PDF(Pubmed)
Abstract：
The early postnatal period is a sensitive time window that is characterized by several neurodevelopmental processes that define neuronal architecture and function later in life. Here, we examined in young adult mice, using an auditory fear conditioning paradigm, whether stress during the early postnatal period 1) impacts fear acquisition and memory consolidation in male and female mice; 2) alters the fear responsiveness to corticosterone and 3) whether effects of early-life stress (ELS) can be prevented by treating mice with a glucocorticoid (GR) antagonist at adolescence. Male and female mice were exposed to a limited nesting and bedding model of ELS from postnatal day (PND) 2-9 and injected i.p with RU38486 (RU486) at adolescent age (PND 28-30). At two months of age, mice were trained in the fear conditioning (FC) paradigm (with and without post training administration of corticosterone - CORT) and freezing behavior during fear acquisition and contextual and auditory memory retrieval was scored. We observed that ELS impaired fear acquisition specifically in male mice and reduced both contextual and auditory memory retrieval in male and female mice. Acute post-training administration of CORT increased freezing levels during auditory memory retrieval in female mice but reduced freezing levels during the tone presentation in particular in control males. Treatment with RU486 prevented ELS-effects in acquisition in male mice and in females during auditory memory retrieval. In conclusion, this study highlights the long-lasting consequences of early-life stress on fear memory processing and further illustrates 1) the potential of a glucocorticoid antagonist intervention during adolescence to mitigate these effects and 2) the partial modulation of the auditory retrieval upon post training administration of CORT, with all these effects being sex-dependent.
摘要：
出生后早期是一个敏感的时间窗口，其特征是几个神经发育过程，这些过程定义了生命后期的神经元结构和功能。这里,我们在年轻的成年小鼠中进行了检查，使用听觉恐惧调节范式，出生后早期的压力是否会影响雄性和雌性小鼠的恐惧获得和记忆巩固；2）改变对皮质酮的恐惧反应；3）是否可以通过在青春期用糖皮质激素（GR）拮抗剂治疗小鼠来预防早期生活压力（ELS）的影响。从出生后第2-9天（PND）开始，将雄性和雌性小鼠暴露于有限的ELS筑巢和垫层模型，并在青春期（PND28-30）时i.p注射RU38486（RU486）。在两个月大的时候，对小鼠进行了恐惧条件（FC）范式（有或没有皮质酮-CORT的训练后给药）训练，并对恐惧获取过程中的冻结行为以及上下文和听觉记忆检索进行了评分。我们观察到，ELS尤其在雄性小鼠中损害了恐惧的获得，并减少了雄性和雌性小鼠的上下文和听觉记忆恢复。CORT的急性训练后给药在雌性小鼠的听觉记忆恢复过程中增加了冻结水平，但在音调呈现过程中降低了冻结水平，尤其是在对照雄性中。在听觉记忆恢复过程中，用RU486处理可防止雄性小鼠和雌性小鼠的ELS效应。总之,这项研究强调了早期生活压力对恐惧记忆处理的长期影响，并进一步说明了1）青春期糖皮质激素拮抗剂干预减轻这些影响的潜力，以及2）培训后对听觉恢复的部分调节CORT，所有这些影响都是性别依赖性的。
