Neuroinflammation as a Mechanism Linking Early Life Stress, Altered Functional Connectivity, and Anhedonia in Major Depression

项目摘要/摘要 应激性生活事件是抑郁症状发生的最强预测因子之一，个人暴露于 早期生活压力(ELs)符合严重抑郁障碍诊断标准的可能性是普通人的2到4倍 (MDD)。快感缺乏，即缺乏动力、努力和快乐，是MDD的核心特征，ELS一直是 在快感缺乏症的病理生理学和表现上有重要的贡献，可能 解释ELS中MDD的较高比率。据推测，ELS通过增强交叉反应而增加快感缺乏的风险。 谈论先天免疫系统和神经回路之间的关系，这些神经回路涉及威胁和奖励相关的处理。 为了支持这一框架，有证据表明，炎症与提高对威胁和 降低了奖赏敏感度。实验诱导的炎症改变了威胁和奖励的激活 相关脑区，即杏仁核和腹侧纹状体(VS)。此外，更高级别的外围设备 炎症与腹内侧前额叶之间的功能连接性降低有关 皮质(VmPFC)和杏仁核，以及vmPFC和VS，这反过来又与减少相关 动机和快感缺乏，特别是在暴露于ELS的个人中。此外，两者之间的关联 在使用放射性配体对MDD患者进行的PET研究中观察到了炎症和快感障碍。 靶向18-kDa转运蛋白(TSPO)，其在经典激活后表达增加 小胶质细胞。然而，先前关于ELS和人类快感缺乏症的研究缺乏直接衡量 神经炎症，研究很少集中于整合奖赏和威胁相关的措施 神经连通性。因此，拟议项目的目标是推进压力诱导的快感缺乏症模型。 这是由威胁和奖励相关的神经炎性介质推动的。我们建议同时收集 临床上有明显快感缺乏的未服药MDD患者和匹配的健康对照组的PET-fMRI 使用放射性配基[18F]PBR111评估神经炎症指标TSPO的表达。在目标1中，我们 将测试早期生活压力对威胁和奖励相关脑中神经炎症(TSPO结合)的影响 地区。在这两组人中，我们假设更多的ELS暴露将预测TSPO结合的增加 大脑中涉及奖赏和威胁处理的区域。在目标2中，我们将测试ELS对威胁的影响- 以及基于奖励网络任务的功能连接。在这两组人中，我们假设 暴露于ELS将预示威胁网络功能连接性降低(例如，杏仁核-vmPFC)和 降低奖励网络功能连接(例如，VS-vmPFC)。在目标3中，我们将评估 ELS通过神经炎症和功能连接性改变影响MDD快感缺乏的严重程度。在MDD中 此外，还将利用调解分析探索重要途径。调查结果将产生初步证据 对于ELS相关的神经炎症，测试ELS之间关联的可能的免疫机制 和快感缺乏，并增进我们对快感缺乏作为一种跨诊断症状的理解。

PROJECT SUMMARY/ABSTRACT Stressful life events are one of the strongest predictors of depressive symptom onset, and individuals exposed to early life stress (ELS) are 2 to 4 times more likely to meet diagnostic criteria for major depressive disorder (MDD). Anhedonia, or deficits in motivation, effort, and pleasure, is a core feature of MDD, and ELS has been implicated as a significant contributor in the pathophysiology and manifestation of anhedonia, which may explain higher rates of MDD in ELS. It is postulated that ELS increases anhedonia risk by potentiating cross- talk between the innate immune system and neural circuits implicated in threat- and reward-related processing. In support of this framework, there is evidence linking inflammation to increased vigilance for threats and dampened reward sensitivity. Experimentally-induced inflammation alters activation of threat- and reward- related brain regions, namely the amygdala and ventral striatum (VS). Further, higher levels of peripheral inflammation have been associated with reduced functional connectivity between the ventromedial prefrontal cortex (vmPFC) and amygdala, as well as the vmPFC and VS, which in turn is associated with decreased motivation and anhedonia, particularly in ELS-exposed individuals. Additionally, associations between inflammation and anhedonia have been observed in PET studies of patients with MDD using radioligands to target the 18-kDa translocator protein (TSPO), whose expression is increased in classically-activated microglia. However, prior research on ELS and anhedonia in humans lacks direct measures of neuroinflammation, and studies have rarely focused on integrating measures of reward- and threat-related neural connectivity. Thus, the goal of the proposed project is to advance a stress-induced model of anhedonia that is driven by threat- and reward-related neuroinflammatory mediators. We propose to collect simultaneous PET-fMRI from unmedicated MDD patients with clinically significant anhedonia and matched healthy controls using the radioligand [18F]PBR111 to assess TSPO expression, an index of neuroinflammation. In Aim 1, we will test the impact of early life stress on neuroinflammation (TSPO binding) in threat- and reward-related brain regions. Across both groups, we hypothesize that greater exposure to ELS will predict increased TSPO binding in brain regions implicated in reward and threat processing. In Aim 2, we will test the impact of ELS on threat- and reward-network task-based functional connectivity. Across both groups, we hypothesize that greater exposure to ELS will predict decreased threat-network functional connectivity (e.g., amygdala-vmPFC) and decreased reward-network functional connectivity (e.g., VS-vmPFC). In Aim 3, we will evaluate the impact of ELS on anhedonia severity via neuroinflammation and altered functional connectivity in MDD. In the MDD group, significant pathways will be explored using mediation analyses. Findings will yield preliminary evidence of ELS-related neuroinflammation, test putative immune mechanisms underlying the association between ELS and anhedonia, and advance our understanding of anhedonia as a transdiagnostic symptom.