Neuroimmune Control of Biobahavioral Processes

生物行为过程的神经免疫控制

基本信息

批准号：
7367107
负责人：
Rodney W Johnson
金额：
$ 28.91万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-01-01 至 2009-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7367107
关键词：
Admission activity Adolescent Affect Age Age-Years Aging Animals Anti-Inflammatory Agents Anti-inflammatory Antibodies Attenuated Behavior Behavior Therapy Behavioral Blood Brain Cardiovascular system Chronic Clinical Clinical Research Cognition Cognitive Cognitive deficits Condition Coupled Craniocerebral Trauma Daily Data Dementia Development Elderly Elevation Equilibrium Etiology Event Fatigue Genetically Engineered Mouse Growth Factor Hippocampus (Brain)Hormones Hospital Nursing Housing Human Impaired cognition In Vitro Independent Living Individual Injection of therapeutic agent Insulin-Like Growth Factor I Interleukin-1 Interleukin-10 Interleukin-6 Investigation Knockout Mice Laboratories Lead Life Living Wills Measurement Measures Mediating Memory Memory Loss Modeling Molecular Mood Disorders Motivation Motor Motor Activity Mus Muscle NF-kappa B Neurodegenerative Disorders Neurons Nursing Homes Parkinson Disease Patient Self-Report Peptides Performance Personal Satisfaction Physiology Plasma Process Protein Biosynthesis Proteins Proto-Oncogene Proteins c-akt Psychomotor Performance Psychoneuroimmunology Puberty Rate Research Personnel Research Project Grants Resistance Rodent Running Symptoms TNF gene TNFRSF5 gene Testing Therapeutic Intervention Thinking Upper arm Walking Withdrawal age related aged base biobehavior cell type concept cytokine day experience falls germ free condition healthy aging immune function in vitro Model in vivo indexing innovation juvenile animal mature animal normal aging novel strategies programs research study retinal rods skills social toll-like receptor 4 wasting

项目摘要

Very little is known about chronic, long-term actions of endogenous proinflammatory cytokines on basic biobehavioral processes, particularly neuroimmune-mediated sickness behavior, motor function, fatigue and memory. We and others have documented a significant rise in the proinflammatory cytokines IL-6, IL-1 and TNF in both the periphery and brain of healthy aging mice. We hypothesize that this chronic elevation in proinflammatory cytokines is responsible for performance deficits in multiple biobehavioral processes in aged animals. We have established that IL-6 increases and IL-10 decreases significantly in the brain and plasma of healthy aging mice. These changes are associated with reduced hippocampal-dependent spatial memory and motor function (as assessed by locomotor activity and treadmill running). We have also shown that two important aspects of sickness behavior, immobility and social investigation following i.c.v, injections of either LPS or IL-1, are ameliorated in IL-6 knockout mice. We postulate that the normal, chronic, age-associated rise in IL-6, IL-1 and TNF impacts numerous biobehavioral processes, as assessed by an increase in sickness-related behaviors (diminished social investigation, spatial memory loss) and a reduction in motor function (fatigue on a treadmill, alternations in a 4-arm plus maze, stationery rod). In Objective 1, we will test the hypothesis that all of these age-associated biobehavioral variables are attenuated in Toll-like receptor-4 and NF-KappaB p50 knockout mice but are exacerbated in mice deficient in IL-10. Objective 2 will use IL-6- deficient mice and cytokine-specific antibodies to define intracellular substrates that lead to age-associated reductions in these biobehavioral events. Objective 3 will expand our exciting findings that IGF-I, a growth factor that behaves as an anti-inflammatory cytokine and declines during aging, counteracts age-associated biobehavioral deficits. Finally, Objective 4 will utilize a well-defined model that is very likely to explain the molecular events that are directly responsible for biobehavioral performance deficits in both muscle and brain. These experiments will use both in vitro and in vivo approaches and are needed to understand how chronic, long-term elevations in proinflammatory cytokines impair important biobehavioral processes.

对于内源性促炎细胞因子对基本生物行为过程的慢性长期作用，尤其是神经免疫性介导的疾病行为，运动功能，疲劳和记忆力很少。我们和其他人已经记录了健康衰老小鼠的周围和大脑中促炎细胞因子IL-6，IL-1和TNF的显着增加。我们假设促炎细胞因子的这种慢性升高是导致老年动物多种生物行为过程中的性能缺陷。我们已经确定，健康衰老小鼠的大脑和血浆中IL-6的增加，IL-10显着降低。这些变化与降低海马依赖性空间记忆和运动功能有关（通过运动活动和跑步机评估）。我们还表明，在IL-6基因敲除小鼠中改善了疾病行为，疾病行为，不动和注射LPS或IL-1后的社会调查的两个重要方面。 We postulate that the normal, chronic, age-associated rise in IL-6, IL-1 and TNF impacts numerous biobehavioral processes, as assessed by an increase in sickness-related behaviors (diminished social investigation, spatial memory loss) and a reduction in motor function (fatigue on a treadmill, alternations in a 4-arm plus maze, stationery rod).在目标1中，我们将检验以下假设：所有这些与年龄相关的生物行为变量都在Toll样受体-4和NF-kappab P50敲除小鼠中衰减，但在IL-10缺乏小鼠中加剧了。目标2将使用IL-6缺乏小鼠和细胞因子特异性抗体来定义细胞内底物，从而导致这些生物行为事件中与年龄相关的降低。目标3将扩大我们令人兴奋的发现，即IGF-I是一种生长因子，它是一种抗炎细胞因子，在衰老期间，与年龄相关的生物行为缺陷相反。最后，目标4将利用一个定义明确的模型，该模型很可能解释了直接导致肌肉和脑部生物行为性能缺陷的分子事件。这些实验将同时使用体外和体内方法，并且需要了解慢性，长期促炎细胞因子的长期升高如何损害重要的生物行为过程。