Role of amygdalostriatal CREB activity in persistent depressive-like behavior

描述（由申请人提供）：本项目的主要目的是表征持久的应激相关抑郁症小鼠模型中延伸杏仁核和延髓核（NAC）核心中细胞外信号调节激酶1/2（ERK）和cAMP反应元件结合蛋白（CREB）活性之间的关系。尽管这些区域长期以来一直被认为是人类情感、情绪、享乐和动机行为的主要基质，但人们对长期压力（抑郁症的主要风险因素）如何破坏这些区域与皮质区域之间的区域活动和连接，从而产生与人类抑郁症一致的抑郁样行为知之甚少。拟议的研究应产生两种类型的信息：第一，独立的ERK 1/2和CREB活性分析（通过蛋白质印迹法）在扩展杏仁核和NAC核心的子区域将阐明依赖于享乐和动机处理的食欲事件中的信号通路的作用。一种新的，持久的抑郁症模型的开发和行为特征的实验室，然后将允许调查的细胞内机制，持续的抑郁样状态和抗抑郁药治疗的影响扩展杏仁核和NAC的核心，以调节快乐驱动和动机的行为。我们假设抑郁样表型的特点是ERK和CREB活性以区域特异性方式调节，与行为结果共同变化;抗抑郁治疗假设恢复正常的ERK/CREB活性。最后，病毒介导的，CREB的局部操作被假设为恢复动机性反应在抑郁症动物暴露于前皮质醇类似的方式抗抑郁药物。每年有9.5%的美国成年人患有抑郁症。抑郁症带来巨大的经济、社会和个人成本;然而，抑郁症损害情绪和动机的方式尚未完全了解，当代抗抑郁药物在治疗抑郁症方面并不比50年前开发的第一代抗抑郁药更有效。只有当科学界更充分地了解疾病的生物学机制时，医学界才能更好地快速治疗抑郁症患者。

DESCRIPTION (provided by applicant): The main objective of this project is to characterize the relationship between Extracellular Signal-Regulated Kinase 1/2 (ERK) and cAMP Response Element-Binding Protein (CREB) activity in the extended amygdala and the nucleus accumbens (NAC) core in a long-lasting, stress-related murine model of depression. Although these regions have long been implicated as major substrates for affective, emotional, hedonic, and motivated behavior in humans, little is known about how long-term stress, a major risk factor for depression, disrupts regional activity and connectivity between these and cortical regions to produce depressive-like behaviors consistent with depression in humans. The proposed studies should yield two types of information: First, independent analyses of ERK1/2 and CREB activity (by Western blot) in the sub-regions of the extended amygdala and NAC core will elucidate the role of the signaling pathway in appetitive events that rely on hedonic and motivated processing. A novel, long-lasting model of depression developed and behaviorally characterized in the laboratory will then allow for the investigation of the intracellular mechanisms by which the persistent depressive-like state and antidepressant treatment influence the extended amygdala and NAC core to regulate hedonically-driven and motivated behaviors. We hypothesize the depressive-like phenotype will be characterized by modulated ERK and CREB activity in a regionally-specific manner that co-varies with behavioral outcomes; antidepressant treatment is hypothesized to restore normal ERK/CREB activity. Finally, viral-mediated, local manipulations of CREB are hypothesized to restore motivated responding in depressive animals exposed to prior CORT in a fashion similar to that of antidepressant drugs. Every year, 9.5% of the adult American population will suffer from a depressive illness. Depression carries immense economic, social, and personal costs; however, the manner in which depression impairs mood and motivation is not entirely understood, and contemporary antidepressant drugs are no more effective in treating depression than were first-generation antidepressants developed 50 years ago. Only when the scientific community more fully understands the biological mechanisms of the disease will the medical community be better equipped to rapidly treat depression in patients.