Understanding Neural Circuits that Control Resistance to Social Stress

了解控制社会压力抵抗力的神经回路

• 批准号: 8586561
• 负责人: Matthew A Cooper
• 金额: $ 14.29万
• 依托单位: UNIVERSITY OF TENNESSEE KNOXVILLE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-01 至 2015-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8586561
• 关键词: Affective; Aggressive behavior; Amygdaloid structure; Animal Model; Animals; Anxiety Disorders; Behavior; Brain region; Brain-Derived Neurotrophic Factor; Buffers; Cells; Cholera Toxin; Development; Etiology; Exposure to; Extinction (Psychology); FOS gene; Fright; Future; Genetic; Glutamates; Hamsters; Individual; Interneurons; Label; Lead; Learned Helplessness; Link; Medial; Mediating; Memory; Mental disorders; Mesocricetus auratus; Modeling; Mood Disorders; Neuronal Plasticity; Output; Play; Post-Traumatic Stress Disorders; Prefrontal Cortex; Process; Pyramidal Cells; Research; Resistance; Role; Signal Transduction; Social status; Stress; Stressful Event; Testing; Time; Tracer; Training; cell cortex; coping; experience; improved; interest; mRNA Expression; neural circuit; neuromechanism; prevent; public health relevance; relating to nervous system; research study; response; social; social stress; stress resilience; stressor

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.

描述（由申请人提供）：暴露于压力事件是多种情感障碍（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的人都会患上与压力相关的精神疾病，人们对是什么使一些人变得脆弱而另一些人具有恢复能力非常感兴趣。在本提案中，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力的机制。在我们的动物模型中，社会失败导致物种典型的领土攻击性完全丧失，并且当个体随后与非攻击性入侵者进行测试时，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已建立支配关系的个体，发现与下属和对照组相比，占主导地位的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，主导的社会地位与对失败引起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，在社交失败后，占主导地位的动物在边缘下皮层 (ILC) 中的 c-Fos 表达增加。这些结果表明，优势动物对条件性失败的抵抗力与社交失败训练期间 ILC 中的神经激活有关。有趣的是，ILC 中的神经活动与压力恢复能力有关，并且被认为通过抑制基底外侧杏仁核 (BLA) 来调节情感处理。在本提案中，我们将测试一个总体假设，即社交失败期间 ILC 中的神经活动会破坏 BLA 内的神经可塑性，从而损害优势仓鼠条件性失败的发展。具体来说，我们将测试三个预测。首先，我们将测试这样的预测：在社交失败之前对 ILC 进行药物失活只会增加优势动物的 CD 并增加 BLA 中失败诱导的 BDNF mRNA 表达。其次，我们将逆行示踪剂霍乱毒素 B (CTB) 注射到 BLA 中，并测试以下预测：与下级仓鼠和对照组相比，在社交失败后，优势仓鼠将显示出 c-Fos 和 CTB 双标记 ILC 细胞比例增加。第三，我们将通过测试预测来研究CD抵抗的时间过程，即只有在经历了14天而不是1或7天的统治遭遇后，与下属相比，占主导地位的仓鼠在社交失败后才会表现出CD减少和ILC中的神经激活增加。