基于大脑奖赏系统的抑郁症客观诊断与优化治疗的神经机制研究

Major depressive disorder (MDD) is a highly disabling mental disorder. The etiology and pathogenesis of MDD remains unknown, which cause the under-diagnosis and under-treatment in clinical practice. Among numerous clinical manifestations of MDD, anhedonia is a cardinal symptom of MDD, especially in patients with melancholic features. Our recent work and update studies in the world have shown that patients with MDD exhibit reward circuit dysfunction. The abnormalities of reward-related core areas, such as the prefrontal cortex - nucleus accumbens - ventral tegmental area, are closely associated with the development of MDD, and underlie an important neural basis of anhedonia. Therefore, we design this study, aiming to explore the pathology and mechanisms of diagnose and optimized treatment of patients with MDD. We will enroll patients with MDD, experiencing the melancholic features. The controls are the other diagnosis and with reward dysfunction features. The patients will be follow up for 8 weeks treatment with the antidepressants of different actions. The functional connectivity of reward regions, such as the ventral striatum, nucleus accumbens, and ventral medial prefrontal cortex, will be analyzed to identify the dysfunction of reward circuit of MDD. We will explore the interactive effects of environment stresses and genetic susceptibility on the functioning of reward circuits using the neuroimaging techniques, and to find the objective markers which are helpful for the early diagnose, and prediction of treatment efficacy of antidepressants. Finally, through modulating the reward circuit activity in mice, we will verify and further investigate reward dysfunction of MDD and its biological mechanisms. The project will provide new evidence for the establishment of reward mechanism-based objective diagnosis and optimized treatment of MDD.

抑郁症是高致残性精神疾病，其病因和病理机制尚不清楚，且早期识别与诊治存在诸多挑战。抑郁症众多的临床表现中，快感缺失是重要的核心症状，在伴有忧郁性特征的患者中最为突出。本课题组前期工作及国内外研究表明，抑郁症患者存在奖赏环路异常。奖赏相关核心区域如内侧前额叶-伏隔核-腹侧被盖区与抑郁症的发生发展密切相关，是导致快感缺失的神经环路基础。据此，本研究以奖赏环路为主线，开展抑郁症的病因、诊断与治疗干预研究。计划收集忧郁型抑郁症及其他存在奖赏异常表征的人群，结合影像学、应激评估、遗传学检测及药物干预的方法，明确抑郁症奖赏环路的异常并探讨其对抑郁症早期识别、诊断以及抗抑郁药疗效预测的意义，阐释遗传与环境因素对抑郁症奖赏功能的影响及其生物学基础。同时，通过操控小鼠奖赏环路活动，验证临床研究结果并探讨抑郁症奖赏功能异常的生物学机制。本项目预期将为建立基于奖赏机制的抑郁症客观诊断与治疗优化策略提供全新依据。

据2017年WHO数据，全球目前约有抑郁症患者3.22亿，并且持续保持大幅增长，已成为全球导致健康损失的首位疾病和导致自杀的主要原因。抑郁症的病因及病理机制不清，疾病的早期识别与诊治均存在诸多挑战。虽然已有药物或心理治疗可供选择，仍有近50%患者经一线治疗效果不佳，30%患者发展为难治性抑郁症。本课题组前期的研究及国内外研究表明，奖赏环路与抑郁症的发生发展以及治疗机制密切相关。本研究以奖赏环路为主线，开展了抑郁症的病因学、诊断与治疗干预研究。在抑郁症早期预警与诊断方面，通过比较抑郁症发作期、缓解期、抑郁症患者一级亲属及正常对照的fMRI 静息态数据，发现了疾病的状态学标记与可能的素质性特征。在fMRI的任务态分析中发现，抑郁症患者在奖赏消费过程中楔前叶、尾状核、额中回和脑岛出现激活增高。通过采用影像遗传学的分析方法发现，挖掘与奖赏脑区功能连接相关的基因表达模式，发现差异性RNA共同参与核糖体相关基因的表达。在抗抑郁药治疗方法优化研究方面，发现基线时中脑边缘皮层环路的脑功能状态可以预测抗抑郁药度洛西汀治疗的疗效，治疗2周后纹状体亚区与额顶控制网络及皮层调节运动脑区的功能连接改变，可预测度洛西汀治疗8周后的疗效。提取动态脑网络特征，表明前扣带回可作为艾司西酞普兰单药治疗疗效的预测指标。在分子机制研究方面，通过建立抑郁症快感缺失应激动物模型，成功勾画出奖赏环路神经元激活图谱，明确不同作用机制抗抑郁药提升小鼠快感水平的分子环路机制，探明内侧前额叶锥体神经元-小清蛋白阳性神经元微环路介导应激负性效应的机制，揭示CRHR1-nectin3-calbindin-IMPase信号通路参与应激所致抑郁症发病的神经发育机制。本项目为建立基于奖赏机制的抑郁症客观诊断与治疗优化策略提供了全新证据。