Roque Susana, Mesquita Ana Raquel, Palha Joana A, Sousa Nuno, Correia-Neves Margarida
Life and Health Sciences Research Institute, School of Health Sciences, University of Minho , Braga , Portugal ; ICVS/3B's - PT Government Associate Laboratory , Braga , Portugal.
Life and Health Sciences Research Institute, School of Health Sciences, University of Minho , Braga , Portugal ; Neuropsychophysiology Laboratory, Center for Research in Psychology (CIPsi), School of Psychology, University of Minho , Braga , Portugal.
Front Behav Neurosci. 2014 May 22;8:192. doi: 10.3389/fnbeh.2014.00192. eCollection 2014.
Maternal separation (MS), an early life stressful event, has been demonstrated to trigger neuropsychiatric disorders later in life, in particular depression. Experiments using rodents subjected to MS protocols have been very informative for the establishment of this association. However, the mechanism by which MS leads to neuropsychiatric disorders is far from being understood. This is probably associated with the multifactorial nature of depression but also with the fact that different research MS protocols have been used (that vary on temporal windows and time of exposure to MS). In the present study, MS was induced in rats in two developmental periods: for 6 h per day for 14 days between postnatal days 2-15 (MS2-15) and 7-20 (MS7-20). These two periods were defined to differ essentially on the almost complete (MS2-15) or partial (MS7-20) overlap with the stress hypo-responsive period. Behavioral, immunological, and endocrine parameters, frequently associated with depressive-like behavior, were analyzed in adulthood. Irrespectively from the temporal window, both MS exposure periods led to increased sera corticosterone levels. However, only MS2-15 animals displayed depressive and anxious-like behaviors. Moreover, MS2-15 was also the only group presenting alterations in the immune system, displaying decreased percentage of CD8(+) T cells, increased spleen T cell CD4/CD8 ratio, and thymocytes with increased resistance to dexamethasone-induced cell death. A linear regression model performed to predict depressive-like behavior showed that both corticosterone levels and T cell CD4/CD8 ratio explained 37% of the variance observed in depressive-like behavior. Overall, these findings highlight the existence of "critical periods" for early life stressful events to exert programing effects on both central and peripheral systems, which are of relevance for distinct patterns of susceptibility to emotional disorders later in life.
母婴分离（MS）是一种早年的应激事件，已被证明会在日后引发神经精神疾病，尤其是抑郁症。使用经历母婴分离方案的啮齿动物进行的实验，对于建立这种关联非常有参考价值。然而，母婴分离导致神经精神疾病的机制仍远未被理解。这可能与抑郁症的多因素性质有关，也与使用了不同的母婴分离研究方案（这些方案在时间窗口和暴露于母婴分离的时间上有所不同）这一事实有关。在本研究中，在大鼠的两个发育阶段诱导母婴分离：在出生后第2至15天（MS2 - 15）和第7至20天（MS7 - 20），每天分离6小时，持续14天。定义这两个阶段的主要区别在于，它们与应激低反应期几乎完全重叠（MS2 - 15）或部分重叠（MS7 - 20）。在成年期分析了与抑郁样行为经常相关的行为、免疫和内分泌参数。无论时间窗口如何，两个母婴分离暴露期都会导致血清皮质酮水平升高。然而，只有MS2 - 15组的动物表现出抑郁和焦虑样行为。此外，MS2 - 15组也是唯一免疫系统出现改变的组，表现为CD8(+) T细胞百分比降低、脾脏T细胞CD4/CD8比值升高以及胸腺细胞对糖皮质激素诱导的细胞死亡的抵抗力增加。用于预测抑郁样行为的线性回归模型表明，皮质酮水平和T细胞CD4/CD8比值共同解释了观察到的抑郁样行为中37%的变异。总体而言，这些发现凸显了早年应激事件对中枢和外周系统产生编程效应的“关键期”的存在，这与日后对情绪障碍易感性的不同模式相关。
