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。候选人 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。K01将在60名首次出现MDD的青少年中测试这一模型 使用创新的多模式方法对3个时间点进行纵向评估。候选人将进行化验 用干血斑技术检测外周促炎细胞因子水平，非侵入性成像 用质子磁共振波谱分析ACC中的谷氨酸和抗氧化剂，并评估 用功能(静息状态fMRI)和结构(扩散)研究ACC连接性的神经发育变化 MRI)方法。K01填补了我们对青春期MDD是否影响发育的理解的关键空白 关于ACC连接性，MDD相关变化背后的炎症和谷氨酸能机制 在患有MDD的青少年中，ACC的连接性有助于随后的复发或复发，以及 抗氧化剂通过缓冲青少年炎症的影响来预防抑郁症的复发 Acc电路的发展。重要的是，应聘者将在收到 应激相关免疫生物学、因果推理建模和发育方面的高级培训 精神变态学。该项目的结果将在R01中达到顶峰，该R01旨在确定 基于临床病程和脑轨迹多模式特征的青春期MDD。

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.