Inflammation-Induced CNS Glutamate Changes in Depression

项目摘要 这项拟议的研究将检验炎症增加导致基底神经节增加的假设。 严重抑郁症患者的谷氨酸及随后的快感缺乏和精神运动迟缓 精神障碍(MDD)。过度的炎症和谷氨酸的兴奋性毒性是两种途径 对包括情绪障碍在内的神经精神疾病的病理生理学日益关注。 抑郁症患者的外周和中枢神经系统(CNS)标志物增加 核磁共振波谱(MRS)显示炎症反应和中枢神经系统谷氨酸改变。在……里面 此外，阻断炎症或谷氨酸信号的药物可以逆转抑郁症状， 尤其是对治疗耐药的抑郁症患者。有趣的是，最近的数据表明， 这两条途径汇聚成病理学。已知炎性细胞因子可抑制谷氨酸 重新摄取和增加星形胶质细胞的谷氨酸释放，谷氨酸拮抗剂已被证明 阻断炎症诱导的小鼠抑郁样行为。此外，使用MRS，我们的数据显示 给予炎性细胞因子干扰素-α可显著增加脑组织谷氨酸的含量。 神经节与干扰素-α诱导的快感减退和精神运动减慢有关。此外，我们集团还拥有 证明外周血C反应蛋白(CRP)反映的炎症增加 与基底节谷氨酸升高相关，与动机和精神运动减少相关 MDD患者的速度。然而，到目前为止，数据是相互关联的，以及是否增加了 炎症导致基底神经节谷氨酸增加，进而导致行为改变。 在抑郁症患者中的作用尚未得到证实。为了检验这一假设，我们计划确定原因 炎症加重与中枢神经系统谷氨酸升高的效应关系 应用高特异性肿瘤坏死因子对伴有高度炎症(C反应蛋白和GT；3 mg/L)的抑郁症患者的炎症反应 拮抗剂英夫利昔单抗(n=30)与安慰剂(n=30)比较。此外，我们还将检查基准线的变化 谷氨酸神经节与基底节相关行为的改变有关，包括快感缺乏和 精神运动发育迟缓(通过基于工作表现、临床应用和自我报告来衡量 评估针对检查正价系统和负价系统的研究领域标准)。最后， 我们将探索影响基底节谷氨酸的特定免疫途径。这些数据将成为 首先在涉及炎症和谷氨酸的病理生理机制之间建立联系，同时还 通过识别炎症的外周生物标记物帮助个性化护理，以指导未来 使用抗炎药和/或谷氨酸拮抗剂治疗抑郁症和 炎症加重的其他精神疾病。

Project Summary The proposed research will test the hypothesis that increased inflammation causes increased basal ganglia glutamate and consequently anhedonia and psychomotor retardation in patients with major depressive disorder (MDD). Excessive inflammation and glutamate excitotoxicity are two pathways that have received increasing attention regarding the pathophysiology of neuropsychiatric disease including mood disorders. Patients with depression exhibit increased peripheral and central nervous system (CNS) markers of inflammation as well as altered CNS glutamate as measured by magnetic resonance spectroscopy (MRS). In addition, drugs that block either inflammation or glutamate signaling can reverse depressive symptoms, especially in depressed patients with treatment resistance. Interestingly, recent data suggest there may be convergence of these two pathways to pathology. Inflammatory cytokines are known to inhibit glutamate reuptake and increase glutamate release from astrocytes, and glutamate antagonists have been shown to block inflammation-induced depressive-like behavior in mice. Moreover, using MRS, our data has shown that administration of the inflammatory cytokine interferon (IFN)-alpha significantly increases glutamate in the basal ganglia in association with IFN-alpha-induced anhedonia and psychomotor slowing. In addition, our group has demonstrated that increased inflammation as reflected by peripheral blood C-reactive protein (CRP) is correlated with increased basal ganglia glutamate in association with decreased motivation and psychomotor speed in patients with MDD. Nevertheless, the data to date has been correlational, and whether increased inflammation causes increased glutamate in the basal ganglia, which in turn contributes to behavioral changes in patients with depression has not been established. To test this hypothesis, we plan to determine the cause and effect relationship between increased inflammation and increased CNS glutamate by blocking inflammation in depressed patients with high inflammation (CRP>3mg/L) using the highly specific TNF antagonist infliximab (n=30) versus placebo (n=30). In addition, we will examine whether changes in basal ganglia glutamate are linked to changes in behaviors related to the basal ganglia including anhedonia and psychomotor retardation (as measured by performance-based, clinical administered and self-report assessments targeting research domain criteria that examine positive and negative valence systems). Finally, we will explore the specific immunologic pathways that affect basal ganglia glutamate. These data will be the first to establish a link between pathophysiologic mechanisms involving inflammation and glutamate, while also helping personalize care through the identification of peripheral biomarkers of inflammation to guide future studies using anti-inflammatory agents and/or glutamate antagonists to treat patients with depression and other psychiatric disorders with increased inflammation.