不同时期产前应激对大鼠子代行为学及分子生物学的影响
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摘要
目的
本实验通过建立两个不同时期的产前应激大鼠动物模型,观察不同时期产前应激对子代大鼠的行为学、细胞因子白介素18 (interleukin 18, IL-18)及细胞外信号调节激酶(Mitogn activated protein kinase kinase 1, MEK-1)的影响,从而探讨产前应激敏感期及性别效应的病理生理机制,以期为与产前应激相关的疾病的发病机制的研究提供依据。
方法
将SD妊娠大鼠随机分成3组,对照组在妊娠期间不给予任何刺激；中期应激组在从妊娠第9-14天给予束缚刺激；晚期妊娠组从妊娠第15-20天给予束缚刺激。待子代出生后第21天断奶并将雌雄大鼠分笼饲养。子代成年后即出生后第75天分别进行敞箱实验、新事物实验、蔗糖喜爱实验、前脉冲抑制及惊恐反射实验和强迫游泳实验5种行为学测试及检测大鼠海马的IL-18和MEK-1。
结果
一.行为学实验结果：
1.敞箱实验：结果显示与对照组雄性子代相比孕晚期产前刺激雄性子代的敞箱总路程减少(p<0.05),中央区域总路程减少(p<0.05),中央区域停留时间减少(p<0.01)。
2.新事物实验：结果显示与对照组雄性子代接触新事物的时间相比孕中期产期应激组雄性子代(p<0.01)及孕晚期产期应激组雄性子代(p<0.05)均减少。
3.糖水消耗实验：结果显示与对照组雄性子代相比孕中期产前应激组雄性子代平均体重糖水消耗量降低(p<0.05)。
4.前脉冲及惊恐抑制实验：结果显示在前脉冲抑制反应中孕中期产前应激组子代与对照组子代相比反应减低(p<0.05)；在惊恐反应孕晚期产前应激子代与对照组子代相比反应增高(p<0.01)。
5.强迫游泳实验：结果显示与对照组子代相比孕晚期的产前应激组雌子代(p<0.05)和雄性子代(p<0.01)的“绝望”行为增加,而孕中期产前应激组仅雄性子代大鼠“绝望”行为增加(p<0.05)。
二.背侧海马和腹侧海马的IL-18含量及MEK-1阳性细胞检测结果：
1.IL-18结果显示与对照组相比孕晚期产前应激可导致雌性子代的腹侧海马IL-18含量增加(p<0.05),而孕中期产前应激对子代海马IL-18含量的无影响(p>0.05)。
2.MEK-1阳性细胞结果显示与对照组相比孕晚期可以导致背侧海马MEK-1的表达增加(p<0.01)及腹侧海马MEK-1的表达下降(p<0.05),而孕中期对海马的MEK-1的表达无影响(p>0.05)。
结论
1.孕中期和孕晚期产期应激均可导致子代行为学的改变,但孕晚期产前应激对子代行为学的影响更多。
2.不同性别的产前应激子代大鼠行为学改变存在差异,产前应激对雄性子代的影响高于对雌性子代的影响。
3.孕晚期产前应激可导致子代大鼠海马的炎性因子IL-18分泌增加及MEK-1信号蛋白表达异常。
4.腹侧和背侧海马的“功能分离”可能与MEK-1信号蛋白的表达及其相关的丝裂原活化蛋白激酶(Mitogen-activated protein kinases, MAPKs)信号传导途径有关。
5.IL-18可能参与MEK-1信号蛋白的表达的调控。
Aims:
In this study, through established two different periods prenatal stress rat model to observe two different pregnancy stress periods affect on offspring's behavior, interleukin-18 and extracellular signal-regulated kinase MEK-1. The purpose of this study is to explore the pathophysiological mechanisms of sensitive period of prenatal stress and gender effect and to provide the evidence for the diseases which associated with prenatal stress.
Methods:
The SD pregnant rats were randomly divided into 3 groups, the control group was left undisturbed throughout the pregnancy, the mid pregnancy stress group was gave restraint stress from GD 9-14 day and the late pregnancy group from GD15-20. Offspring were weaned 21 days after birth and left undisturbed until the behavior test at 75 day. The behavior tests including open field test, novel object test, sucrose preference test, prepulse inhibition test and forced swimming test. After that the IL-18 and the MEK-1 of hippocampus were been tested.
