The Roles of Inflammatory and Glutamatergic Processes in the Neurodevelopmental Mechanisms Underlying Adolescent Depression

项目总结 严重抑郁障碍(MDD)的第一次发作通常始于青春期。尽管事实是 青春期发病的MDD与更严重和反复发作的MDD有关，但很少有研究 这样做是为了确定抑郁症复发或复发的潜在机制。应聘者之前的工作 已记录的涉及前扣带回(ACC)的功能和结构连接的差异 在患有MDD的青少年和精神健康对照组之间；这些表型被认为反映了 改变了关键情绪调节回路中的神经发育。然而，我们还不知道是否以及如何 MDD影响青少年ACC连接性的发育，从而增加患 抑郁症复发或复发。一种机制可能是免疫系统，它会激活以响应 心理社会应激源和影响神经递质系统，包括主要兴奋性物质谷氨酸 大脑中的神经递质。基础研究表明，较高水平的促炎细胞因子会导致 谷氨酸能神经元的过度兴奋达到神经毒性的程度，从而减少 神经可塑性。此外，成人MDD的神经成像研究报告了炎症水平的升高。 并改变了ACC中的谷氨酸水平。这些数据，再加上越来越多的证据表明， 连接性在青春期经历了广泛的成熟，这表明炎症和 过量的谷氨酸可能会导致患有MDD的青少年这种回路的非典型发展。《少年派》 因此试图验证中心假设，即炎症加剧通过谷氨酸起作用 传播干扰患有MDD的青少年ACC连接的典型神经发育增加风险 抑郁症复发或复发的。鉴于阻碍父母研究培训进展的障碍 K01在新冠肺炎期间，本补编旨在扩大基线赠款的样本规模，以测试 这一模式在75名患有MDD的青少年中使用创新的多模式纵向评估超过18个月 接近。PI将使用干血斑点技术检测外周血促炎症细胞因子的水平， 使用质子磁共振波谱对ACC中的谷氨酸和抗氧化剂进行非侵入性成像，以及 根据18个月内的9次评估，生成抑郁症状的轨迹。此K01填充键 在我们对炎症和谷氨酸能机制如何促进随后的 患有MDD的青少年的复发或复发，以及抗氧化剂是否能预防抑郁 通过缓冲炎症对青春期ACC回路发育的影响而复发。重要的是 候选人将在接受与压力相关的免疫方面的高级培训的情况下进行这项研究 生物学、因果推理模型和发展精神病理学。这个项目的结果将是 最终获得R级拨款，旨在根据临床病程确定青少年MDD的亚型/生物型 以及大脑轨迹的多模式表征。

PROJECT SUMMARY First episodes of major depressive disorder (MDD) typically begin during adolescence. Despite the fact that adolescent-onset MDD is associated with more severe and recurrent episodes of MDD, little work has been done to identify mechanisms underlying depressive relapse or recurrence. Prior work by the candidate has documented differences in functional and structural connectivity involving the anterior cingulate cortex (ACC) between adolescents with MDD and psychiatrically healthy controls; these phenotypes are posited to reflect altered neurodevelopment in key emotion regulation circuitry. We do not yet know, however, whether and how MDD impacts adolescent development of ACC connectivity in a manner that contributes to an increased risk of depressive relapse or recurrence. One mechanism may be the immune system, which activates in response to psychosocial stressors and influences neurotransmitter systems including glutamate, the primary excitatory neurotransmitter in the brain. Basic research indicates that higher levels of pro-inflammatory cytokines leads to overexcitation of glutamatergic neurons to the point of neurotoxicity and, consequently, to reduced neuroplasticity. Further, neuroimaging studies of adult MDD have reported heightened levels of inflammation and altered levels of glutamate in the ACC. These data, combined with growing evidence that ACC connectivity undergoes extensive maturation during adolescence, suggest that heightened inflammation and excessive glutamate may lead to atypical development of this circuitry in adolescents with MDD. The PI therefore seeks to test the central hypothesis that heightened inflammation acts through glutamate transmission to disrupt typical neurodevelopment of ACC connectivity in adolescents with MDD to increase risk of depressive relapse or recurrence. In light of barriers that hampered research training progress on the parent K01 during COVID-19, this supplement seeks to expand the sample size of the baseline grant in order to test this model in 75 adolescents with MDD assessed longitudinally over 18 months using an innovative multimodal approach. The PI will assay peripheral levels of pro-inflammatory cytokines using dried blood spot technology, noninvasively image glutamate and antioxidants in ACC using proton magnetic resonance spectroscopy, and generate trajectories of depression symptoms based on 9 assessments over 18 months. This K01 fills key gaps in our understanding of how inflammatory and glutamatergic mechanisms contribute to subsequent relapse or recurrence in adolescents with MDD, and whether antioxidants protect against depression recurrence by buffering the effects of inflammation on adolescent development of ACC circuitry. Importantly, the candidate will execute this research in the context of receiving advanced training in stress-related immune biology, causal inference modeling, and developmental psychopathology. Results from this project will culminate in R-level grants that aim to identify subtypes/biotypes of adolescent MDD based on clinical course and multimodal characterizations of brain trajectories.