Understanding Neural Circuits that Control Resistance to Social Stress

描述(由申请人提供)：暴露在应激事件中是几种情感障碍的病因中的一个关键因素，包括创伤后应激障碍。重要的是，不是 所有暴露在应激事件中的人都会患上与压力有关的精神疾病，人们对是什么让一些人变得脆弱，另一些人变得有弹性有相当大的兴趣。在这项提议中，我们将使用叙利亚仓鼠的社会失败模型(称为条件性失败)来研究控制对社会压力的抵抗的机制。在我们的动物模型中，社会失败会导致物种的完全丧失--典型的领土攻击，以及当个体后来与非侵略性入侵者进行测试时，顺从和防御行为的大幅增加。最近，我们在我们的条件性失败模型中测试了建立了优势关系的个体，发现在测试中，优势动物比从属动物和对照动物表现出更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对失败导致的行为变化的发展的抵制有关。此外，我们最近发现，与从属动物相比，优势动物在社交失败后，其下缘皮质(ILC)中c-Fos的表达增加。这些结果表明，优势动物对条件性失败的抵抗与社会失败训练中ILC的神经激活有关。有趣的是，ILC中的NeuRA活性与应激恢复能力有关，并被认为通过抑制杏仁基底外侧核(BLA)来调节情感处理。在这项提议中，我们将测试最重要的假设，即社交失败期间ILC中的神经活动破坏了BLA内的神经可塑性，从而损害了优势仓鼠的条件性失败的发展。具体地说，我们将测试三个预测。首先，我们将检验这一预测，即在社会失败之前，ILC的药物失活将增加CD，并仅在优势动物中增加失败诱导的BLA中BDNF mRNA的表达。其次，我们将向BLA注入逆行示踪剂霍乱毒素B(CTB)，并测试以下预测：与从属仓鼠和对照组相比，优势仓鼠在社交失败后，ILC细胞中c-Fos和CTB双标的比例将增加。第三，我们将通过测试以下预测来研究CD抗性的时间进程：与经历14天而不是1或7天的优势遭遇后的从属仓鼠相比，在社交失败后，优势仓鼠的ILC中CD减少而神经激活增加。

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.