Blocking glucocorticoid receptors at adolescent age prevents enhanced freezing between repeated cue-exposures after conditioned fear in adult mice raised under chronic early life stress
Blocking glucocorticoid receptors at adolescent age prevents enhanced freezing between repeated cue-exposures after conditioned fear in adult mice raised under chronic early life stress
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DOI：
10.1016/j.nlm.2016.05.009
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发表时间：
2016-09-01
影响因子：
2.7
通讯作者：
Krugers, Harm J.
中科院分区：
文献类型：
--
作者：
Arp, J. Marit;ter Horst, Judith P.;Krugers, Harm J.
早期生活逆境可能对学习和记忆过程产生长期影响，并增加日后患上与压力相关的精神病理学的风险。在这项研究中，我们调查了（i）慢性早期生活压力（ELS）-由出生后第2天至第9天的有限筑巢和垫料引起-如何影响成年小鼠的条件性恐惧，以及（ii）这些影响是否可以通过阻断青少年时期的糖皮质激素受体（GR）来预防。在成年雄性和雌性小鼠，ELS没有影响冻结行为的第一个音24小时后，在听觉恐惧条件反射训练范例。训练后24小时暴露于重复音调也导致ELS和对照小鼠（雄性和雌性）的冻结行为相当。然而，与对照小鼠相比，雄性（而非雌性）ELS在色调暴露之间（即在提示关闭期间）显示出明显更多的冻结行为。在青春期（出生后第28-30天）腹腔注射GR拮抗剂RU 38486完全防止成年ELS男性在提示关闭期间增强的冻结行为。Western印迹分析显示，ELS对海马糖皮质激素受体的表达没有影响，无论是在出生后第28天，也不是在成年后，当小鼠进行行为测试。我们得出结论，ELS增强冻结行为成年小鼠在一个潜在的安全背景下，线索曝光后，可以正常化的糖皮质激素受体在关键的发育窗口期的青春期短暂封锁。(C)2016 Elsevier Inc. All rights reserved.
Early life adversity can have long-lasting impact on learning and memory processes and increase the risk to develop stress-related psychopathologies later in life. In this study we investigated (i) how chronic early life stress (ELS) - elicited by limited nesting and bedding material from postnatal day 2 to 9- affects conditioned fear in adult mice and (ii) whether these effects can be prevented by blocking glucocorticoid receptors (GRs) at adolescent age. In adult male and female mice, ELS did not affect freezing behavior to the first tone 24 h after training in an auditory fear-conditioning paradigm. Exposure to repeated tones 24 h after training also resulted in comparable freezing behavior in ELS and control mice, both in males and females. However, male (but not female) ELS compared to control mice showed significantly more freezing behavior between the tone-exposures, i.e. during the cue-off periods. Intraperitoneal administration of the GR antagonist RU38486 during adolescence (on postnatal days 28-30) fully prevented enhanced freezing behavior during the cue-off period in adult ELS males. Western blot analysis revealed no effects of ELS on hippocampal expression of glucocorticoid receptors, neither at postnatal day 28 nor at adult age, when mice were behaviorally tested. We conclude that ELS enhances freezing behavior in adult mice in a potentially safe context after cue-exposure, which can be normalized by brief blockade of glucocorticoid receptors during the critical developmental window of adolescence. (C) 2016 Elsevier Inc. All rights reserved.