A NOVEL ELECTROPHYSIOLOGICAL MODEL OF CHEMOTHERAPY-INDUCED COGNITIVE IMPAIRMENTS IN MICE
A NOVEL ELECTROPHYSIOLOGICAL MODEL OF CHEMOTHERAPY-INDUCED COGNITIVE IMPAIRMENTS IN MICE
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DOI：
10.1016/j.neuroscience.2008.08.060
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发表时间：
2008-11-11
期刊：
影响因子：
3.3
通讯作者：
Siegel, S. J.
中科院分区：
文献类型：
--
作者：
Gandal, M. J.;Ehrlichman, R. S.;Siegel, S. J.
目的：已知化疗药物可使癌症患者产生持续性认知缺陷。然而，在开发动物模型以探索潜在的机制和潜在的治疗干预方面进展甚微。我们报告的电生理模型化疗引起的认知功能障碍，使用感觉门控范式，对应于性能在两个behavioral tasks.Experimental design：小鼠接受每周注射四次甲氨蝶呤和5-氟尿嘧啶。全脑事件相关电位（ERP）记录使用配对点击范例。结果：化疗组动物在药物治疗开始后5周，ERP第一个正峰（P1）与第一个负峰（N1）之比明显降低，门控功能明显受损。药物对P1-N1波幅和P1潜伏期无影响。药物治疗的动物也表现出显着增加冻结在恐惧条件反射和增加探索没有记忆障碍在新的物体recognition.Conclusions：化疗导致门传入的听觉刺激，这可能是相关的认知障碍的基础能力下降。这些门控缺陷与对恐惧条件反射的过度活跃反应和对新物体的适应性降低有关，这表明情绪调节障碍的另一个组成部分。然而，ERP组件的振幅和潜伏期不受影响，因为是NOR性能，突出了这些赤字的微妙性质。(C)2008年IBRO。由爱思唯尔有限公司出版。保留所有权利。
Purpose: Chemotherapeutic agents are known to produce persistent cognitive deficits in cancer patients. However, little progress has been made in developing animal models to explore underlying mechanisms and potential therapeutic interventions. We report an electrophysiological model of chemotherapy-induced cognitive deficits using a sensory gating paradigm, to correspond with performance in two behavioral tasks.Experimental design: Mice received four weekly injections of methotrexate and 5-fluorouracil. Whole-brain event-related potentials (ERPs) were recorded throughout using a paired-click paradigm. Mice underwent contextual fear conditioning (CFC) and novel-object recognition testing (NOR).Results: Chemotherapy-treated animals showed significantly impaired gating 5 weeks after drug treatments began, as measured by the ratio of the first positive peak in the ERP (P1) minus the first negative peak (N1) between first and second auditory stimuli. There was no effect of drug on the amplitude of P1-N1 or latency of P1. The drug-treated animals also showed significantly increased freezing during fear conditioning and increased exploration without memory impairment during novel object recognition.Conclusions: Chemotherapy causes decreased ability to gate incoming auditory stimuli, which may underlie associated cognitive impairments. These gating deficits were associated with a hyperactive response to fear conditioning and reduced adaptation to novel objects, suggesting an additional component of emotional dysiregulation. However, amplitudes and latencies of ERP components were unaffected, as was NOR performance, highlighting the subtle nature of these deficits. (C) 2008 IBRO. Published by Elsevier Ltd. All rights reserved.