Timing-dependent effects of maternal separation stress in female rats: Insights into sex differences

Rodent maternal separation (MS) models have been widely used to investigate the effects of early life stress (ELS) on neural development. However, the presence of sex differences in timing-dependent specificity has yet to be confirmed. The objective of this was to elucidate the timing-dependent specificity of MS in female rats and compare it with that previously reported using male rats. Female Long-Evans rat pups were randomly divided into three groups: early MS (Early-MS: postnatal day [PND] 1‒9); late MS (Late-MS: PND 10‒20); and control (CTL). All groups were evaluated for psychiatric disorder-like behaviours using several behavioural tests, and Drebrin and Golgi-Cox staining were performed to assess changes in dendritic spines immunohistochemically. Both Early- and Late-MS groups exhibited learned helplessness-like behaviour, as shown by increased immobility in the forced swim test. However, only the Early-MS group demonstrated reduced active coping behaviour, as measured by climbing. Only the Late-MS group exhibited obsessive-compulsive-like behaviour, as reflected by increased marble burying. Neuroanatomically, spine density in the hippocampal CA1 region increased in the Early-MS group in the basal dendrites, whereas it decreased in the Late-MS group in the apical dendrites. These behavioural and neuroanatomical alterations suggest that ELS affects female rats depending on the timing of exposure. These patterns differ partially from those reported in males, contributing to our understanding of sex-specific mechanisms underlying the impact of ELS on brain plasticity and behaviour.