Early life stress accelerates age-induced effects on neurogenesis, depression, and metabolic risk.

Early life stress (ELS) affects hippocampal neurogenesis, increases depressive-like behavior, and causes mild metabolic imbalance in early adulthood (2 months). However, whether these effects worsen in mid life remains unclear. To test whether age-dependent effects of ELS on hippocampal neurogenesis are related to deficient hypothalamic-pituitary-adrenal (HPA) axis feedback that causes increased comorbidity of depression and metabolic risk, we evaluated the effects of periodic maternal separation (MS180) in young (4-months-old) and middle-aged (10-months-old) adult rats. MS180 caused more severe depressive-like behavior in middle-aged adults than in young animals. There were no behavioral phenotypic differences between young MS180 and control middle-aged groups. MS180 similarly affected glucose tolerance, increased fasting corticosterone, insulin, and the quantitative insulin sensitivity check index (QUICKI) at both ages. However, middle-aged adult MS180 rats showed more severe age-induced obesity (>40% BW) than controls (>22% BW). MS180 differentially affected dorsal and ventral neurogenesis. In young adults, MS180 animals only showed a decrease in dorsal hippocampal neurogenesis as compared to their age-matched counterparts. In contrast, at 10 months of age, MS180 caused a similar decrease in both dorsal and ventral hippocampal neurogenesis as compared to age-matched controls, and a more severe decrease as compared to young animals. Taken together, our data indicate that MS180 animals show an early onset of age-induced alterations on depression and metabolic risk, and these effects relate to alterations in hippocampal neurogenesis.