, pre pregnancy mother (PPM), pregnancy mother (PM), and lactationg mother (LM) on behavioral and molecular, and structural outcomes in male offspring. Nulliparous Wistar rats were exposed to constant light (300 lux, 14 days) to induce CRD, while controls remained on a 12:12 h light/dark cycle. Male offspring were assessed for anxiety-like behavior (Elevated Plus Maze), depressive-like behavior (Forced Swim Test), hedonic behavior (Sucrose Preference Test), and recognition memory (Novel Object Recognition Test). Histological analysis of the hippocampal CA1 region and expression of Brain-Derived Neurotrophic Factor (BDNF) and PER2 were also evaluated. PPM and PM offspring exhibited increased anxiety- and depressive-like behaviors, reduced birth weight, disorganized hippocampal CA1 cytoarchitecture, and molecular alterations, decreased BDNF expression in PM offspring and reduced PER2 expression in the suprachiasmatic nucleus (SCN) of PPM offspring, without impairments in hedonic or cognitive performance. In contrast, LM offspring displayed behavioral resilience, suggesting that postnatal circadian realignment may mitigate prenatal vulnerability. Considering the functional and neurodevelopmental similarities between the third trimester of human pregnancy and the lactation period in rat, these findings underscore the clinical relevance of maintaining robust circadian regulation during the pre-pregnancy phase and the first-second trimesters, rather than focusing solely on the final trimester, to support optimal fetal brain development and overall health.