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: 8445753
• 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 2014-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8445753
• 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）：暴露于压力事件是几种情感障碍（包括创伤后应激障碍）病因的关键因素。重要的是，不是 所有暴露于压力事件的人都会出现与压力相关的精神疾病，并且对某些人脆弱和其他人有弹性的原因引起了极大的兴趣。在此提案中，我们将使用叙利亚仓鼠中的社会失败模式调查控制对社会压力的抵抗的机制，称为有条件失败。在我们的动物模型中，社交失败导致物种典型的领土侵略彻底丧失，并在以后用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，我们测试了在条件失败模型中具有建立优势关系的个体，发现与下属和对照相比，在测试时，主动性动物在测试时表现出较少的服从和防御行为。这些结果表明，主要的社会地位与对失败引起的行为变化的发展有关。同样，我们最近发现，与下属相比，社交失败后的占C-FOS表达增加了C-FOS的表达。这些结果表明，在社交失败训练期间，ILC的神经激活在统治动物中的有条件失败的抵抗力。有趣的是，ILC中的Neura活性与压力弹性有关，被认为可以通过抑制基底外侧杏仁核（BLA）来调节情感处理。在该提案中，我们将检验以下总体假设：社交失败期间ILC中的神经活动破坏了BLA内的神经可塑性，从而损害了占主导地位的仓鼠中有条件失败的发展。具体来说，我们将测试三个预测。首先，我们将测试以下预测：在社交失败之前对ILC的药理灭活将增加CD并增加失败诱导的BLA在BLA中仅在主要动物中的BLA表达。其次，我们将向BLA注入逆行示踪性霍乱毒素B（CTB），并测试与下属失败相比，在社交失败后，主要的仓鼠在CTB和CTB上显示出比例增加的ILC细胞的比例增加。第三，我们将通过测试以这样的预测来研究CD阻力的时间过程，即在社交​​失败后，与下属相比，在社交失败后，主要的CD和神经激活增加了，仅在他们经历了14天而不是1或7天的统治力遭遇之后。