Neuroimaging Studies of Reward Processing in Depression

严重抑郁障碍(MDD)仍然是一个主要的公共卫生问题，人们对其了解很少 病因学和病理生理学。奖赏加工障碍和快感缺乏是 MDD。前一次获奖期间的研究结果表明，MDD和无享乐表型是 以皮质纹状体内的功能、结构和分子异常为特征 评估电路在价值编码和强化学习中具有重要意义。主要目标是 此次R37更新的目的是在几个基本的新方向上扩展这项工作，以(1) 通过关注一个新的目标，更好地从机制上理解MDD和快感缺失- Niciceptin/Orphanin FQ受体--预计会导致与以下相关的分子异常 皮质纹状体评估回路和应激诱导的炎性异常(目标1和2)； 以及(2)识别绘制病程图的异常(目标3)。这将通过一个 (1)分子成像技术与新型正电子发射的创新集成 断层扫描(PET)NOP示踪剂([11C]NOP1A)在既往或现在患有MDD的未服药个体中的研究，(2) 应激相关促炎转录调控途径的最新分析(3) 关键抑郁表型的行为和功能神经成像标志物，以及(4)自然主义者 后续设计。为了区分易损性的状态标记和特征标记， 目前抑郁患者(MDD)、有MDD病史的缓解者(RMDD)，以及 从未抑郁的健康对照将被包括在内。根据前一个项目期的调查结果， 我们假设，相对于健康对照组，MDD和rMDD参与者将表现出 与应激密切相关的脑区[11C]NOP1A结合潜能显著升高 调节和奖励加工(假设1)。 此外，在目前或过去患有MDD的个体中，大脑区域的N/OFQ异常 参与压力调节和奖赏处理将与(1)行为和 非享乐表型的神经标志物；(2)调节应激反应的能力较低；以及(3) 更高的应激相关的促炎细胞因子和转录调控途径(假设2)。 最后，我们预计N/OFQ异常(以及相关的行为、功能磁共振、激素和 炎症标志物)将预测非享乐症状和较差的总体功能在随访中 (假设3)。总而言之，拟议的研究承诺改善我们的机制 了解应激引起的快感缺乏和MDD的病理生理学，以及我们的能力 确定前瞻性地预测奖励不足相关症状的机制，从而开启了一篇新的 改善治疗和预防的途径。

Major Depressive Disorder (MDD) remains a major public health problem with poorly understood etiology and pathophysiology. Impairment in reward processing and anhedonia are core features of MDD. Findings during the prior award period have shown that MDD and anhedonic phenotypes are characterized by functional, structural and molecular abnormalities within a CorticoStriatal Valuation Circuit critically implicated in value encoding and reinforcement learning. The main goal of the this R37 renewal is to expand this line of work in several fundamental new directions to (1) attain a better mechanistic understanding of MDD and anhedonia by focusing on a novel target - Nociceptin/Orphanin FQ Receptors - expected to yield molecular abnormalities associated with CorticoStriatal Valuation Circuit and stress- induced inflammatory abnormalities (Aims 1 and 2); and (2) identify abnormalities that map disease course (Aim 3). This will be achieved through an innovative integration of (1) molecular imaging techniques with a novel positron emission tomography (PET) NOP tracer ([11C]NOP1A) in unmedicated individuals with current or past MDD, (2) state-of-the-art analyses of stress-related pro-inflammatory transcription control pathways, (3) behavioral and functional neuroimaging markers of key depressive phenotypes, and (4) a naturalistic follow-up design. To differentiate between state- and trait-like markers of vulnerability, currently depressed individuals (MDD), remitted individuals with a history of MDD (rMDD), and never-depressed healthy controls will be included. Based on findings from the prior project period, we hypothesize that, relative to healthy controls, MDD and rMDD participants will show significantly higher [11C]NOP1A binding potential in brain regions critically implicated in stress regulation and reward processing (Hypotheses 1). Moreover, among individuals with current or past MDD, N/OFQ abnormalities in brain regions implicated in stress regulation and reward processing will be associated with (1) behavioral and neural markers of anhedonic phenotypes; (2) lower ability to regulate stress responses; and (3) higher stress-related proinflammatory cytokines and transcription control pathways (Hypotheses 2). Finally, we expect that N/OFQ abnormalities (and associated behavioral, fMRI, hormonal, and inflammatory markers) will predict anhedonic symptoms and poorer general functioning at follow-up (Hypothesis 3). Collectively, the proposed research promises to improve our mechanistic understanding of stress-induced anhedonia and the pathophysiology of MDD, as well as our ability to identify mechanisms that prospectively predict reward deficit-related symptoms, thus opening novel avenues for improved treatment and prevention.