Cytokines, Behavior, and Mental Health

描述（由申请人提供）：在理解正常和病理行为的神经生物学基础方面的一个重大进展是发现促炎细胞因子在中枢神经系统中起作用，改变行为并诱导情感和认知障碍。促炎细胞因子可以在神经免疫系统中通过调节几种神经递质的合成和释放来改变行为。我们现在有数据表明，TNFalpha也可以与传统的神经递质一起改变行为。在这两种情况下，对调节大脑中促炎细胞因子的内源性保护分子及其行为影响知之甚少。我们在体内有令人兴奋的新的初步证据表明，IGF-1抑制由TNFalpha诱导的疾病行为和由谷氨酸/海碱盐以依赖TNFalpha的方式诱导的空间记忆障碍。我们扩展了这些在体内的研究结果，表明TNFalpha仅在谷氨酸盐和海因酸盐存在时加剧神经元应激，而IGF-I在体外保护神经元免受这些损伤。在目标1中，我们将进一步评估IGF-I改善TNFalpha的情感和认知效应的可能性。将使用缺乏TNF受体和关键细胞内TNF受体信号蛋白FAN的小鼠。注射TNFalpha后，社会探索、不活动和饲养活动的变化将被用来量化疾病行为。Objective 2将使用TNFalpha和TNF受体缺乏的小鼠来确定TNFalpha在体内对盐酸盐诱导的空间记忆丧失的贡献。这一目标将证实igf - 1在预防这种形式的认知障碍中的作用。目的3将探索igf -i诱导的信号蛋白直接靶向谷氨酸受体并增加存活蛋白的表达以减少兴奋性神经元应激的新可能性。目的4中的实验将通过使用缺乏TNF受体或FAN的小鼠，并确定TNFalpha是否增加谷氨酸受体激活，来描述TNFalpha促进神经元功能障碍和空间记忆丧失的分子信号。这一目标也将确定IGF-I如何抵消tnfalpa诱导的神经元应激。这些研究需要了解TNFalpha如何与大脑中的内源性保护因子相互作用。这些创新的实验将促进我们对控制行为障碍的神经生物学基础的大脑和免疫通讯系统的理解

DESCRIPTION (provided by applicant): A major advance in understanding the neurobiological basis of normal and pathological behavior was the discovery that proinflammatory cytokines act in the CNS to alter behavior and induce affective and cognitive disorders. Proinflammatory cytokines can act in the neuroimmune system to alter behavior by regulating synthesis and release of several neurotransmitters. We now have data to show that TNFalpha can also act in conjunction with classical neurotransmitters to change behavior. In both cases, very little is known about endogenous protective molecules that regulate actions of proinflammatory cytokines in the brain and hence their behavioral effects. We have exciting new preliminary evidence in vivo showing that IGF-1 inhibits both sickness behavior induced by TNFalpha and spatial memory disorders that are induced by glutamate/kainate in a TNFalpha-dependent manner. We have extended these in vivo findings by showing that TNFalpha exacerbates neuronal stress only in the presence of glutamate and kainate and that IGF-I protects neurons from these insults in vitro. In Objective 1, we will further assess the possibility that IGF-I ameliorates the affective and cognitive effects of TNFalpha. Mice deficient in TNF receptors and a critical intracellular TNF receptor signaling protein known as FAN will be used. Changes in social exploration, immobility and rearing activities will used to quantify sickness behavior following i.c.v, injection of TNFalpha Objective 2 will use both TNFalpha- and TNF receptor-deficient mice to determine the in vivo contribution of TNFalpha to kainate-induced loss of spatial memory. This objective will then confirm the role of IGF-I in preventing this form of cognitive disorder. Objective 3 will explore the novel possibility that IGF-I-induced signaling proteins directly target glutamate receptors and increase expression of survival proteins to reduce excitation-induced neuronal stress. Experiments in Objective 4 will delineate the molecular signals by which TNFalpha promotes neuronal dysfunction and loss of spatial memory by using mice that lack TNF receptors or FAN and determining if TNFalpha increases glutamate receptor activation. This objective will also determine how IGF-I counterbalances TNFalpha-induced neuronal stress. These studies are needed to learn how TNFalpha interacts with an endogenous protective factor in the brain. These innovative experiments will advance our understanding of brain and immune communication systems that control the neurobiological basis of behavioral disorders