Li Yingzhuo, Wang Xuejiao, Chen Jingyu, Li Zijie, Yang Pingting, Qin Ling
Department of Physiology, China Medical Univeristy, Shenyang, China.
Department of Rheumatology and Immunology, First Affiliated Hospital, China Medical University, Shenyang, China.
Front Pharmacol. 2021 Jan 27;11:584425. doi: 10.3389/fphar.2020.584425. eCollection 2020.
Patients receiving the cytokine immunotherapy of interferon-alpha (IFN-α) frequently present with depression. This is one of the excellent models to explore the action of peripheral cytokine on central nervous system (CNS) and to study the development of depression. The auditory steady-state response (ASSR), electroencephalogram (EEG) oscillations induced by periodic acoustic stimulation, is an effective approach to evaluate the neural function in mental illness including depression. The aim of the present study was to investigate the effect of IFN-α on the cortical ASSR and its correlation with depressive-like behavior. Chronic electrodes were implanted on the skull over the auditory cortex (AC) of male C57BL/6 mice. The animals were treated with daily injection of IFN-α or saline (vehicle) for three weeks. EEGs were recorded in AC of the same mouse before and after the injection treatment to monitor the changes of ASSR induced by IFN-α. Depressive-like behavior was analyzed in the forced swim test (FST). Immunohistochemical staining was used to examine the status of neuron and glia in the hippocampus and AC. Compared to pretreatment condition, injection of IFN-α significantly reduced the power of 40 Hz ASSR in the mouse AC from the second week. Such a decrease continued to the third week. The immobility times of FST were significantly increased by a 3-week treatment of IFN-α and the immobility time was negatively correlated with the power of 40 Hz ASSR. Astrocytes and microglia in the hippocampus and AC were activated by IFN-α, but the density of neuron was not significantly affected. Our results suggest that EEG measurement of ASSR may be used as a biomarker to monitor the CNS side effects of IFN-α treatment and to search a novel intervention with potential therapeutic implications.
接受干扰素-α（IFN-α）细胞因子免疫治疗的患者经常出现抑郁症状。这是探索外周细胞因子对中枢神经系统（CNS）作用以及研究抑郁症发病机制的优秀模型之一。听觉稳态反应（ASSR）是由周期性声刺激诱发的脑电图（EEG）振荡，是评估包括抑郁症在内的精神疾病神经功能的有效方法。本研究的目的是探讨IFN-α对皮质ASSR的影响及其与抑郁样行为的相关性。将慢性电极植入雄性C57BL/6小鼠听觉皮层（AC）上方的颅骨上。动物每天注射IFN-α或生理盐水（载体），持续三周。在注射治疗前后，记录同一只小鼠AC的EEG，以监测IFN-α诱导的ASSR变化。在强迫游泳试验（FST）中分析抑郁样行为。采用免疫组织化学染色检测海马和AC中神经元和胶质细胞的状态。与预处理条件相比，从第二周开始，注射IFN-α显著降低了小鼠AC中40Hz ASSR的功率。这种降低持续到第三周。IFN-α治疗3周后，FST的不动时间显著增加，且不动时间与40Hz ASSR的功率呈负相关。IFN-α激活了海马和AC中的星形胶质细胞和小胶质细胞，但神经元密度未受到显著影响。我们的结果表明，ASSR的EEG测量可作为一种生物标志物，用于监测IFN-α治疗的CNS副作用，并寻找具有潜在治疗意义的新型干预措施。
