Department of Psychology, Marquette University, Milwaukee, WI 53201, United States.
Neurobiol Learn Mem. 2010 Sep;94(2):254-62. doi: 10.1016/j.nlm.2010.06.003. Epub 2010 Jun 19.
In three experiments, chronic stress enhancement of subsequent fear learning was investigated in C57Bl/6 mice. The first experiment focused on the influence of stressor type on subsequent Pavlovian fear learning. Male mice were subjected to 7d of either repeated restraint stress or chronic variable stress before undergoing a fear conditioning procedure with three tone-shock trials. Subsequent tests were conducted of contextual and tone fear, through measures of the freezing response. Repeated restraint altered pre-training activity and the unconditional response to shock, but was ineffective in influencing conditional fear. Chronic variable stress significantly inflated contextual fear without altering tone fear. In a second experiment, investigating potential sex differences in the fear-enhancing effects of stress, female mice were subjected to the very same procedures. Among females, chronic variable stress selectively altered tone fear, rather than contextual fear. A final experiment investigated the potential role of ovarian hormones by subjecting female mice to either ovariectomy or sham surgery before the stress procedures. Ovariectomy had no significant effect on the ability of stress to enhance fear in females. In sum, the experiments indicate that stressor type significantly influences subsequent fear learning, that males and females are differentially sensitive to fear enhancement by stress, and that the mechanisms mediating these sex differences lie outside of the immediate influence of ovarian hormones. The findings should allow for refinement of animal models of human psychiatric disorders and for further investigations into the genetic and molecular substrates of significant gender differences in fear and anxiety.
在三项实验中，研究了慢性应激增强 C57Bl/6 小鼠随后的恐惧学习。第一项实验侧重于应激类型对随后的巴甫洛夫恐惧学习的影响。雄性小鼠接受 7 天的重复束缚应激或慢性可变应激，然后进行三次音调-电击试验的恐惧条件反射程序。通过冻结反应的测量，进行了上下文和音调恐惧的后续测试。重复束缚改变了预训练活动和对电击的无条件反应，但对条件恐惧没有影响。慢性可变应激显著增加了上下文恐惧，而不改变音调恐惧。在第二项实验中，研究了应激对恐惧增强作用的潜在性别差异，雌性小鼠接受了完全相同的程序。在雌性中，慢性可变应激选择性地改变了音调恐惧，而不是上下文恐惧。最后一项实验通过在应激程序之前对雌性小鼠进行卵巢切除术或假手术，研究了卵巢激素的潜在作用。卵巢切除术对应激增强雌性恐惧的能力没有显著影响。总之，这些实验表明，应激类型显著影响随后的恐惧学习，雄性和雌性对应激引起的恐惧增强的敏感性不同，介导这些性别差异的机制不在卵巢激素的直接影响范围内。这些发现应该能够完善人类精神疾病的动物模型，并进一步研究恐惧和焦虑方面显著性别差异的遗传和分子基础。
