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

神经炎症是一种与早期生活压力、功能连接改变和重度抑郁症快感缺失相关的机制

• 批准号: 10606174
• 负责人: Rachel Deanna Phillips
• 金额: $ 3.82万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10606174
• 关键词: Adolescence; Adult; Age; Amygdaloid structure; Anhedonia; Autopsy; Binding Proteins; Brain; Brain region; Childhood; Development; Exposure to; Functional Magnetic Resonance Imaging; Functional disorder; Funding; Genes; Goals; Grant; Health; Human; Immune; Individual; Inflammation; Inflammatory; Innate Immune System; Intervention; Knowledge; Link; Longevity; Major Depressive Disorder; Measures; Mediating; Mediation; Mediator of activation protein; Mental disorders; Microglia; Modeling; Motivation; National Institute of Mental Health; Neurobiology; Outcome; Parents; Pathway interactions; Patients; Peripheral; Phenotype; Positron-Emission Tomography; Prefrontal Cortex; Process; Proteins; Psychopathology; Research; Rewards; Risk; Severities; Stress; Stressful Event; Symptoms; Testing; Time; Ventral Striatum; Work; base; clinically significant; depressive symptoms; diagnostic criteria; early life adversity; early life stress; human imaging; imaging study; indexing; neural circuit; neuroinflammation; peripheral blood; pleasure; prevent; protein expression; radioligand; relating to nervous system; reward processing; vigilance

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.

项目总结/摘要 压力性生活事件是抑郁症状发作的最强预测因子之一， 早期生活压力（ELS）是2至4倍更有可能达到重度抑郁症的诊断标准 （MDD）。快感缺失，或动机，努力和快乐的缺陷，是MDD的核心特征，而ELS一直是 在快感缺乏的病理生理学和表现中起重要作用， 解释了ELS中MDD发生率较高的原因。据推测，ELS通过增强交叉- 讨论先天免疫系统和涉及威胁和奖励相关处理的神经回路之间的关系。 为了支持这一框架，有证据表明炎症与对威胁的警惕性增加有关， 抑制了奖励敏感性。实验诱导的炎症改变了威胁和奖励的激活 相关的大脑区域，即杏仁核和腹侧纹状体（VS）。此外，更高水平的外周 炎症与腹内侧前额叶和前额叶之间的功能连接减少有关， 皮质（vmPFC）和杏仁核，以及vmPFC和VS，这反过来又与减少 动机和快感缺乏，特别是在ELS暴露的个人。此外， 在使用放射性配体对MDD患者进行的PET研究中观察到炎症和快感缺乏， 靶向18-kDa转运蛋白（TSPO），其表达在经典激活的 小胶质细胞然而，先前对人类ELS和快感缺乏的研究缺乏直接的测量方法。 神经炎症，研究很少集中在整合奖励和威胁相关的措施， 神经连接因此，本研究的目标是建立一个压力诱导的快感缺乏模型 由威胁和奖励相关的神经炎症介质驱动。我们建议同时收集 来自未用药的MDD患者的PET-fMRI，具有临床显著的快感缺失和匹配的健康对照 使用放射性配体[18F] PBR 111评估TSPO表达，这是神经炎症的指标。目标1： 将测试早期生活压力对威胁和奖励相关大脑中神经炎症（TSPO结合）的影响 地区在两组中，我们假设ELS暴露越多，TSPO结合率越高 大脑中与奖励和威胁处理有关的区域。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。在这两组中，我们假设， 暴露于ELS将预测降低的威胁网络功能连接（例如，杏仁核-vmPFC）和 降低的奖励网络功能连接（例如，VS-vmPFC）。在目标3中，我们将评估 ELS通过神经炎症和MDD中功能连接改变对快感缺失严重程度的影响。在MDD中 小组将利用调解分析探讨重要途径。调查结果将提供初步证据 ELS相关的神经炎症，测试ELS之间相关性的假定免疫机制， 和快感缺失，并推进我们对快感缺失作为一种转诊断症状的理解。