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

 描述(申请人提供)：为了确定逆转炎症细胞因子对行为的影响的新的治疗靶点，本研究将利用从细胞因子诱导的抑郁样行为的反向翻译模型收集的死后脑组织来探索干扰素(干扰素)-α影响中枢谷氨酸的机制。在相当大比例的抑郁症患者中，炎性细胞因子及其信号通路可靠地升高，在实验室动物和人类中，细胞因子的应用与抑郁症状的发展有关。例如，众所周知，外周注射干扰素-α治疗丙型肝炎和恶性黑色素瘤会在高达50%的患者中导致临床抑郁，并已被证明在实验室动物中引起厌食症和抑郁样行为。尽管越来越多的证据表明炎性细胞因子影响行为，但细胞因子导致抑郁症状的中枢神经系统机制才刚刚开始被理解。其中一个受到越来越多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，丙型肝炎患者应用干扰素-α会增加基底节和前扣带皮质(ACC)中的谷氨酸，这与抑郁症状有关。此外，我们的死后组织RNA测序的初步结果表明，外周注射干扰素-α不仅降低了体内谷氨酸转运体(兴奋性氨基酸转运体2)的表达，而且增加了与谷氨酸神经传递相关的基因表达，包括参与谷氨酸兴奋性毒性的N-甲基-D-天冬氨酸(NMDA)受体亚基和代谢性谷氨酸受体。干扰素-α也可能通过激活犬尿氨酸途径和激活的小胶质细胞和中枢神经系统巨噬细胞产生NMDA受体激动剂和神经毒素喹啉酸(Quin)来增加谷氨酸的神经传递。值得注意的是，我们的初步数据表明，干扰素-α增加了血管周围巨噬细胞，并增加了特定基底节核中的小胶质细胞激活。基于动物和人类的这些发现，这一建议将检验这一假说，即慢性干扰素-α通过减少谷氨酸转运体，增加兴奋性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，从而增加谷氨酸并影响基底节和ACC中的谷氨酸神经传递。这项研究将首次阐明细胞因子在体内引起的谷氨酸神经传递的变化，并将这些变化与激活的巨噬细胞和小胶质细胞在已建立的反向翻译模型中诱导的Quin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性细胞因子水平升高的患者的抑郁症状。

 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.