Role of amygdalostriatal CREB activity in persistent depressive-like behavior

描述(由申请人提供)：本项目的主要目标是在一个长期的应激相关的抑郁症小鼠模型中，表征扩展的杏仁核和伏隔核(NAC)核心中细胞外信号调节蛋白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础，但人们对长期应激--抑郁症的主要风险因素--如何扰乱这些区域的活动以及这些区域和皮质区域之间的联系从而产生与人类抑郁相一致的抑郁样行为知之甚少。拟议的研究应该产生两种类型的信息：第一，对扩展的杏仁核和NAC核心亚区ERK1/2和CREB活性的独立分析(通过Western印迹)将阐明该信号通路在依赖享乐和动机加工的食欲事件中的作用。一个新的，持久的模型，在实验室中发展和行为特征，然后将允许研究细胞内的机制，其中持续的抑郁状态和抗抑郁药物治疗影响扩展杏仁核和NAC核心，以调节享乐驱动和动机的行为。我们假设抑郁样表型的特征将是ERK和CREB活性的调节，这种方式与行为结果共同变化；抗抑郁治疗被假设恢复正常的ERK/CREB活性。最后，病毒介导的局部操纵CREB被假设为以类似于抗抑郁药物的方式恢复暴露于先前皮质醇的抑郁动物的动机反应。每年，9.5%的美国成年人口都会患上抑郁症。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不完全清楚，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物更有效。只有当科学界更充分地了解这种疾病的生物学机制时，医学界才能更好地装备起来，迅速治疗患者的抑郁症。

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.