Adverse and stressful early life events can impact on later-life cognitive, physiological and neurological outcomes, but direct mechanisms through which these so-called “programming effects” occur are still under investigation. In this review, we systematically examine early-life stress (ELS) paradigms in non-human animals, focusing on three key biological systems: the hypothalamic-pituitary-adrenal (HPA) axis, immune system and oxytocinergic system. We developed a ranking system to assess and compare stress severity across different ELS paradigms. We also consider how different theoretical frameworks influence the interpretation of ELS outcomes, from primarily adaptive to pathological. Effects of chronic ELS on peripheral measures of HPA- and oxytocinergic system function were variable, but centrally, ELS more consistently triggered region-specific alterations in mRNA expression, including increased hypothalamic corticotropin-releasing hormone (CRH) mRNA and decreased oxytocin (OXT) mRNA in the amygdala. Altered gene expression in amygdala was linked to later-life behavioral alterations. Central markers of immune function were consistently altered following ELS, including higher microglia or astrocyte densities or ameboid microglial morphology. These changes are likely mechanisms linking ELS to cognitive deficits and depressive symptoms, which were consistently found across studies assessing behavior. Other behaviors, including anxiety and risk-taking, were less consistently altered by ELS. Increasing stress severity scores of ELS paradigms predicted the likelihood of long-term alterations in key biological systems, emphasizing the importance of greater standardization of ELS paradigms to increase comparability across studies. Interventions that provided social support during ELS, or increased post-ELS maternal care showed promise for promoting resilience, and deserve more attention in future studies.
