Prenatal hypoxia induced by transient intrauterine ischemia is a serious clinical problem, and at present, effective treatments are lacking. Currently, it is unknown how prenatal hypoxia affects behaviors in adulthood. Therefore, we developed a mouse model that mimics prenatal hypoxia in humans using uterine artery occlusion in late gestation. We examined whether prenatal hypoxia induces behavioral changes in adult male and female offspring by conducting a series of behavioral tests. In adulthood, longer immobility was observed in the forced swim test in males, whereas females showed decreased inhibition in the prepulse inhibition test. We then investigated the effects of two different selective serotonin reuptake inhibitors (SSRIs), fluoxetine (FLX) and escitalopram (ESC), on these behavioral changes. These drugs affect the neurodevelopmental process and have long-term neurological consequences. FLX treatment from postnatal day 3 (P3) to P21 ameliorated the behavioral changes in both male and female mice. In comparison, ESC treatment ameliorated the behavioral changes only in female mice. Neurochemical analysis revealed that dopamine was increased in the female hippocampus, but not in males. Thus, neonatal SSRI treatment decreases dopamine levels in the hippocampus in females selectively. Our findings suggest that prenatal hypoxia is a risk factor for behavioral abnormalities in adulthood, and that neonatal SSRI treatment might have clinical potential for alleviating these long-term behavioral deficits.

译文

短暂性宫内缺血引起的产前缺氧是一个严重的临床问题,目前缺乏有效的治疗方法。目前,尚不清楚产前缺氧如何影响成年后的行为。因此,我们开发了一种小鼠模型,该模型在妊娠后期使用子宫动脉闭塞来模拟人类的产前缺氧。我们通过进行一系列行为测试,检查了产前缺氧是否会引起成年雄性和雌性后代的行为变化。成年后,男性在强迫游泳测试中观察到较长的不动,而女性在脉冲前抑制测试中表现出抑制作用降低。然后,我们研究了两种不同的选择性5-羟色胺再摄取抑制剂 (SSRIs) 氟西汀 (FLX) 和艾司西酞普兰 (ESC) 对这些行为变化的影响。这些药物会影响神经发育过程,并具有长期的神经后果。从出生后第3天 (P3) 到P21的FLX治疗改善了雄性和雌性小鼠的行为变化。相比之下,ESC治疗仅改善了雌性小鼠的行为变化。神经化学分析显示,多巴胺在雌性海马中增加,但在雄性中却没有。因此,新生儿SSRI治疗选择性地降低了女性海马中的多巴胺水平。我们的发现表明,产前缺氧是成年期行为异常的危险因素,新生儿SSRI治疗可能具有缓解这些长期行为缺陷的临床潜力。

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