Long-term Effects of Maternal Separation on Anxiety-Like Behavior and Neuroendocrine Parameters in Adult Balb/c Mice

Abstract

Introduction: Disruption of maternal care using maternal separation (MS) models has provided significant evidence of the deleterious long-term effects of early life stress. Several preclinical studies investigating MS showed multiple behavioral and biomolecular alterations. However, there is still conflicting results from MS studies, which represents a challenge for reliability and replicability of those findings. Objective: To address that, this study was conducted to investigate whether MS would affect anxiety-like behaviors using a battery of classical tasks, as well as central and peripheral stress-related biomarkers. Methods: Male Balb/c mice were exposed to MS from postnatal day (PND) 2 to 14 for 180-min per day. Two independent cohorts were performed to evaluate both baseline and anxiety-like behavior responses to MS at PND60. We performed composite scores to evaluate MS effects on anxiety and risk assessment phenotypes. Also, we assessed mRNA gene expression in the medial pre-frontal cortex (mPFC) of glucocorticoid and mineralocorticoid receptors (GR and MR) using real-time PCR and peripheral corticosterone levels (CORT) to investigate possible neurobiological correlates to anxiety behaviors. Results: We found increased anxiety-like behavior and decreased risk assessment and exploratory behaviors in MS mice. The animals exposed to MS also presented a decrease in MR mRNA expression and higher levels of CORT compared to controls. Conclusions: Our findings reinforce the body of evidence suggesting that long-term MS induces effects on anxiety and risk assessment phenotypes following the exposure to a standardized MS protocol. Moreover, MS affected the expression of MR mRNA and induced significant changes on CORT response. This data highlights that the reprograming MS effects on HPA axis could be mediate by MR gene expression in mPFC and chronic overactivity of peripheral CORT levels.