Maternal social isolation during pre-conception and pregnancy programs inflammatory markers and biobehavioural aging trajectories in distant F4 offspring

Social isolation and loneliness during pregnancy can negatively impact maternal and offspring health. Here we report that maternal social isolation in pregnant rats generates a distinct physiological and behavioural phenotype in 4 th generation great-great-grandoffspring. Male and female F4 offspring born to lineages of transgenerational prenatal stress (TPS, i.e. the F0 mother was socially isolated before and during pregnancy), multigenerational prenatal stress (MPS, where gestational isolation occurred in four consecutive generations), and group-housed controls were tested at 6, 12 and 18 months of age. Assessments included endocrine (corticosterone) and immune markers (IL-18, MCP-1 and M-CSF), motor and cognitive function, and brain morphology via in vivo magnetic resonance imaging (MRI) across the lifespan. Ancestral social isolation in F4 generation rats exacerbated aging-associated stress responses and elevated the production of proinflammatory cytokines and chemokines across all groups. Exploratory behaviours, skilled reaching, skilled walking, spatial learning and memory revealed a stress-sensitive phenotype in TPS males and females along with greater hippocampal and prefrontal cortex atrophy. Thus, maternal social isolation mainly represents a stressful challenge with lifelong consequences for future generations. By contrast, MPS females revealed superior reaching skills that indicate behavioural flexibility with adaptive benefits. The MPS model therefore allows interpretations about the origins of resilience in the face of ongoing stress. Both TPS and MPS shifted cognitive strategies indicative of accelerated aging. Thus, social isolation may represent a significant stressor with potential long-term consequences for future generations. These findings provide a conceptual framework for better risk prediction and prevention of developmental disabilities and aging-related disorders.