Understanding Neural Circuits that Control Resistance to Social Stress

描述（由申请人提供）：暴露于压力事件是几种情感障碍（包括创伤后应激障碍）病因学的关键因素。重要的是，不 所有暴露于压力事件中的个体都会发展出与压力相关的精神疾病，人们对是什么使一些个体易受伤害而另一些个体具有弹性产生了相当大的兴趣。在这项提案中，我们将调查机制控制社会压力的抵抗力使用社会失败模型在叙利亚仓鼠，称为条件性失败。在我们的动物模型中，当个体后来与非攻击性入侵者进行测试时，社会失败导致物种典型的领土攻击性完全丧失，顺从和防御行为大幅增加。最近，我们在条件性失败模型中测试了具有既定优势关系的个体，发现与下属和对照组相比，优势动物在测试中表现出较少的顺从和防御行为。这些结果表明，占主导地位的社会地位与阻力的发展失败引起的行为变化。此外，我们最近发现，占主导地位的动物表现出增加c-Fos表达的边缘皮层（ILC）后，社会失败相比，下属。这些结果表明，在优势动物的条件性失败的阻力与在社会失败训练过程中的ILC的神经激活。有趣的是，ILC中的神经元活动与压力恢复有关，并被认为通过抑制基底外侧杏仁核（BLA）来调节情感处理。在这个建议中，我们将测试的总体假设，在ILC的神经活动在社会失败破坏BLA内的神经可塑性，从而损害了条件性失败的发展占主导地位的仓鼠。具体来说，我们将测试三个预测。首先，我们将测试的预测，药理学失活的ILC之前，社会失败将增加CD和增加失败诱导的BDNF mRNA表达的BLA在占主导地位的动物。第二，我们将逆行示踪剂霍乱毒素B（CTB）注入BLA，并测试预测，占主导地位的仓鼠将显示出增加的比例ILC细胞双标记的c-Fos和CTB相比，社会失败。第三，我们将调查的CD阻力的时间过程中，测试的预测，占主导地位的仓鼠将显示减少CD和增加的神经激活的ILC后，社会失败相比，下属只有在他们经历了14天，而不是1天或7天，优势遭遇。

DESCRIPTION (provided by applicant): Exposure to stressful events is a key factor in the etiology of several affective disorders, including post-traumatic stress disorder. Importantly, not all individuals exposed to stressful events develop stress- related mental illness, and there is considerable interest in what makes some individuals vulnerable and others resilient. In this proposal, we will investigate the mechanisms controlling resistance to social stress using a social defeat model in Syrian hamsters, called conditioned defeat. In our animal model, social defeat results in a complete loss of species-typical territorial aggression and a substantial increase in submissive and defensive behavior when individuals are later tested with a non-aggressive intruder. Recently, we tested individuals with established dominance relationships in our conditioned defeat model and found that dominant animals showed less submissive and defensive behavior at testing compared to subordinates and controls. These results suggest that the dominant social status is associated with resistance to the development of defeat-induced changes in behavior. Also, we have recently found that dominant animals show increased c-Fos expression in the infralimbic cortex (ILC) after social defeat compared to subordinates. These results suggest that resistance to conditioned defeat in dominant animals is associated with neural activation in the ILC during social defeat training. Interestingly, neura activity in the ILC has been linked to stress resilience and is thought to regulate affective processing by inhibiting the basolateral amygdala (BLA). In this proposal we will test the overarching hypothesis that neural activity in the ILC during social defeat disrupts neural plasticity within the BLA and thereby impairs the development of conditioned defeat in dominant hamsters. Specifically, we will test three predictions. First, we will test the prediction that pharmacological inactivation of the ILC prior to social defeat will increase CD and increase defeat-induced BDNF mRNA expression in the BLA in dominant animals only. Second, we will inject the retrograde tracer Cholera Toxin B (CTB) into the BLA and test the prediction that dominant hamsters will show an increased proportion of ILC cells double-labeled for c-Fos and CTB following social defeat compared to subordinates and controls. Third, we will investigate the time course of CD resistance by testing the prediction that dominant hamsters will show reduced CD and increased neural activation in the ILC following social defeat compared to subordinates only after they experience 14 days, and not 1 or 7 days, of dominance encounters.