Neurobiology of cytokine effects on CNS glutamate in IFN-alpha-induced depression

IFN-α 诱导的抑郁症中细胞因子对中枢神经系统谷氨酸影响的神经生物学

• 批准号: 8970385
• 负责人: Jennifer C Felger
• 金额: $ 22.63万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8970385
• 关键词: Adult; Affect; Agonist; Amino Acid Transporter; Animal Model; Animals; Anterior; Astrocytes; Attention; Autopsy; Back; Basal Ganglia; Behavior; Behavioral; Cell Nucleus; Cerebrospinal Fluid; Chronic; Clinical Trials; Data; Development; Dioxygenases; Enzymes; Excitatory Amino Acid Transporter 2; Excitatory Amino Acids; Exhibits; Female; Fresh Tissue; Future; Gene Expression; Glutamate Receptor; Glutamate Transporter; Glutamates; Goals; Health; Hepatitis C; Hepatitis C virus; High Pressure Liquid Chromatography; Human; Immune system; Immunoblotting; Immunohistochemistry; In Vitro; Inflammation; Inflammatory; Interferon-alpha; Kynurenine; Laboratory Animals; Lead; Light; Link; Macaca mulatta; Magnetic Resonance Spectroscopy; Major Depressive Disorder; Measures; Mediating; Mental Depression; Metabotropic Glutamate Receptors; Microglia; Microscopy; Modeling; Monkeys; N-Methyl-D-Aspartate Receptors; Neurobiology; Neurotoxins; Neurotransmitters; Pathway interactions; Patients; Peripheral; Production; Proteins; Quinolinic Acid; RNA Sequences; Research; Rodent; Role; Severities; Signal Pathway; Signal Transduction Pathway; Testing; Therapeutic Agents; Tissues; Tryptophan; United States; Work; aged; animal data; base; behavioral study; brain tissue; chemokine; cingulate cortex; cytokine; depressed patient; depressive symptoms; enzyme pathway; excitotoxicity; extracellular; genome-wide; human data; in vivo; indoleamine; macrophage; male; melanoma; metabotropic glutamate receptor type 1; neurotransmission; new therapeutic target; nonhuman primate; novel; novel strategies; prevent; sex; tissue fixing; transcriptome sequencing; translational study; treatment strategy

 DESCRIPTION (provided by applicant): To identify novel therapeutic targets to reverse inflammatory cytokine effects on behavior, this study will explore mechanisms by which interferon (IFN)-alpha affects CNS glutamate using post-mortem brain tissue collected from a back translational model of cytokine-induced depressive-like behavior. Inflammatory cytokines and their signaling pathways are reliably elevated in a significant proportion of depressed patients, and administration of cytokines is associated with development of depressive symptoms in laboratory animals and humans. For instance, peripheral administration of IFN-alpha for treatment of hepatitis C and malignant melanoma is well known to induce clinical depression in up to 50% of patients, and has been shown to cause anhedonic and depressive-like behavior in laboratory animals. Despite the mounting evidence that inflammatory cytokines affect behavior, the CNS mechanisms by which cytokines cause depressive symptoms are only beginning to be understood. One pathway that is receiving increasing attention is CNS glutamate. Recent results from our group using magnetic resonance spectroscopy indicate that administration of IFN-alpha to patients with hepatitis C increased glutamate in the basal ganglia and anterior cingulate cortex (ACC), which correlated with depressive symptoms. In addition, our preliminary results from RNA sequencing in postmortem tissue demonstrate that peripheral administration of IFN-alpha not only decreased in vivo expression of the glutamate transporter (excitatory amino acid transporter 2), but also increased in vivo gene expression relevant to glutamate neurotransmission, including N-methyl-D-aspartate (NMDA) receptor subunits and metabotropic glutamate receptors that are involved in glutamate excitotoxicity. IFN-alpha may also increase glutamate neurotransmission through activation of the kynurenine pathway and production of quinolinic acid (QUIN), an NMDA receptor agonist and neurotoxin, by activated microglia and CNS macrophages. Of note, our preliminary data indicate that IFN-alpha increased perivascular macrophages and increased microglia activation in specific basal ganglia nuclei. Based on these findings from animals and humans, this proposal will test the hypothesis that chronic IFN-alpha increases glutamate and affects glutamate neurotransmission in the basal ganglia and ACC through decreasing glutamate transporters, increasing excitotoxic glutamate receptor subtypes and their signaling pathways, and increasing the production of QUIN by activated microglia and perivascular macrophages. This study will be the first to elucidate cytokine-induced changes in glutamate neurotransmission in vivo and link these changes to QUIN induction by activated macrophages and microglia in an established, back translational model. This study will also reveal new treatment strategies for future clinical trials to reverse or prevent depressive symptoms in patients exposed to elevated levels of inflammatory cytokines.

 描述（由申请方提供）：为了确定逆转炎性细胞因子对行为影响的新型治疗靶点，本研究将使用从马槟榔诱导的抑郁样行为的反向翻译模型中收集的死后脑组织探索干扰素（IFN）-α影响CNS谷氨酸的机制。炎症细胞因子及其信号通路在相当大比例的抑郁症患者中可靠地升高，并且细胞因子的施用与实验室动物和人类中抑郁症状的发展相关。例如，用于治疗丙型肝炎和恶性黑素瘤的IFN-α的外周给药众所周知在高达50%的患者中诱导临床抑郁，并且已经显示在实验室动物中引起快感缺乏和抑郁样行为。尽管越来越多的证据表明炎性细胞因子影响行为，但细胞因子引起抑郁症状的CNS机制才刚刚开始被理解。一个越来越受到关注的途径是中枢神经系统谷氨酸。 我们小组最近使用磁共振波谱的结果表明，给予丙型肝炎患者IFN-α增加了基底神经节和前扣带皮层（ACC）中的谷氨酸盐，这与抑郁症状相关。此外，我们的初步结果，从RNA测序在死后组织表明，外周给药的IFN-α不仅降低了体内表达的谷氨酸转运蛋白（兴奋性氨基酸转运蛋白2），但也增加了体内基因表达相关的谷氨酸神经传递，包括N-甲基-D-天冬氨酸（NMDA）受体亚单位和代谢型谷氨酸受体参与谷氨酸兴奋性毒性。IFN-α还可以通过激活犬尿氨酸途径和通过激活的小胶质细胞和CNS巨噬细胞产生喹啉酸（QUIN）（一种NMDA受体激动剂和神经毒素）来增加谷氨酸神经传递。值得注意的是，我们的初步数据表明，IFN-α增加血管周围的巨噬细胞和特定基底神经节细胞核中的小胶质细胞活化。基于动物和人类的这些发现，本提案将检验以下假设：慢性IFN-α通过减少谷氨酸转运蛋白、增加兴奋毒性谷氨酸受体亚型及其信号通路以及通过激活的小胶质细胞和血管周围巨噬细胞增加QUIN的产生来增加谷氨酸并影响基底神经节和ACC中的谷氨酸神经传递。这项研究将是第一个阐明精氨酸诱导的体内谷氨酸神经传递的变化，并将这些变化与已建立的反向翻译模型中活化的巨噬细胞和小胶质细胞的QUIN诱导联系起来。这项研究还将为未来的临床试验揭示新的治疗策略，以逆转或预防暴露于炎症细胞因子水平升高的患者的抑郁症状。