Integrated Reward-Inflammation Model of First Onset of Major Depression in Adolescence

7. 项目总结/摘要 青春期是首次出现重度抑郁症（MD）的“风险年龄”。尽管其 流行率和公共卫生意义，有关机制存在主要未解答的问题 涉及MD的脆弱性。抑郁症 (Dep) 与奖励敏感性降低和情绪低落有关 皮质纹状体回路中与奖励相关的大脑功能。然而，研究尚未测试是否 青春期奖励反应性 (RR) 长期较低或 RR 发育减弱预示着第一次发作 医学博士。另一篇文献记录了该部门外周炎症的升高。然而，研究还没有 检查慢性炎症升高或青春期炎症增加是否预示 MD 第一次发作。此外，关于炎症和 RR 的研究大多是并行进行的。最近， 然而，我们和其他人提出了 Dep 的神经免疫网络模型。这些模型借鉴了工作 表明外周炎症介质（例如细胞因子）进入大脑，从而降低 RR。 当失调时，这种免疫至大脑的信号传导可能导致慢性且恶化的低 RR，这是 表现为烦躁不安和快感缺乏。这种低 RR 被认为会引发不健康的行为（物质使用、 饮食不良），以及睡眠中断和压力产生，这些都会进一步加剧炎症。随着时间的推移， RR 和免疫信号传导失调可能在正反馈循环中协同作用，从而调节失调 每个系统的失调都会加剧另一个系统的失调。我们认为奖赏免疫失调是 MD 第一次发作的两次打击脆弱性和青春期期间 Dep 症状 (Sxs) 的增加。 此外，童年和青少年时期的逆境和近期的压力因素都会影响 RR 和炎症，并且 可能为奖赏免疫失调奠定基础。该提案是对这些的首次系统测试 假设。我们将使用创新的生物行为高风险设计来检查双向关系 外周炎症与 RR 的多个指标和领域（货币、社会）及其联合之间的关系 预测 MD 第一次发作和 Dep Sxs 增加，特别是快感缺乏。三百名14-15岁 参与者（Ps）将完成一项为期 3 年的前瞻性纵向研究。之前没有 MD 的 P 将被选择 沿着自报告 RR 的整个维度，在维度的低尾部进行过采样，以便 增加MD发病的可能性。在时间 1 (T1)、T3 和 T5（每个相隔一年），Ps 将完成血液 旨在量化炎症、RR 的自我报告和行为测量以及奖赏神经的功能磁共振成像扫描 活动和功能连接。在 T1-T5（T2 和 T4 年会之间间隔 6 个月），Ps 还将 完整的诊断访谈、Dep Sxs 的测量、与奖励相关的生活事件以及行为 增加炎症。仅在 T1 时评估逆境历史。这个提议是一个创新的整合 关于奖励和炎症信号传导的研究有助于了解青春期第一次 MD 的发作。它有 促进新型神经免疫和行为干预治疗并理想地预防MD的潜力。

7. Project Summary/Abstract Adolescence is an “age of risk” for the emergence of 1st onset of major depressive disorder (MD). Despite its prevalence and public health significance, major unanswered questions exist regarding the mechanisms involved in vulnerability to MD. Depression (Dep) is associated with a reduced sensitivity to rewards and low reward-related brain function in cortico-striatal circuitry. However, research has not yet tested whether chronically low reward responsivity (RR) or attenuated RR development during adolescence predicts 1st onset of MD. A separate literature documents elevated peripheral inflammation in Dep. Yet, research also has not examined whether chronically elevated inflammation or increases in inflammation during adolescence predicts 1st onset of MD. Further, research on inflammation and RR mostly has proceeded in parallel. Recently, however, we and others have proposed neuroimmune network models of Dep. These models draw on work indicating that peripheral inflammatory mediators (e.g., cytokines) access the brain, where they lower RR. When dysregulated, this immune-to-brain signaling can lead to chronic and worsening low RR, which is reflected in dysphoria and anhedonia. This low RR is proposed to initiate unhealthy behaviors (substance use, poor diet), as well as sleep disruption and stress generation, which further heighten inflammation. Over time, dysregulation in RR and immune signaling may synergize in a positive feedback loop, whereby dysregulation in each system exacerbates dysregulation in the other. We propose that reward-immune dysregulation is a two-hit vulnerability for the 1st onset of MD and increases in Dep symptoms (Sxs) during adolescence. Moreover, childhood and adolescent adversity and recent stressors influence both RR and inflammation, and may set the foundation for reward-immune dysregulation. This proposal is the first systematic test of these hypotheses. We will use an innovative biobehavioral high-risk design to examine bidirectional relationships between peripheral inflammation and multiple indices and domains (monetary, social) of RR and their joint prediction of 1st onset of MD and increases in Dep Sxs, particularly anhedonia. Three hundred 14-15 year old participants (Ps) will complete a prospective 3-year longitudinal study. Ps with no prior MD will be selected along the entire dimension of self-reported RR, with oversampling at the low tail of the dimension in order to increase the likelihood of MD onsets. At Time 1 (T1), T3, and T5, each a year apart, Ps will complete blood draws to quantify inflammation, self-report and behavioral measures of RR, and fMRI scans of reward neural activity and functional connectivity. At T1-T5 (with T2 and T4 6 mo. between the yearly sessions), Ps also will complete diagnostic interviews, and measures of Dep Sxs, reward-relevant life events, and behaviors that increase inflammation. Adversity history will be assessed at T1 only. This proposal is an innovative integration of research on reward and inflammatory signaling in understanding 1st onset of MD in adolescence. It has the potential to facilitate novel neuroimmune and behavioral interventions to treat, and ideally prevent, MD.