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

项目摘要 重度抑郁症（MDD）的首次发作通常开始在青春期。尽管事实上 抑郁症的发作与更严重和更反复的抑郁症发作有关， 以确定抑郁症复发或复发的潜在机制。候选人之前的工作 记录了涉及前扣带皮层（ACC）的功能和结构连接的差异 MDD青少年和精神健康对照之间的差异;这些表型被认为反映了 改变了关键情绪调节回路的神经发育。然而，我们还不知道， MDD影响青少年ACC连接性的发展，其方式有助于增加以下风险： 抑郁症复发或复发。一种机制可能是免疫系统，它响应于 心理社会压力和影响神经递质系统，包括谷氨酸，主要的兴奋性 神经传递素基础研究表明，较高水平的促炎细胞因子导致 过度兴奋的多巴胺能神经元的神经毒性的点，因此，减少 神经可塑性此外，成人MDD的神经影像学研究报告了炎症水平的升高 这些数据，结合越来越多的证据表明，ACC 连接在青春期经历了广泛的成熟，表明炎症加剧， 过量的谷氨酸盐可能导致患有MDD的青少年中该回路的非典型发育。的PI 因此，他试图验证一个核心假设，即炎症的加剧是通过谷氨酸起作用的， 传播破坏患有MDD的青少年中ACC连接的典型神经发育， 抑郁症的复发或复发。鉴于阻碍研究培训进展的障碍， K 01在COVID-19期间，本补充文件旨在扩大基线补助金的样本量，以测试 该模型在75名患有MDD的青少年中进行了18个月的纵向评估，使用创新的多模式 approach. PI将使用干血斑技术测定促炎细胞因子的外周水平， 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， 根据18个月内的9次评估生成抑郁症状的轨迹。此K 01填充键 在我们理解炎症和血管生成机制如何促进随后的 抑郁症青少年的复发或复发，以及抗氧化剂是否可以预防抑郁症 通过缓冲炎症对青少年ACC回路发育的影响来预防复发。重要的是， 候选人将在接受压力相关免疫高级培训的情况下执行这项研究。 生物学、因果推理建模和发展精神病理学。该项目的成果将 最终获得R级赠款，旨在根据临床病程确定青少年MDD的亚型/生物型 和大脑轨迹的多模态表征。

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.