CNS Diseases Research Germany, Boehringer Ingelheim Pharma GmbH & Co. KG., Biberach, Germany.
Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland; Neuroscience Center, University and ETH Zurich, Switzerland.
Brain Behav Immun. 2016 May;54:59-72. doi: 10.1016/j.bbi.2015.12.020. Epub 2015 Dec 24.
Psychosocial stress is a major risk factor for mood and anxiety disorders, in which excessive reactivity to aversive events/stimuli is a major psychopathology. In terms of pathophysiology, immune-inflammation is an important candidate, including high blood and brain levels of metabolites belonging to the kynurenine pathway. Animal models are needed to study causality between psychosocial stress, immune-inflammation and hyper-reactivity to aversive stimuli. The present mouse study investigated effects of psychosocial stress as chronic social defeat (CSD) versus control-handling (CON) on: Pavlovian tone-shock fear conditioning, activation of the kynurenine pathway, and efficacy of a specific inhibitor (IDOInh) of the tryptophan-kynurenine catabolising enzyme indoleamine 2,3-dioxygenase (IDO1), in reversing CSD effects on the kynurenine pathway and fear. CSD led to excessive fear learning and memory, whilst repeated oral escitalopram (antidepressant and anxiolytic) reversed excessive fear memory, indicating predictive validity of the model. CSD led to higher blood levels of TNF-α, IFN-γ, kynurenine (KYN), 3-hydroxykynurenine (3-HK) and kynurenic acid, and higher KYN and 3-HK in amygdala and hippocampus. CSD was without effect on IDO1 gene or protein expression in spleen, ileum and liver, whilst increasing liver TDO2 gene expression. Nonetheless, oral IDOInh reduced blood and brain levels of KYN and 3-HK in CSD mice to CON levels, and we therefore infer that CSD increases IDO1 activity by increasing its post-translational activation. Furthermore, repeated oral IDOInh reversed excessive fear memory in CSD mice to CON levels. IDOInh reversal of CSD-induced hyper-activity in the kynurenine pathway and fear system contributes significantly to the evidence for a causal pathway between psychosocial stress, immune-inflammation and the excessive fearfulness that is a major psychopathology in stress-related neuropsychiatric disorders.
心理社会应激是心境和焦虑障碍的一个主要危险因素，其中对厌恶事件/刺激的过度反应是主要的精神病理学特征。就病理生理学而言，免疫炎症是一个重要的候选因素，包括血液和大脑中属于犬尿氨酸途径的代谢物水平升高。需要动物模型来研究心理社会应激、免疫炎症和对厌恶刺激的过度反应之间的因果关系。本研究旨在探讨慢性社会挫败（CSD）与对照处理（CON）对以下方面的影响：条件性恐惧反应、犬尿氨酸途径的激活，以及色氨酸犬尿氨酸分解酶吲哚胺 2,3-双加氧酶（IDO1）的特异性抑制剂（IDOInh）的疗效，以逆转 CSD 对犬尿氨酸途径和恐惧的影响。CSD 导致过度的恐惧学习和记忆，而重复口服艾司西酞普兰（抗抑郁药和抗焦虑药）则逆转了过度的恐惧记忆，表明该模型具有预测效度。CSD 导致血液中 TNF-α、IFN-γ、犬尿氨酸（KYN）、3-羟基犬尿氨酸（3-HK）和犬尿氨酸水平升高，杏仁核和海马中 KYN 和 3-HK 水平升高。CSD 对脾、回肠和肝中 IDO1 基因或蛋白表达没有影响，但增加了肝 TDO2 基因表达。然而，口服 IDOInh 可降低 CSD 小鼠血液和大脑中的 KYN 和 3-HK 水平，使其达到 CON 水平，因此我们推断 CSD 通过增加其翻译后激活来增加 IDO1 活性。此外，重复口服 IDOInh 可使 CSD 小鼠的过度恐惧记忆恢复到 CON 水平。IDOInh 逆转 CSD 诱导的犬尿氨酸途径和恐惧系统的过度活跃，为心理社会应激、免疫炎症与应激相关神经精神障碍中过度恐惧这一主要精神病理学特征之间的因果关系提供了重要证据。
