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。候选 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。K 01将在60名首次发作MDD的青少年中测试该模型 使用创新的多模式方法在3个时间点上进行纵向评估。候选人将分析 使用干血斑技术，非侵入性成像检测促炎细胞因子的外周水平 谷氨酸和抗氧化剂在ACC使用质子磁共振光谱，并评估 使用功能（静息态fMRI）和结构（弥散）研究ACC连接的神经发育变化 MRI）方法。这个K 01填补了我们对青少年MDD是否影响发展的理解的关键空白 ACC的连接，炎症和炎症机制是如何导致MDD相关变化的， ACC连接有助于MDD青少年随后的复发或复发， 抗氧化剂通过缓冲炎症对青少年的影响来防止抑郁症复发 ACC电路的发展。重要的是，候选人将在接收的背景下执行这项研究 在压力相关的免疫生物学，因果推理建模和发展的高级培训 精神病理学该项目的结果将在R 01中达到高潮，该R 01旨在识别 青少年MDD的基础上的临床过程和多模态表征的大脑轨迹。

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 candidate 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. This K01 will test this model in 60 adolescents with first episodes of MDD assessed longitudinally over 3 time points using an innovative multimodal approach. The candidate 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 assess neurodevelopmental changes of ACC connectivity using functional (resting-state fMRI) and structural (diffusion MRI) methods. This K01 fills key gaps in our understanding of whether adolescent MDD impacts development of ACC connectivity, how inflammatory and glutamatergic mechanisms underlying MDD-related changes in ACC connectivity 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 an R01 that aims to identify subtypes/biotypes of adolescent MDD based on clinical course and multimodal characterizations of brain trajectories.