Department of Obstetrics and Gynecology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan.
Department of Pharmacology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan.
Neuroscience. 2017 Sep 30;360:95-105. doi: 10.1016/j.neuroscience.2017.07.051. Epub 2017 Aug 1.
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.
宫内暂时性局部缺血导致的胎儿缺氧是一个严重的临床问题，目前缺乏有效的治疗方法。目前尚不清楚胎儿缺氧如何影响成年后的行为。因此，我们使用胎鼠子宫动脉结扎法建立了一个模拟人类胎儿缺氧的小鼠模型。我们通过一系列行为学测试来检测宫内缺氧是否会引起成年雄性和雌性后代的行为变化。在成年期，雄性在强迫游泳试验中表现出更长的不动时间，而雌性在预脉冲抑制试验中表现出抑制减少。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。这些药物影响神经发育过程，并具有长期的神经学后果。从出生后第 3 天（P3）到 P21 开始，FLX 治疗改善了雌雄小鼠的行为变化。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，雌性小鼠海马中的多巴胺增加，但雄性小鼠没有。因此，新生儿 SSRI 治疗选择性地降低了雌性小鼠海马中的多巴胺水平。我们的研究结果表明，胎儿缺氧是成年后行为异常的一个危险因素，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。
