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

抑郁症中强啡肽/卡帕阿片类药物对应激反应的 PET 成像

基本信息

批准号：
10705218
负责人：
Elizabeth Adams Bartlett
金额：
$ 18.13万
依托单位：
NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-15 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10705218
关键词：
Acceleration Addictive Behavior Adrenal Glands Agonist Anhedonia Anterior Anxiety Autopsy Award Biological Biology Biomedical Engineering Brain Brain imaging Brain region Brain scan Cellular Phone Characteristics Clinic DSM-V Depressed mood Development Diagnosis Disease remission Drug Targeting Dynorphins Ecological momentary assessment Exhibits Functional disorder Goals Human Hydrocortisone Hypothalamic structure Image Individual Intervention Laboratories Life Life Stress Link MRI Scans Magnetic Resonance Imaging Major Depressive Disorder Measurable Measures Mediating Mental Depression Mental disorders Mood Disorders Neurobiology Opioid Receptor Binding Outcome Study Participant Pathogenesis Peripheral Physiological Pilot Projects Pituitary Gland Positron-Emission Tomography Principal Investigator Process Regulation Reporting Research Rest Rodent Role Sensitivity and Specificity Severities Standardization Stress Structure Testing Thick Tracer Training Work biological adaptation to stress depressive symptoms design disability drug development dysphoria efficacious treatment follow-up hypothalamic-pituitary-adrenal axis improved in vivo in vivo monitoring innovation investigator training kappa opioid receptors multimodal neuroimaging neural neural correlate neurobiological mechanism personalized medicine pre-clinical programs prospective psychologic research study response single episode major depressive disorder skills social stress reactivity stressor symptomatology therapeutic target trait transmission process

项目摘要

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.

项目摘要/摘要：重度抑郁症 (MDD) 是全球残疾的主要原因长期以来，生活压力源一直被证明可以有效地预测。尽管如此，神经生物学仍然存在抑郁症状和重度抑郁发作的情况。人类尚未完全了解抑郁症压力调节的机制。初步的人体研究表明 MDD 的发病机制中存在 kappa 阿片受体 (KOR) 缺陷，并表明 K01 中提出的创新研究表明，应激反应可能会导致这些 KOR 缺陷。第一步确定 KOR 结合缺陷和哮喘强啡肽/KOR 介导的应激反应性是否与健康对照 (HC) 相比，MDD 中观察到的情况如果确实如此，那么第二步将是确定。这些缺陷是否代表了一种状态效应，它存在于当前抑郁症中而不是在正常情绪中患有 MDD 或当前抑郁症和缓解型 MDD 中均存在特质效应的受试者（将在后续 R01）因此，我们寻求评估静息时的 KOR 结合和内源性强啡肽释放。未接受药物治疗、目前患有 MDD 的抑郁参与者与 KOR 结合的实验室压力源。强啡肽释放将通过功能性正电子发射断层扫描（PET）在人体体内进行定量新的示踪剂 [11C]EKAP 已在哥伦比亚 PET 中心可靠地合成并用于啮齿动物，具有高敏感性和特异性的针对 KOR 的简短、经过验证的生理和心理压力任务。在 PET 扫描期间将给出激发下丘脑-垂体-肾上腺 (HPA) 轴激活的成分。将获取最接近任务的 HPA 激活的生理标志物，例如皮质醇，以便与 MDD 与 HC 中静息时的 KOR 结合和应激诱导的内源性强啡肽释放。研究者 (PI) 的初步研究表明，智能手机管理的生态瞬时评估相对于对照组参与者，抑郁症患者的日常压力源（EMA）更大，并且具有不同的结构和特征在本研究中，将获取并评估日常压力源的 EMA，以确定是否存在功能性神经相关性。 PET 扫描之前以及结构磁共振成像 (MRI) 扫描之前的日常压力，调节抑郁症中的大脑结构、KOR 结合和应激诱导的内源性强啡肽释放。将是第一个研究 KOR 在 MDD 体内应激反应中的作用的研究，并将结合多模式无论结果如何，神经影像学、HPA 激活的外周标志物和 EMA 日常压力。研究，它将增加我们对 KOR 在 MDD 以及 MDD 应激反应失调中的作用的理解，该奖项可能表明 KOR 调节的压力敏感型抑郁症亚型。促进 PI 进行具有高度影响力的研究和理解神经生物学方面的培训这将推动 PI 走向研究独立性，启动她的研究计划。阐明压力对情绪障碍的影响并制定缓解措施。