Neural correlates of learning and memory are altered by early-life stress

The ability to learn and remember, which is fundamental for behavioral adaptation, is susceptible to stressful experiences during the early postnatal period, such as abnormal levels of maternal care. The exact mechanisms underlying these effects still remain elusive. This study examined whether early life stress (ELS) alters memory and brain activation patterns in male mice. Therefore, we examined the expression of the immediate early genes (IEGs) c-Fos and Arc in the dentate gyrus (DG) and basolateral amygdala (BLA) after training and memory retrieval in a fear conditioning task. Furthermore, we examined the potential of RU38486 (RU486), a glucocorticoid receptor antagonist, to mitigate ELS-induced memory deficits by blocking stress signalling during adolescence. Arc::dVenus reporter mice, which allow investigating experience-dependent expression of the immediate early gene Arc also at more remote time points, were exposed to ELS by housing dams and offspring with limited bedding and nesting material (LBN) between postnatal days (PND) 2-9 and trained in a fear conditioning task at adult age. We found that ELS reduced both fear acquisition and contextual memory retrieval. RU486 did not prevent these effects. ELS reduced the number of Arc::dVenus⁺ cells in DG and BLA after training, while the number of c-Fos⁺ cells were left unaffected. After memory retrieval, ELS decreased c-Fos⁺ cells in the ventral DG and BLA. ELS also altered the colocalization of c-Fos⁺ cells with Arc::dVenus⁺ cells in the ventral DG, possibly indicating impaired engram allocation in the ventral DG after memory retrieval. In conclusion, this study shows that ELS alters neuronal activation patterns after fear acquisition and retrieval, which may provide mechanistic insights into enduring impact of ELS on the processing of fear memories, possibly via changes in cell (co-) activation and engram cell allocation.