Early-life stress and maternal immune activation alter stress coping behavior and brain metabolic activity in young male rats

Early-life stress (ELS) and maternal immune activation (MIA) are two major environmental risk factors for the development of affective disorders. While their individual effects have been extensively studied, their combined impact on adult affective behavior and brain metabolism remains unclear. This study investigated the independent and interactive effects of MIA (LPS, bacterial lipopolysaccharide, 100 μg/kg, i.p. on gestational days 15-16) and ELS (maternal separation of pups from postnatal days 2 to 14) on affective behavior and brain oxidative metabolism in young male rats. Behavioral outcomes were assessed using the elevated zero maze and the forced swim test. Regional brain activity was quantified by cytochrome c oxidase (CCO) histochemistry in cortico-limbic and subcortical regions. MIA significantly increased anxiety-like behavior, whereas ELS reduced locomotor activity in the elevated zero maze. A synergistic effect of both insults was observed in the forced swim test, with combined MIA and ELS animals displaying the highest immobility time. At the neurobiological level, both MIA and ELS independently increased brain CCO activity across several subcortical regions, including the amygdala, striatum, ventral hippocampus, thalamus, and substantia nigra. Neurobehavioral correlation analyses revealed distinct patterns linking behavioral outcomes with regional metabolic activity, particularly in the nucleus accumbens and bed nucleus of the stria terminalis. These findings suggest that MIA and ELS exert synergistic effects on stress coping behavior and long-term brain oxidative metabolism. Combined exposure to gestational immune challenge and early postnatal stress may exacerbate vulnerability to developing mood disorders in adulthood by disrupting the functional development of affective- and motivation-related brain regions.