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.

项目摘要/摘要 压力大的生活事件是抑郁症状发作的最强预测指标之一，个人暴露 到早期生活压力（EL）满足重度抑郁症的诊断标准的可能性高2至4倍 （MDD）。 Anhedonia或动机，努力和愉悦的缺陷是MDD的核心特征，Els一直是 被视为抗议的病理生理学和表现的重要因素，这可能 解释EL中MDD的较高速率。据推测，ELS通过增强交叉来增加Anhedonia的风险 先天免疫系统与与威胁和奖励相关的处理有关的神经回路之间的对话。 为了支持该框架，有证据表明炎症与对威胁和威胁的警惕性增加有关 降低了奖励灵敏度。实验引起的炎症改变了威胁和奖励的激活 相关的大脑区域，即杏仁核和腹纹状体（VS）。此外，外围水平较高 炎症与腹侧前额叶之间的功能连通性降低有关 皮质（VMPFC）和杏仁核，以及VMPFC和VS，这又与减少有关 动机和紧张的人，特别是在暴露于ELS的个体中。另外，之间的关联 在使用放射性的MDD患者的PET研究中，已经观察到炎症和抗肿瘤 靶向18-kDa易位蛋白（TSPO），其表达在经典激活中被增加 小胶质细胞。但是，先前对人类EL和Anhedonia的研究缺乏直接措施 神经炎症，研究很少专注于整合奖励和威胁相关的度量 神经连通性。因此，拟议项目的目的是提高压力引起的抗议模型 这是由威胁和奖励相关的神经炎症介体驱动的。我们建议同时收集 来自临床意义的Anhedonia并与健康对照组相匹配的未药物MDD患者的PET-FMI 使用放射性[18F] PBR111评估TSPO表达，这是神经炎症的指标。在AIM 1中，我们 将测试早期生活压力对威胁和奖励相关的大脑中神经炎症（TSPO结合）的影响 地区。在这两组中，我们假设更多接触EL将预测TSPO结合的增加 在涉及奖励和威胁处理的大脑区域中。在AIM 2中，我们将测试ELS对威胁的影响 - 和奖励网络基于任务的功能连接。在两组中，我们假设这更大 接触ELS将预测威胁网络功能连接的降低（例如，杏仁核VMPFC）和 奖励网络功能连接降低（例如VS-VMPFC）。在AIM 3中，我们将评估 通过神经炎症和MDD中的功能连通性改变了甲向多症的严重程度。在MDD中 小组，将使用中介分析探索重要的途径。调查结果将产生初步证据 EL相关的神经炎症，测试ELS之间关联的基础的假定免疫机制 和Anhedonia，并促进我们对Anhedonia作为转诊症状的理解。