Neuroimmune Control of Biobahavioral Processes

关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，特别是神经免疫介导的疾病行为、运动功能、疲劳和记忆，知之甚少。我们和其他人已经记录了促炎细胞因子IL-6，IL-1和TNF在健康老龄小鼠的外周和大脑中的显著升高。我们推测，这种慢性升高的促炎细胞因子是负责在老年动物的多个生物行为过程中的性能缺陷。我们已经确定，在健康老龄小鼠的脑和血浆中，IL-6显著增加，IL-10显著降低。这些变化与降低的大脑依赖性空间记忆和运动功能（如通过自发活动和跑步机跑步评估）有关。我们还表明，在IL-6敲除小鼠中，i.c.v注射LPS或IL-1后，疾病行为的两个重要方面，即不动性和社会调查得到改善。我们假设，正常的，慢性的，与年龄相关的IL-6，IL-1和TNF的升高会影响许多生物行为过程，如通过疾病相关行为的增加（减少社会调查，空间记忆丧失）和运动功能的减少（跑步机上的疲劳，在4臂加迷宫中的交替，文具杆）所评估的。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在Toll样受体-4和NF-KappaB p50敲除小鼠中减弱，但在IL-10缺陷小鼠中加剧。目标2将使用IL-6缺陷小鼠和精氨酸特异性抗体来定义导致这些生物行为事件中与年龄相关的减少的细胞内底物。目标3将扩展我们令人兴奋的发现，即IGF-I，一种生长因子，作为抗炎细胞因子，在衰老过程中下降，抵消与年龄相关的生物行为缺陷。最后，目标4将利用一个定义明确的模型，该模型很可能解释直接导致肌肉和大脑生物行为表现缺陷的分子事件。这些实验将使用体外和体内方法，并且需要了解促炎细胞因子的慢性长期升高如何损害重要的生物行为过程。

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.