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

青春期首次重性抑郁发作的综合奖赏-炎症模型

• 批准号: 10376869
• 负责人: LAUREN Bersh ALLOY
• 金额: $ 72.1万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10376869
• 关键词: 15 year old; Adolescence; Adolescent; Age; Anhedonia; Attenuated; Behavior; Behavior Therapy; Behavioral; Biological; Birth History; Blood; Brain; Childhood; Chronic; Code; Corpus striatum structure; Development; Diagnostic; Diet; Dimensions; Etiology; Event; Excision; Failure; Fatty acid glycerol esters; Feedback; Foundations; Generations; Immune; Immune signaling; Immune system; Inflammation; Inflammation Mediators; Inflammatory; Intervention; Interview; Joints; Lead; Life; Literature; Longitudinal Studies; Major Depressive Disorder; Measures; Mediating; Mediator of activation protein; Mental Depression; Modeling; Neuroimmune; Participant; Pathway interactions; Patient Self-Report; Peripheral; Prevalence; Public Health; Recording of previous events; Research; Resources; Rewards; Risk; Signal Transduction; Sleep disturbances; Specific qualifier value; Stress; System; Tail; Testing; Time; Unhealthy Diet; Work; behavior measurement; biobehavior; child depression; cytokine; depression model; depressive symptoms; design; dysphoria; follow-up; functional MRI scan; high risk; high school; indexing; innovation; longitudinal design; multimodality; network models; novel; pathogen; persistent symptom; predict responsiveness; prevent; prospective; relating to nervous system; reward processing; social; stressor; substance use; sugar; tool; wound healing

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.

7.项目总结/摘要 青春期是抑郁症首次发病的“高危年龄”。尽管 流行率和公共卫生意义，主要的未回答的问题存在有关的机制 与MD易感性有关。抑郁症（Dep）与对奖励的敏感性降低和低 皮质-纹状体回路中与奖赏相关的脑功能。然而，研究尚未测试是否 长期低回报反应性（RR）或衰减的RR发展在青春期预测第一次发作 的MD。另一篇文献记录了Dep.然而，研究也没有 研究是否慢性炎症升高或青春期炎症增加预测 第一次出现MD。此外，对炎症和RR的研究大多是平行进行的。最近， 然而，我们和其他人已经提出了Dep的神经免疫网络模型。这些模型利用工作 表明外周炎症介质（例如，细胞因子）进入大脑，在那里它们降低RR。 当失调时，这种免疫到大脑的信号传导可导致慢性和恶化的低RR， 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， 不良饮食），以及睡眠中断和压力的产生，这进一步加剧了炎症。随着时间的推移， RR和免疫信号传导的失调可以在正反馈回路中协同作用， 会加剧另一个系统的失调我们认为奖赏免疫失调是一种 两次打击的脆弱性，第一次发病的MD和增加的Deps症状（SXS）在青春期。 此外，儿童和青少年的逆境和最近的压力源影响RR和炎症， 可能为奖赏免疫失调奠定了基础。这一建议是对这些建议的第一次系统性测试。 假设我们将使用一个创新的生物行为高风险设计来研究双向关系 外周炎症与RR的多个指标和领域（货币、社会）及其联合 预测MD的首次发作和Dep Sx的增加，特别是快感缺乏。300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。将选择既往无MD的患者 沿着自我报告RR的整个维度，在维度的低尾进行过采样，以便 增加MD发病的可能性。在时间1（T1），T3和T5，每隔一年，Ps将完成血液 绘制量化炎症，自我报告和行为措施的RR，和功能磁共振成像扫描的奖励神经 活动和功能连接。在T1-T5（T2和T4 6个月），在每年的会议之间），PS也将 完整的诊断访谈，以及对Dep Sxs，奖励相关生活事件和行为的测量， 增加炎症。仅在T1时评估逆境史。这一建议是一个创新的整合 奖励和炎症信号的研究，以了解青春期首次发病的MD。它有 潜在的促进新的神经免疫和行为干预，以治疗和理想地预防，MD。