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

为疲劳神经生物学奠定基础：验证动物模型

• 批准号: 8242265
• 负责人: MARY E HARRINGTON
• 金额: $ 18.76万
• 依托单位: SMITH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-15 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8242265
• 关键词: Age; Aging; Animal Model; Animals; Anxiety; Arousal; Behavior; Behavioral; Biological; Bioluminescence; Chronic; Chronobiology; Circadian Rhythms; Darkness; Data; Development; Disease; Fatigue; Foundations; Future; Gender; Goals; Grant; House mice; Human; In Vitro; Inflammation; Inflammatory; Interleukin-12; Intervention; Laboratory Animals; Lead; Link; Malignant Neoplasms; Maps; Measures; Mediating; Mental Depression; Mission; Modeling; Motor Activity; Multiple Sclerosis; Mus; Neural Pathways; Neurobiology; Neurotransmitters; Outcome; Output; Parkinson Disease; Pathway interactions; Physiological; Poliomyelitis; Population; Quality of life; Reporting; Research; Research Personnel; Research Project Grants; Risk; Rodent; Role; Running; Sleep; Stroke; Symptoms; System; Testing; Transgenes; Work; aged; base; circadian pacemaker; cytokine; disability; disease diagnosis; experience; genetic manipulation; improved; innovation; mortality; neural circuit; novel; relating to nervous system; research study

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 PUBLIC HEALTH RELEVANCE: The project is relevant to NIH's mission to alleviate symptoms associated with illness and aging because these animal models will allow future work targeted toward understanding of underlying biological mechanisms and the development of new treatments for fatigue. Treatments developed in laboratory animals could be applied to help reduce fatigue in humans, and improve quality of life.

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（例如焦虑和抑郁）至关重要，但目前研究人员还没有广泛接受的用于疲劳研究的动物模型。这笔赠款将基于预期降低昼夜节律幅度的干预措施开发一种新的疲劳动物模型。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。当前应用的目的是验证疲劳动物模型，以我们的初步研究为基础，证明慢性促炎细胞因子的选择性行为效应。中心假设是，昼夜节律输出的减少会引起行为变化，这些变化可以被验证为啮齿类动物的“疲劳”。我们进行这一研究的理由是认识到，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器的作用，将有助于理解疲劳的神经生物学的进展。预期结果将是一种新型的疲劳动物模型。具体目标 1：开发基于慢性低度炎症的疲劳动物模型。实验将测试基于初步数据的工作假设，即长期施用促炎细胞因子 IL-12 将显着减少更费力的隧道挖掘和车轮行驶活动，但对一般运动活动几乎没有影响。为了将该模型描述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中断。实验将验证以下假设：用促炎细胞因子治疗会导致昼夜节律紊乱，在持续黑暗的环境下测量小鼠的昼夜节律，并与动物的年龄和性别相互作用。为了评估这种治疗，一些实验将使用带有 Per2Luc 转基因的小鼠，并通过体外生物发光测量来评估昼夜节律不同步。该项目的创新之处在于将 PI 在时间生物学方面的专业知识应用于疲劳的神经基础问题。这一贡献意义重大，因为它将向实验动物研究人员和时间生物学家开放疲劳研究，从而能够在绘制神经回路、调节神经递质或针对基因操作等层面上进行疲劳研究。 1 公共健康相关性：该项目与 NIH 减轻与疾病和衰老相关的症状的使命相关，因为这些动物模型将使未来的工作能够致力于了解潜在的生物机制和开发新的疲劳疗法。在实验动物身上开发的治疗方法可用于帮助减轻人类疲劳并提高生活质量。