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

项目概要 重度抑郁症 (MDD) 的首次发作通常始于青春期。尽管事实上 青少年发作的 MDD 与更严重和反复发作的 MDD 相关，但目前对此的研究还很少。 这样做是为了确定抑郁症复发或复发的机制。候选人之前的工作有 记录了涉及前扣带皮层（ACC）的功能和结构连接的差异 患有重度抑郁症的青少年与精神健康对照者之间的比较；这些表型被认为反映了 改变关键情绪调节回路的神经发育。然而，我们还不知道是否以及如何 MDD 会影响青少年 ACC 连接性的发展，从而导致增加以下风险： 抑郁症复发或复发。一种机制可能是免疫系统，它会响应 心理社会压力源并影响神经递质系统，包括谷氨酸，主要兴奋剂 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 谷氨酸能神经元过度兴奋达到神经毒性，从而减少 神经可塑性。此外，成人 MDD 的神经影像学研究表明炎症水平升高 以及 ACC 中谷氨酸水平的改变。这些数据与越来越多的证据相结合，表明 ACC 连接性在青春期经历了广泛的成熟，表明炎症和炎症加剧 过量的谷氨酸可能会导致患有重度抑郁症的青少年的这一回路出现非典型发育。候选人 因此，我们试图检验一个中心假设：炎症加剧是通过谷氨酸发挥作用的 传播会破坏患有 MDD 的青少年 ACC 连接的典型神经发育，从而增加风险 抑郁症复发或复发。 K01 将在 60 名首次出现 MDD 的青少年中测试该模型 使用创新的多模式方法在 3 个时间点进行纵向评估。候选人将进行测试 使用干血点技术、无创图像测定外周促炎细胞因子水平 使用质子磁共振波谱法检测 ACC 中的谷氨酸和抗氧化剂，并评估 使用功能性（静息态功能磁共振成像）和结构性（扩散）观察 ACC 连接的神经发育变化 MRI）方法。本 K01 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 连接性、MDD 相关变化背后的炎症和谷氨酸机制 ACC 连接是否会导致患有 MDD 的青少年随后复发或复发，以及是否 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电路的开发。重要的是，候选人将在接受的背景下进行这项研究 压力相关免疫生物学、因果推理模型和发育方面的高级培训 精神病理学。该项目的结果将最终形成 R01，旨在识别以下疾病的亚型/生物型： 基于临床病程和大脑轨迹多模态特征的青少年 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.