Neuroimaging Studies of Reward Processing in Depression

抑郁症奖励处理的神经影像学研究

• 批准号: 10307643
• 负责人: Diego A Pizzagalli
• 金额: $ 78.56万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10307643
• 关键词: Anhedonia; Animals; Anterior; Antidepressive Agents; Award; Behavioral; Binding; Brain region; Corpus striatum structure; Depressed mood; Disease; Etiology; Frequencies; Functional Imaging; Functional Magnetic Resonance Imaging; Functional disorder; Goals; Hormonal; Imaging Techniques; Impairment; Individual; Inflammatory; Knockout Mice; Lead; Learning; Life; Major Depressive Disorder; Maps; Mental Depression; Messenger RNA; Molecular Abnormality; ORL1 receptor; Participant; Pathway interactions; Peptide Receptor; Peptides; Peripheral Blood Mononuclear Cell; Phenotype; Play; Positron-Emission Tomography; Prefrontal Cortex; Prevention; Psychological reinforcement; Public Health; Rattus; Recording of previous events; Regulation; Reporting; Research; Rewards; Rodent; Role; Stress; Stressful Event; Structural defect; Symptoms; System; Tracer; Transcriptional Regulation; Up-Regulation; Ventral Tegmental Area; Work; antagonist; base; biological adaptation to stress; cingulate cortex; cytokine; depressive behavior; depressive symptoms; design; follow up assessment; follow-up; improved; inflammatory marker; innovation; longitudinal design; molecular imaging; neuroimaging; neuroimaging marker; nociceptin; novel; pre-clinical; preclinical study; prospective; relating to nervous system; response; reward processing; social defeat; trait

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.

重度抑郁症（MDD）仍然是一个主要的公共卫生问题，但人们对其知之甚少 病因学和病理生理学。奖励处理受损和快感缺乏是核心特征 医学博士。上一奖项期间的研究结果表明，MDD 和快感缺乏表型是 以皮质纹状体内的功能、结构和分子异常为特征 估值电路与价值编码和强化学习密切相关。主要目标 此次 R37 更新的目的是将这一工作范围扩展到几个基本的新方向：(1) 通过关注一个新目标，更好地理解 MDD 和快感缺失 - 伤害感受肽/孤啡肽 FQ 受体 - 预计会产生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症异常（目标 1 和 2）； (2) 识别异常情况，绘制疾病进程图（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) 用于当前或过去患有 MDD 的未接受药物治疗的个体，(2) 对应激相关促炎症转录控制途径的最先进分析，(3) 关键抑郁表型的行为和功能神经影像标记，以及（4）自然主义 后续设计。为了区分状态和特质的脆弱性标记， 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。根据项目前期的调查结果， 我们假设，相对于健康对照，MDD 和 rMDD 参与者将表现出 在与压力密切相关的大脑区域中 [11C]NOP1A 结合潜力显着升高 监管和奖励处理（假设 1）。 此外，在当前或过去患有 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的将与（1）行为和 快感缺失表型的神经标志物； (2)调节应激反应的能力较低；和（3） 较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、激素和 炎症标记物）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 了解压力诱发的快感缺失和 MDD 的病理生理学，以及我们的能力 确定前瞻性预测奖赏赤字相关症状的机制，从而开启新的 改善治疗和预防的途径。