Chen Mo-Xian, Liu Qiang, Cheng Shu, Lei Lei, Lin Ai-Jin, Wei Ran, K Hui Tomy C, Li Qi, Ao Li-Juan, Sham Pak C
School of Rehabilitation, Kunming Medical University, Kunming, Yunnan Province, China.
Department of Surgery, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.
Neural Regen Res. 2020 Sep;15(9):1748-1756. doi: 10.4103/1673-5374.276358.
Exposure to maternal stress during prenatal life is associated with an increased risk of neuropsychiatric disorders, such as depression and anxiety, in offspring. It has also been increasingly observed that prenatal stress alters the phenotype of offspring via immunological mechanisms and that immunological dysfunction, such as elevated interleukin-18 levels, has been reported in cultures of microglia. Prenatal restraint stress (PRS) in rats permits direct experimental investigation of the link between prenatal stress and adverse outcomes. However, the majority of studies have focused on the consequences of PRS delivered in the second half of pregnancy, while the effects of early prenatal stress have rarely been examined. Therefore, pregnant rats were subjected to PRS during early/middle and late gestation (days 8-14 and 15-21, respectively). PRS comprised restraint in a round plastic transparent cylinder under bright light (6500 lx) three times per day for 45 minutes. Differences in interleukin-18 expression in the hippocampus and in behavior were compared between offspring rats and control rats on postnatal day 75. We found that adult male offspring exposed to PRS during their late prenatal periods had higher levels of anxiety-related behavior and depression than control rats, and both male and female offspring exhibited higher levels of depression-related behavior, impaired recognition memory and diminished exploration of novel objects. Moreover, an elevated level of interleukin-18 was observed in the dorsal and ventral hippocampus of male and female early- and late-PRS offspring rats. The results indicate that PRS can cause anxiety and depression-related behaviors in adult offspring and affect the expression of interleukin-18 in the hippocampus. Thus, behavior and the molecular biology of the brain are affected by the timing of PRS exposure and the sex of the offspring. All experiments were approved by the Animal Experimentation Ethics Committee at Kunming Medical University, China (approval No. KMMU2019074) in January 2019.
孕期暴露于母体应激与后代患神经精神疾病（如抑郁症和焦虑症）的风险增加有关。越来越多的研究还发现，产前应激通过免疫机制改变后代的表型，并且在小胶质细胞培养物中已报道存在免疫功能障碍，如白细胞介素-18水平升高。大鼠的产前束缚应激（PRS）使得能够直接通过实验研究产前应激与不良后果之间的联系。然而，大多数研究集中于妊娠后半期施加的PRS的后果，而早期产前应激的影响很少被研究。因此，将妊娠大鼠在妊娠早期/中期和晚期（分别为第8 - 14天和第15 - 21天）进行PRS处理。PRS包括每天在明亮光线（6500勒克斯）下将大鼠置于圆形塑料透明圆筒中束缚3次，每次45分钟。在出生后第75天，比较后代大鼠和对照大鼠海马中白细胞介素-18表达及行为的差异。我们发现，产前晚期暴露于PRS的成年雄性后代比对照大鼠具有更高水平的焦虑相关行为和抑郁，并且雄性和雌性后代均表现出更高水平的抑郁相关行为、识别记忆受损和对新物体的探索减少。此外，在雄性和雌性早期及晚期PRS后代大鼠的背侧和腹侧海马中观察到白细胞介素-18水平升高。结果表明，PRS可导致成年后代出现焦虑和抑郁相关行为，并影响海马中白细胞介素-18的表达。因此，行为和大脑分子生物学受PRS暴露时间和后代性别的影响。所有实验于2019年1月获得中国昆明医科大学动物实验伦理委员会批准（批准号：KMMU2019074）。
