Building foundations for a neurobiology of fatigue: validating an animal model

描述（由申请人提供）：动物模型对于我们理解其他主观定义的症状（如焦虑和抑郁）的进展至关重要，但目前研究人员还没有广泛接受的疲劳研究动物模型。该基金将开发一种新的疲劳动物模型，该模型基于预期降低昼夜节律振幅的干预措施。长期目标是了解昼夜节律系统在疲劳的生理和神经基础中的作用。本申请的目的是验证疲劳的动物模型，建立在我们的初步研究的基础上，这些研究证明了慢性促炎细胞因子的选择性行为作用。中心假设是昼夜节律输出的减少诱导行为变化，其可以被验证为指示啮齿动物中的“疲劳”。我们进行这一研究的基本原理是认识到，通过详细说明昼夜节律系统作为刺激唤醒和活动的神经和生理途径的重要调节剂的作用，将有助于理解疲劳的神经生物学的进展。预期的结果将是一种新的疲劳动物模型。具体目标1：建立基于慢性低度炎症的疲劳动物模型。实验将基于初步数据来检验工作假设，即慢性促炎细胞因子IL-12给药将显著降低更费力的隧道挖掘和轮跑活动，但对一般运动活动几乎没有影响。为了将该模型表征为与衰老相关的模型，该实验将证明慢性促炎细胞因子对疲劳的不同影响取决于动物的年龄或性别。具体目标2：确定我们的疲劳动物模型是否涉及生物钟输出的中断。实验将测试工作假设，即用促炎细胞因子治疗将导致在恒定黑暗下饲养的小鼠中测量的昼夜节律破坏，与动物的年龄和性别相互作用。为了评估这种治疗，一些实验将使用具有Per 2Luc转基因的小鼠，并将通过生物发光的体外测量来评估昼夜节律。什么可能使拟议中的项目特别创新的是PI的专业知识在时间生物学的疲劳的神经基础的问题的应用。这一贡献意义重大，因为它将向实验室动物研究人员和时间生物学家开放疲劳研究，使疲劳研究能够在神经回路映射，调节神经递质或靶向遗传操作等水平上进行。1

DESCRIPTION (provided by applicant): Animal models have been essential in allowing progress in our understanding of other subjectively- defined symptoms such as anxiety and depression, but currently researchers have no widely accepted animal model for the study of fatigue. This grant will develop a new animal model of fatigue based on interventions expected to decrease circadian amplitude. The long-term goal is to understand the role of the circadian system in the physiological and neural basis for fatigue. The objective in the current application is to validate an animal model of fatigue, building on our preliminary studies that demonstrate selective behavioral effects of chronic proinflammatory cytokines. The central hypothesis is that reduction of circadian outputs induces behavioral changes that can be validated as indicating "fatigue" in rodents. Our rationale for pursuing this line of research is the recognition that progress in understanding the neurobiology of fatigue will be facilitated by detailing the role of the circadian system as an important modulator of the neural and physiological pathways stimulating arousal and activity. The expected outcomes will be a novel animal model of fatigue. Specific Aim 1: Develop an animal model of fatigue based on chronic low-grade inflammation. Experiments will test the working hypothesis, based on preliminary data, that chronic pro-inflammatory cytokine IL-12 administration will dramatically decrease more effortful tunnel burrowing and wheel-running activity but will have little effect on general locomotor activity. To characterize this model as one related to aging, this experiment will demonstrate differential effects of chronic pro-inflammatory cytokines on fatigue depending on the age or gender of the animal. Specific Aim 2: Determine if our animal model of fatigue involves disruption of circadian clock output. Experiments will test the working hypothesis that treatment with pro-inflammatory cytokines will lead to circadian disruption measured in mice housed under constant darkness, interacting with the age and gender of the animal. To assess this treatment some experiments will use mice with the Per2Luc transgene and will assess circadian desynchrony by in vitro measures of bioluminescence. What may make the proposed project particularly innovative is the application of the PI's expertise in chronobiology to the question of the neural basis of fatigue. This contribution is significant because it will open the study of fatigue to laboratory animal researchers and chronobiologists, enabling studies of fatigue at levels such as mapping neural circuits, modulating neurotransmitters, or targeting genetic manipulations. 1