Kestering-Ferreira Erika, Tractenberg Saulo Gantes, Lumertz Francisco Sindermann, Orso Rodrigo, Creutzberg Kerstin Camile, Wearick-Silva Luis Eduardo, Viola Thiago Wendt, Grassi-Oliveira Rodrigo
Developmental Cognitive Neuroscience Lab (DCNL), Pontifical University Catholic of Rio Grande do Sul.
University of Milan, Italy.
Chronic Stress (Thousand Oaks). 2021 Dec 21;5:24705470211067181. doi: 10.1177/24705470211067181. eCollection 2021 Jan-Dec.
: 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. 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. 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. 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. 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.
使用母婴分离（MS）模型扰乱母性照料已提供了大量证据，证明早期生活应激具有有害的长期影响。多项调查母婴分离的临床前研究显示出多种行为和生物分子改变。然而，母婴分离研究仍存在相互矛盾的结果，这对这些研究结果的可靠性和可重复性构成了挑战。为解决这一问题，本研究旨在使用一系列经典任务以及中枢和外周应激相关生物标志物，调查母婴分离是否会影响焦虑样行为。雄性Balb/c小鼠在出生后第2天至第14天每天接受180分钟的母婴分离。进行了两个独立的队列研究，以评估在出生后第60天对母婴分离的基线和焦虑样行为反应。我们进行综合评分以评估母婴分离对焦虑和风险评估表型的影响。此外，我们使用实时PCR评估糖皮质激素和盐皮质激素受体（GR和MR）在内侧前额叶皮质（mPFC）中的mRNA基因表达，并检测外周皮质酮水平（CORT），以研究与焦虑行为可能相关的神经生物学机制。我们发现母婴分离小鼠的焦虑样行为增加，风险评估和探索行为减少。与对照组相比，暴露于母婴分离的动物还表现出MR mRNA表达降低和CORT水平升高。我们的研究结果进一步证明，长期母婴分离在暴露于标准化母婴分离方案后会对焦虑和风险评估表型产生影响。此外，母婴分离影响了MR mRNA的表达，并诱导了CORT反应的显著变化。这些数据表明，母婴分离对下丘脑-垂体-肾上腺（HPA）轴的重新编程作用可能是通过mPFC中MR基因的表达和外周CORT水平的慢性过度激活介导的。
