Neuroimmune Control of Biobahavioral Processes

内源性促炎细胞因子对基本生物行为过程的慢性、长期作用知之甚少，特别是神经免疫介导的疾病行为、运动功能、疲劳和记忆。我们和其他人已经证明，在健康衰老小鼠的外周和大脑中，促炎细胞因子IL-6、IL-1和TNF显著升高。我们假设这种促炎细胞因子的慢性升高是导致老年动物在多种生物行为过程中的表现缺陷的原因。我们已经确定，在健康衰老小鼠的大脑和血浆中，IL-6显著增加，IL-10显著降低。这些变化与海马依赖的空间记忆和运动功能的减少有关（通过运动活动和跑步机跑步来评估）。我们还表明，注射LPS或IL-1后，IL-6敲除小鼠的疾病行为、不动和社会调查的两个重要方面都得到了改善。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，通过疾病相关行为的增加（社会调查减少、空间记忆丧失）和运动功能的减少（跑步机上的疲劳、四臂迷宫的交替、固定杆）来评估。在目标1中，我们将验证以下假设：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缺乏小鼠中加剧。目的2将使用IL-6缺陷小鼠和细胞因子特异性抗体来确定导致这些生物行为事件与年龄相关减少的细胞内底物。目标3将扩展我们令人兴奋的发现，即igf - 1，一种生长因子，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将利用一个定义良好的模型，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。这些实验将采用体外和体内两种方法，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.