Results:
The behavior tests result:
1.Open field test:The result showed that compare to the control male offspring the later prenatal stress group male offspring reduced in total distance (p<0.05), the central total distance (p<0.05) and the central duration time (p<0.01)
2.Novel object test:The result showed that compared to the control male offspring both mid prenatal stress group (p<0.01) and later prenatal stress groups (p<0.05) were reduce in the time spent on the novel object.
3.Sucrose preference test:The result showed that compare to the control male offspring the mid prenatal stress male offspring had lower average weight of sugar consumption (p<0.05)
4. Prepulse inhibition test:The result showed that in the prepulse inhibition reactivity the mid prenatal stress offspring had lower reaction than control group offspring (p<0.05); in the startle reactivity the later prenatal stress offspring had higher reaction than control group offspring (p<0.01)
5.Forced swimming test:The result showed that compare to the control group offspring the later prenatal stress female offspring (p<0.05) and male offspring (p<0.01) were increased the "depression" behavior and mid prenatal stress group just male offspring increased the "depression" behavior (p<0.05)
The IL-18 and MEK-1 result:
1.The IL-18 result showed that the later prenatal stress could lead female offspring ventral hippocampus of IL-18 to increase (p<0.05),while no affected on mid prenatal stress's offspring (p>0.05)
2.MEK-1 result showed that the later prenatal stress could lead dorsal hippocampus to increase (p<0.01) and ventral hippocampus to reduce (p<0.05), while no affected on mid prenatal stress's offspring (p>0.05)
Conclusion:
1.Both mid prenatal stress and later prenatal stress could change offspring behavior and later prenatal stress could lead more behavior change than mid prenatal stress.
2.There was different behavior change between different gender offspring and the prenatal stress could lead more behavior change in male than female offspring.
3.The later prenatal stress could lead IL-18 to increase and MEK-1 abnormal express in hippocampus.
4.The dorsal and ventral hippocampus "function separate" may related to the MEK-1 signaling relation protein and MAPKs signal transduction pathway.
5.IL-18 may involved in regulate the MEK-1 signaling expression.
本实验通过建立两个不同时期的产前应激大鼠动物模型,观察不同时期产前应激对子代大鼠的行为学、细胞因子白介素18 (interleukin 18, IL-18)及细胞外信号调节激酶(Mitogn activated protein kinase kinase 1, MEK-1)的影响,从而探讨产前应激敏感期及性别效应的病理生理机制,以期为与产前应激相关的疾病的发病机制的研究提供依据。
方法
将SD妊娠大鼠随机分成3组,对照组在妊娠期间不给予任何刺激；中期应激组在从妊娠第9-14天给予束缚刺激；晚期妊娠组从妊娠第15-20天给予束缚刺激。待子代出生后第21天断奶并将雌雄大鼠分笼饲养。子代成年后即出生后第75天分别进行敞箱实验、新事物实验、蔗糖喜爱实验、前脉冲抑制及惊恐反射实验和强迫游泳实验5种行为学测试及检测大鼠海马的IL-18和MEK-1。
结果
一.行为学实验结果：
1.敞箱实验：结果显示与对照组雄性子代相比孕晚期产前刺激雄性子代的敞箱总路程减少(p<0.05),中央区域总路程减少(p<0.05),中央区域停留时间减少(p<0.01)。
2.新事物实验：结果显示与对照组雄性子代接触新事物的时间相比孕中期产期应激组雄性子代(p<0.01)及孕晚期产期应激组雄性子代(p<0.05)均减少。
3.糖水消耗实验：结果显示与对照组雄性子代相比孕中期产前应激组雄性子代平均体重糖水消耗量降低(p<0.05)。
4.前脉冲及惊恐抑制实验：结果显示在前脉冲抑制反应中孕中期产前应激组子代与对照组子代相比反应减低(p<0.05)；在惊恐反应孕晚期产前应激子代与对照组子代相比反应增高(p<0.01)。
5.强迫游泳实验：结果显示与对照组子代相比孕晚期的产前应激组雌子代(p<0.05)和雄性子代(p<0.01)的“绝望”行为增加,而孕中期产前应激组仅雄性子代大鼠“绝望”行为增加(p<0.05)。
二.背侧海马和腹侧海马的IL-18含量及MEK-1阳性细胞检测结果：
1.IL-18结果显示与对照组相比孕晚期产前应激可导致雌性子代的腹侧海马IL-18含量增加(p<0.05),而孕中期产前应激对子代海马IL-18含量的无影响(p>0.05)。
2.MEK-1阳性细胞结果显示与对照组相比孕晚期可以导致背侧海马MEK-1的表达增加(p<0.01)及腹侧海马MEK-1的表达下降(p<0.05),而孕中期对海马的MEK-1的表达无影响(p>0.05)。
结论
1.孕中期和孕晚期产期应激均可导致子代行为学的改变,但孕晚期产前应激对子代行为学的影响更多。
2.不同性别的产前应激子代大鼠行为学改变存在差异,产前应激对雄性子代的影响高于对雌性子代的影响。
3.孕晚期产前应激可导致子代大鼠海马的炎性因子IL-18分泌增加及MEK-1信号蛋白表达异常。
