PET imaging of dynorphin/kappa-opioid reactivity to stress in depression

项目摘要/摘要：严重抑郁障碍(MDD)是全球残疾的主要原因 缺乏个性化、有效的治疗方法。长期以来，生活压力源被证明可以有效地预测 抑郁症状和主要抑郁发作的发作。尽管如此，神经生物学 抑郁症潜在的压力调节机制在人类身上还没有完全被理解。临床前和 最初的人类研究表明kappa-阿片受体(KOR)缺陷与MDD的发病有关，并提示 压力反应性可能是造成韩国汇率赤字的原因之一。本K01中提出的创新研究代表 确定KOR结合缺陷和强啡肽/KOR介导的应激反应增强是否 在MDD患者中观察到与健康对照(HCS)的关系。如果事实证明是这样，那么第二步将是确定 这些缺陷是否代表了一种状态效应，即它存在于目前抑郁的情绪中，而不存在于欣快感中 患有MDD或特质效应的受试者在目前抑郁和缓解的MDD中都存在(将在 跟进R01)。因此，我们试图评估静息状态下KOR结合和内源性强啡肽释放到 未服药、目前抑郁的MDD与HCS参与者的实验室应激源。KOR绑定和 强啡肽的释放将在人体内用功能正电子发射断层扫描(PET)进行量化， 新的示踪剂[11C]EKAP已经可靠地合成并在哥伦比亚宠物中心的啮齿动物身上使用， 以KOR为靶标，具有高度的敏感性和特异性。一项简短、有效的生理和心理压力任务 在正电子发射计算机断层扫描期间，将给出激发下丘脑-垂体-肾上腺(HPA)轴激活的成分。 HPA激活的生理标记物将在任务的近端获得，例如皮质醇，以与 静息时Kor结合和应激诱导的内源性强啡肽在MDD和HCS中的释放。此外，校长 研究人员(PI)的初步研究表明，智能手机管理的生态瞬时评估 抑郁症患者的日常应激源(EMA)比对照组参与者更大，并具有明显的结构性和 功能神经相关。在这项研究中，将获取和评估日常应激源的EMA，以确定是否 在PET扫描之前以及结构磁共振成像(MRI)扫描之前的每日应力， 调节抑郁症患者的脑结构、KOR结合和应激诱导的内源性强啡肽释放。这 将是第一个研究KOR在MDD体内应激反应中的作用的研究，并将结合多模式 神经成像、HPA激活的外周标记物和EMA日常应激。不管结果如何 研究，它将增加我们对KOR在MDD中的作用以及MDD中失调的应激反应的理解， 潜在地提示KOR调节的应激敏感型抑郁亚型。这项奖励将会很明显地 提高专业人员进行高影响力研究的培训，并了解 情绪障碍。这将推动PI走向研究独立，推出她的研究计划旨在 在阐明压力在情绪障碍中的后果并开发缓解这些后果的干预措施方面。

PROJECT SUMMARY/ABSTRACT: Major depressive disorder (MDD) is a leading cause of disability worldwide with a paucity of personalized, efficacious treatments. Life stressors have long been shown to potently predict depressive symptomatology and onset of major depressive episodes. Despite this, the neurobiological mechanisms underlying stress regulation in depression are not yet fully understood in humans. Preclinical and initial human studies implicate kappa-opioid receptor (KOR) deficits in the pathogenesis of MDD and suggest that stress reactivity might contribute to these KOR deficits. The innovative study proposed in this K01 represents a first step to determine if KOR binding deficits and heightened dynorphin/KOR-mediated stress reactivity are observed in MDD relative to healthy controls (HCs). If shown to be so, then the second step will be to determine whether these deficits represent a state effect that it is present in currently depressed and not in euthymic subjects with MDD or a trait effect present in both currently depressed and remitted MDD (to be tested in a follow-up R01). Therefore, we seek to evaluate KOR binding at rest and endogenous dynorphin release to a laboratory stressor in unmedicated, currently depressed participants with MDD vs. HCs. KOR binding and dynorphin release will be quantified in vivo in humans with functional positron emission tomography (PET) with the new tracer [11C]EKAP, already reliably synthesized and used in rodents at the Columbia PET Center, that targets KOR with high sensitivity and specificity. A brief, validated stress task with physiologic and psychologic components will be given during the PET scan that elicits hypothalamic-pituitary-adrenal (HPA) axis activation. Physiologic markers of HPA activation will be acquired proximal to the task, e.g., cortisol, to be compared with KOR binding at rest and stress-induced endogenous dynorphin release in MDD vs. HCs. Further, the Principal Investigator’s (PI) preliminary studies suggest that smartphone-administered ecological momentary assessment (EMA) of daily stressors is greater in depressed relative to control participants and has distinct structural and functional neural correlates. In this study, EMA of daily stressors will be acquired and evaluated to determine if daily stress preceding the PET scan, as well as preceding a structural magnetic resonance imaging (MRI) scan, modulate brain structure, KOR binding, and stress-induced endogenous dynorphin release in depression. This will be the first study to investigate KOR’s role in stress-reactivity in vivo in MDD, and will combine multimodal neuroimaging, peripheral markers of HPA activation, and EMA daily stress. Regardless of the outcome of this study, it will increase our understanding of KOR’s role in MDD and in dysregulated stress reactivity in MDD, potentially suggesting KOR-regulated, stress-sensitive depression subtypes. This award will measurably advance the PI’s training in conducting highly impactful research studies and understanding the neurobiology of mood disorders. This will propel the PI toward research independence, launching her research program aimed at elucidating the consequences of stress in mood disorders and developing interventions to mitigate them.