Developmental fluoxetine exposure increases behavioral despair and alters epigenetic regulation of the hippocampal BDNF gene in adult female offspring
Developmental fluoxetine exposure increases behavioral despair and alters epigenetic regulation of the hippocampal BDNF gene in adult female offspring
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DOI：
10.1016/j.yhbeh.2016.01.017
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发表时间：
2016-04-01
影响因子：
3.5
通讯作者：
van den Hove, Daniel L. A.
中科院分区：
文献类型：
--
作者：
Boulle, Fabien;Pawluski, Jodi L.;van den Hove, Daniel L. A.
越来越多的婴儿在围产期接触选择性5-羟色胺再摄取抑制剂（SSRI）药物。围产期暴露于SSRI药物会改变神经可塑性并增加抑郁和焦虑相关行为，特别是在男性后代中，因为迄今为止在女性后代中几乎没有做过工作。SSRI对发育的长期影响也可能与先前暴露于产前压力（一种母体抑郁模型）不同。由于对发育性SSRI暴露对雌性后代神经行为结局的作用的研究有限，本研究的目的是研究发育性氟西汀暴露如何影响成年雌性后代的焦虑和抑郁样行为，以及海马脑源性神经营养因子（BDNF）信号转导的调节。为此，将雌性Sprague-Dawley大鼠后代通过母体暴露于产前应激和氟西汀，总共四组雌性后代：1）无应激+媒介物，2）无应激+氟西汀，3）产前应激+媒介物，和4）产前应激+氟西汀。初步结果表明，在成年雌性后代，发展SSRI曝光显着增加行为绝望措施强迫游泳测试，降低海马BDNF外显子IV mRNA水平，并增加水平的抑制性组蛋白3赖氨酸27三甲基化标记在相应的启动子。在强迫游泳实验中，海马BDNF外显子IV mRNA水平与不动性呈显著负相关。在焦虑样行为测试中未观察到产前压力或发育期氟西汀暴露的影响。这项研究为早期生活暴露于SSRIs对雌性后代的长期编程影响提供了重要证据，特别是关于影响相关行为及其潜在的分子机制。(C)2016 Elsevier Inc. All rights reserved.
A growing number of infants are exposed to selective serotonin reuptake inhibitor (SSRI) medications during the perinatal period. Perinatal exposure to SSRI medications alter neuroplasticity and increase depressive- and anxiety-related behaviors, particularly in male offspring as little work has been done in female offspring to date. The long-term effects of SSRI on development can also differ with previous exposure to prenatal stress, a model of maternal depression. Because of the limited work done on the role of developmental SSRI exposure on neurobehavioral outcomes in female offspring, the aim of the present study was to investigate how developmental fluoxetine exposure affects anxiety and depression-like behavior, as well as the regulation of hippocampal brain-derived neurotrophic factor (BDNF) signaling in the hippocampus of adult female offspring. To do this female Sprague-Dawley rat offspring were exposed to prenatal stress and fluoxetine via the dam, for a total of four groups of female offspring: 1) No Stress + Vehicle, 2) No Stress + Fluoxetine, 3) Prenatal Stress + Vehicle, and 4) Prenatal Stress + Fluoxetine. Primary results show that, in adult female offspring, developmental SSRI exposure significantly increases behavioral despair measures on the forced swim test, decreases hippocampal BDNF exon IV mRNA levels, and increases levels of the repressive histone 3 lysine 27 trimethylated mark at the corresponding promoter. There was also a significant negative correlation between hippocampal BDNF exon IV mRNA levels and immobility in the forced swim test. No effects of prenatal stress or developmental fluoxetine exposure were seen on tests of anxiety-like behavior. This research provides important evidence for the long-term programming effects of early-life exposure to SSRIs on female offspring, particularily with regard to affect-related behaviors and their underlying molecular mechanisms. (C) 2016 Elsevier Inc. All rights reserved.