4.腹侧和背侧海马的“功能分离”可能与MEK-1信号蛋白的表达及其相关的丝裂原活化蛋白激酶(Mitogen-activated protein kinases, MAPKs)信号传导途径有关。
5.IL-18可能参与MEK-1信号蛋白的表达的调控。
Aims:
In this study, through established two different periods prenatal stress rat model to observe two different pregnancy stress periods affect on offspring's behavior, interleukin-18 and extracellular signal-regulated kinase MEK-1. The purpose of this study is to explore the pathophysiological mechanisms of sensitive period of prenatal stress and gender effect and to provide the evidence for the diseases which associated with prenatal stress.
Methods:
The SD pregnant rats were randomly divided into 3 groups, the control group was left undisturbed throughout the pregnancy, the mid pregnancy stress group was gave restraint stress from GD 9-14 day and the late pregnancy group from GD15-20. Offspring were weaned 21 days after birth and left undisturbed until the behavior test at 75 day. The behavior tests including open field test, novel object test, sucrose preference test, prepulse inhibition test and forced swimming test. After that the IL-18 and the MEK-1 of hippocampus were been tested.
Results:
The behavior tests result:
1.Open field test:The result showed that compare to the control male offspring the later prenatal stress group male offspring reduced in total distance (p<0.05), the central total distance (p<0.05) and the central duration time (p<0.01)
2.Novel object test:The result showed that compared to the control male offspring both mid prenatal stress group (p<0.01) and later prenatal stress groups (p<0.05) were reduce in the time spent on the novel object.
3.Sucrose preference test:The result showed that compare to the control male offspring the mid prenatal stress male offspring had lower average weight of sugar consumption (p<0.05)
4. Prepulse inhibition test:The result showed that in the prepulse inhibition reactivity the mid prenatal stress offspring had lower reaction than control group offspring (p<0.05); in the startle reactivity the later prenatal stress offspring had higher reaction than control group offspring (p<0.01)
5.Forced swimming test:The result showed that compare to the control group offspring the later prenatal stress female offspring (p<0.05) and male offspring (p<0.01) were increased the "depression" behavior and mid prenatal stress group just male offspring increased the "depression" behavior (p<0.05)
The IL-18 and MEK-1 result:
1.The IL-18 result showed that the later prenatal stress could lead female offspring ventral hippocampus of IL-18 to increase (p<0.05),while no affected on mid prenatal stress's offspring (p>0.05)
2.MEK-1 result showed that the later prenatal stress could lead dorsal hippocampus to increase (p<0.01) and ventral hippocampus to reduce (p<0.05), while no affected on mid prenatal stress's offspring (p>0.05)
Conclusion:
1.Both mid prenatal stress and later prenatal stress could change offspring behavior and later prenatal stress could lead more behavior change than mid prenatal stress.
2.There was different behavior change between different gender offspring and the prenatal stress could lead more behavior change in male than female offspring.
3.The later prenatal stress could lead IL-18 to increase and MEK-1 abnormal express in hippocampus.
4.The dorsal and ventral hippocampus "function separate" may related to the MEK-1 signaling relation protein and MAPKs signal transduction pathway.
5.IL-18 may involved in regulate the MEK-1 signaling expression.
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