Suppression of Locomotor Activity in Female C57Bl/6J Mice Treated with Interleukin-1β: Investigating a Method for the Study of Fatigue in Laboratory Animals.
Suppression of Locomotor Activity in Female C57Bl/6J Mice Treated with Interleukin-1β: Investigating a Method for the Study of Fatigue in Laboratory Animals.
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DOI：
10.1371/journal.pone.0140678
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Harrington ME
中科院分区：
文献类型：
--
作者：
Bonsall DR;Kim H;Tocci C;Ndiaye A;Petronzio A;McKay-Corkum G;Molyneux PC;Scammell TE;Harrington ME
疲劳是多发性硬化症和帕金森病患者的一种致残症状，在脑外伤、癌症和炎症性疾病患者中也很常见。人们对疲劳的神经生物学知之甚少，部分原因是缺乏诱导实验动物疲劳的方法。疲劳是对病原体全身攻击的常见反应，这种反应部分是通过促炎细胞因子白介素 1 β (IL-1 β) 的作用介导的。我们研究了小鼠对 IL-1β 的行为反应。对 3 个年龄的雌性 C57Bl/6J 小鼠进行不同剂量的 IL-1β 腹腔注射。 Interleukin-1β 会降低运动活动，并且敏感性随着年龄的增长而增加。对中年女性进行了进一步的实验。集中施用 IL-1β 会剂量依赖性地降低运动活性。使用抑制运动活动的 IL-1β 剂量，我们测量了最轻微的疾病症状，例如高热、疼痛或快感缺乏（分别用腹部温度探针、镇痛剂丁丙诺啡预处理和蔗糖偏好进行测量），所有这些都是通常报告的较高剂量的反应。我们发现中年食欲素-/-小鼠表现出与野生型对照小鼠相同的IL-1β对运动活动的影响，这表明食欲素对于IL-1β诱导的轮跑减少不是必需的。鉴于目前疲劳治疗方法的可用性和成功率有限，我们研究了两种潜在的临床治疗方法莫达非尼和哌醋甲酯的有效性。我们发现这些治疗在给予 IL-1β 后恢复运动活性方面取得了不同程度的成功。这为开发令人满意的多维疲劳体验动物模型迈出了一步，该模型可以让我们确定炎症诱发疲劳的可能途径，并可能导致逆转疲劳的新疗法。
Fatigue is a disabling symptom in patients with multiple sclerosis and Parkinson’s Disease, and is also common in patients with traumatic brain injury, cancer, and inflammatory disorders. Little is known about the neurobiology of fatigue, in part due to the lack of an approach to induce fatigue in laboratory animals. Fatigue is a common response to systemic challenge by pathogens, a response in part mediated through action of the pro-inflammatory cytokine interleukin-1 beta (IL-1β). We investigated the behavioral responses of mice to IL-1β. Female C57Bl/6J mice of 3 ages were administered IL-1β at various doses i.p. Interleukin-1β reduced locomotor activity, and sensitivity increased with age. Further experiments were conducted with middle-aged females. Centrally administered IL-1β dose-dependently reduced locomotor activity. Using doses of IL-1β that caused suppression of locomotor activity, we measured minimal signs of sickness, such as hyperthermia, pain or anhedonia (as measured with abdominal temperature probes, pre-treatment with the analgesic buprenorphine and through sucrose preference, respectively), all of which are responses commonly reported with higher doses. We found that middle-aged orexin-/- mice showed equivalent effects of IL-1β on locomotor activity as seen in wild-type controls, suggesting that orexins are not necessary for IL-1β -induced reductions in wheel-running. Given that the availability and success of therapeutic treatments for fatigue is currently limited, we examined the effectiveness of two potential clinical treatments, modafinil and methylphenidate. We found that these treatments were variably successful in restoring locomotor activity after IL-1β administration. This provides one step toward development of a satisfactory animal model of the multidimensional experience of fatigue, a model that could allow us to determine possible pathways through which inflammation induces fatigue, and could lead to novel treatments for reversal of fatigue.