Neuroimaging Studies of Reward Processing in Depression

重度抑郁症（MDD）仍然是一个主要的公共卫生问题， 病因学和病理生理学。奖赏加工障碍和快感缺乏是 MDD。在前一个奖励期的研究结果表明，MDD和快感缺失表型是 其特征在于皮质纹状体内的功能、结构和分子异常， Valuation Circuit在价值编码和强化学习中有重要意义。主要目标 这次R37更新的目的是在几个基本的新方向上扩展这条工作线，以（1） 通过关注一个新的目标，更好地理解MDD和快感缺失的机制- 孤啡肽/孤啡肽FQ受体-预期产生与以下相关的分子异常： 皮质-纹状体评估回路与应激诱导的炎症异常（目的1和2）; 以及（2）识别映射疾病过程的异常（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整合 当前或既往MDD未用药个体的断层扫描（PET）NOP示踪剂（[11 C] NOP 1A），（2） 应激相关促炎转录控制途径的最新分析，（3） 关键抑郁症表型的行为和功能神经影像学标记物，以及（4）一个自然的 后续设计。为了区分脆弱性的状态和特质标记， 目前抑郁的个体（MDD），有MDD病史的缓解个体（rMDD），以及 将包括从未抑郁的健康对照。根据上一个项目期间的调查结果， 我们假设，相对于健康对照组，MDD和rMDD参与者将显示 在与应激密切相关的大脑区域中显著更高的[11 C] NOP 1A结合潜力 调节和奖励处理（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 涉及压力调节和奖励处理将与（1）行为和 快感缺失表型的神经标记物;（2）调节应激反应的能力较低;和（3） 更高的应激相关促炎细胞因子和转录控制途径（假设2）。 最后，我们预计N/OFQ异常（以及相关的行为，功能磁共振成像，激素， 炎症标志物）将预测随访时的快感缺失症状和较差的一般功能 （假设3）。总的来说，拟议的研究有望改善我们的机制， 了解压力引起的快感缺失和MDD的病理生理学，以及我们的能力， 确定前瞻性预测奖励缺乏相关症状的机制，从而打开新的 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.