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

7.项目摘要/摘要 青春期是首次出现严重抑郁障碍(MD)的“危险年龄”。尽管它的 关于流行率和公共卫生意义，有关机制存在重大悬而未决的问题 与MD的脆弱性有关。抑郁(Dep)与对奖励的敏感性降低和情绪低落有关 大脑皮质-纹状体环路中与奖赏相关的大脑功能。然而，研究还没有测试是否 长期低奖赏反应性(RR)或青春期RR发展减弱预测首发 医学博士。一份单独的文献记录显示，Dep的外周炎症升高。然而，研究也没有 检查慢性炎症升高或青春期炎症增加是否预示 首次发病的MD。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。这些模型靠做功来工作 这表明外周炎症介质(如细胞因子)进入大脑，在那里它们降低RR。 当失控时，这种免疫到大脑的信号可能导致慢性和恶化的低RR，这是 反映在烦躁不安和快感缺乏上。这种低RR是为了引发不健康的行为(物质使用， 饮食不良)，以及睡眠中断和压力产生，这进一步加剧了炎症。随着时间的推移, RR和免疫信号的失调可能在正反馈环路中协同作用，从而导致失调 在两个体系中，都加剧了另一个体系中的监管失调。我们认为奖赏免疫失调是一种 首次发病的MD的两次易感性和青春期副症状(SXS)的增加。 此外，童年和青春期的逆境和最近的压力源都会影响RR和炎症，并且 可能会为奖赏免疫失调奠定基础。这项提议是对这些方面的第一次系统测试 假设。我们将使用一种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 预测首次发病的MD和Dep SXS的增加，特别是快感缺乏。300名14-15岁的青少年 参与者(P)将完成一项为期3年的前瞻性纵向研究。将选择没有以前MD的PS 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。在间隔一年的时间1(T1)、T3和T5，Ps将完成血液 绘制量化炎症、自我报告和RR的行为测量，以及奖励神经的fMRI扫描 活动和功能连接。在T1-T5(T2和T4为6个月。在每年届会之间)，P也将 完成诊断性访谈，以及对Dep SXS、与奖励相关的生活事件和行为的测量 增加炎症。逆境历史将仅在T1进行评估。这项提议是一项创新的整合 对奖赏和炎症信号的研究有助于了解青春期首次发病的MD。它有一个 有可能促进新的神经免疫和行为干预，以治疗和理想地预防MD。

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.