In Vivo Targeting of Neuroactive Steroid and Immune Networks for Depression in People Living with HIV.

项目摘要 艾滋病毒携带者中抑郁症的患病率估计为20%-45%，尽管 抗逆转录病毒治疗三分之二的成年人没有得到充分的治疗，只有三分之一的成年人达到了 减刑。下丘脑-垂体-肾上腺轴功能障碍和慢性炎症 PLWH中的抑郁症状，代表了靶向的替代途径。神经活性类固醇 可以改善精神状态下的抑郁症状，对慢性疼痛有效。在人类中 研究表明，这种作用是由孕烯醇酮介导的，孕烯醇酮是第一种从胆固醇中提取的神经活性类固醇。 在这项建议中，我们假设神经心理疾病发病的一个中心机制 是一种神经活性类固醇的相对缺乏，它定义了抑郁症的一种生物学亚型 PLWH。神经活性类固醇的变化通过几种方式促进神经功能，包括 增加GABA能神经传递，减少全身炎症。向我们的 假设，我们将进行3：1的双盲试验，纳入120名抑郁症患者接受抗逆转录病毒治疗， 随机服用孕烯醇酮或安慰剂，作为补充治疗，为期8周，并将系统地 研究GABA介导的抑制和外周免疫反应与抑郁的关系 心情。该项目利用磁共振波谱和基于任务的功能磁学 磁共振成像探测孕烯醇酮治疗后的行为和神经反应。我们会 免疫细胞群的纵向分布及单核细胞转录反应的研究 以确定与临床反应相关的基因。最后，我们将使用基线预测值来建模 神经活性类固醇水平是否可预测接受PLWH患者的临床改善 孕烯醇酮。这一建议利用了广泛的神经成像和免疫分析基础设施 以及合作研究人员和实验室的广泛科学专业知识。我们的方法可能 明确孕烯醇酮与抑郁症发病机制之间的新关系，可能提示 基于神经活性类固醇生物学的新治疗靶点，以解决 PLWH。

Project Summary The prevalence of depression in people living with HIV (PLWH) is estimated at 20-45% despite antiretroviral therapy with two-thirds of adults inadequately treated, and only one-third of adults achieving remission. Hypothalamic-pituitary-adrenal axis dysfunction and chronic inflammation contribute to depressive symptoms in PLWH and represent alternative pathways for targeting. Neuroactive steroids can improve depressive symptoms in psychiatric conditions and are effective in chronic pain. In human studies, the effect was mediated by pregnenolone, the first neuroactive steroid derived from cholesterol. In this proposal, we hypothesize that a central mechanism of pathogenesis in neuropsychological disease is a relative deficiency of neuroactive steroids that defines a biological subtype of depressed mood in PLWH. Changes in neuroactive steroids promote neurological functioning by several means that include increasing GABAergic neurotransmission and reducing systemic inflammation. To address our hypothesis, we will perform a 3:1 double-blind trial enrolling 120 PLWH on ART with depression, randomized to pregnenolone or placebo, as add-on therapy, for 8 weeks, and will systematically investigate GABA-mediated inhibition and peripheral immune responses as they relate to depressed mood. This project utilizes magnetic resonance spectroscopy and task-based functional magnetic resonance imaging to probe the behavioral and neural responses after pregnenolone. We will longitudinally profile immune cell populations and investigate the transcriptional responses in monocytes to identify genes associated with clinical response. Finally, we will use baseline predictors to model whether levels of neuroactive steroids predict clinical improvement among PLWH receiving pregnenolone. This proposal leverages an extensive neuroimaging, and immune profiling infrastructure and the extensive scientific expertise of collaborating investigators and laboratories. Our approach may define novel relationships between pregnenolone and mechanisms of depression, potentially suggesting new therapeutic targets based on the biology of neuroactive steroids, to address a critical unmet need in PLWH.