Inflammatory and neurocircuit mechanisms of anhedonia in human depression

抑郁症是世界上最致残的人类疾病之一，目前的治疗方法还达不到 以满足这一巨大的公共卫生需求。快感缺乏症--对快乐的反应明显减弱--是 抑郁症的一个核心特征，与社会心理功能受损、治疗效果差， 自杀行为，并经常持续，尽管治疗血清素选择性再摄取抑制剂。增加 促炎细胞因子，包括白细胞介素6（IL-6）的信号传导，导致动物的快感缺乏行为， 抑郁症患者的特征在于IL-6和其他细胞因子水平升高， 促炎细胞因子触发抑郁症状和大脑对奖励反应的变化 科目尽管有这些数据，但文献中存在显著的异质性，现在很清楚， 而不是促炎细胞因子与抑郁症状的一一对应。目前的提案寻求 通过测试外周血淋巴细胞与抑郁症之间的关系， 炎症因子和神经行为反应的奖励和社会刺激患者 一系列抑郁症中的快感缺失该提案利用了最先进的免疫学 从病人身上收集白细胞并刺激其表达， vivo.我们的目标是表征有意义的免疫脑行为概况的表型， 在人类中的快感缺乏症，以促进新的诊断和治疗开发的努力。我们将确认 并扩展了我们先前发表的关于抑郁症患者IL-6基础水平升高的研究结果， 通过检查IL-6与一组细胞因子增强的患者中， 在非刺激（基础）和刺激条件下的抑郁症谱中的快感缺失（目标1）。 在目标1中开发的外周免疫谱的基础上，我们将使用基于定量计算机的 奖励学习[概率奖励任务（PRT）]和功能磁共振成像的评估 （功能磁共振成像）与金钱激励[激励侧翼任务（IFT）]和积极社会情绪[积极面孔任务 (PFT)10]任务，以开发快感缺失的免疫-大脑-行为多模态谱（目标2）。支持这些 我们的试验工作表明，（a）高IL-6与不良奖励学习有关，（B）高IL-6与减少奖励学习有关，（c）高IL-6与减少奖励学习有关，（d）高IL-6与减少奖励学习有关，（e）高IL-6与减少奖励学习有关。 对正面情绪的反应在喙前扣带皮层（rACC），和（c）高IL-6与 减少对腹内侧前额叶皮层（vmPFC）内的金钱激励（奖励结果）的反应。 我们的项目有可能通过开发多模式免疫脑， 行为特征，以推进新的诊断和治疗开发。

Depression is among the most disabling human illnesses worldwide, and current treatments fall short of what is required to meet this large public health need. Anhedonia – the markedly diminished response to pleasure – is a core feature of depression and is linked to impaired psychosocial functioning, poor treatment outcome, suicidal behavior and often persists despite treatment with a serotonin selective reuptake inhibitor. Increased signaling of pro-inflammatory cytokines, including interleukin 6 (IL-6), lead to anhedonic behavior in animals, patients with depression are characterized by elevated levels of IL-6 and other cytokines, and administration of pro-inflammatory cytokines triggers depressive symptoms and changes in brain responses to reward in human subjects. Despite these data, there is significant heterogeneity in the literature and it is now clear that there is not a one-to-one mapping of pro-inflammatory cytokines to depressive symptoms. The current proposal seeks to go beyond linking inflammation to depressive phenotypes by testing the relationships between peripheral inflammatory factors and neural and behavioral responses to reward and social stimuli in patients with anhedonia across a range of depressive disorders. The proposal leverages state-of-the-art immunological techniques to examine inflammatory response profiles of leukocytes harvested from patients and stimulated ex vivo. Our goal is to characterize meaningful immune-brain-behavior profiles underlying the phenotype of anhedonia in humans in order to promote novel diagnostic and treatment development efforts. We will confirm and expand on our previous published finding of elevated basal levels of IL-6 in patients with major depressive disorder (MDD) by examining IL-6 augmented with a board panel of cytokines in patients enriched for anhedonia across a spectrum of depression in both un-stimulated (basal) and stimulated conditions (Aim 1). Building on the peripheral immune profiles developed in Aim 1, we will use quantitative computer-based assessments of reward learning [probabilistic reward task (PRT)] and functional magnetic resonance imaging (fMRI) with monetary incentive [incentive flanker task (IFT)] and positive social emotion [positive faces task (PFT) 10] tasks to develop immune-brain-behavior multimodal profiles of anhedonia (Aim 2). Supporting these aims, our pilot work show that (a) high IL-6 is linked to poor reward learning, (b) high IL-6 is linked to reduced response to positive emotion within the rostral anterior cingluate cortex (rACC), and (c) high IL-6 is linked to reduced response to monetary incentives (reward outcome) within the ventromedial prefrontal cortex (vmPFC). Our project has the potential to have a major public health impact by developing multimodal immune-brain- behavior profiles in order to advance novel diagnostic and treatment development.