Cytokines, Behavior, and Mental Health

描述(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主要进展是发现促炎症细胞因子在中枢神经系统中作用于改变行为并导致情感和认知障碍。促炎细胞因子可以通过调节几种神经递质的合成和释放，在神经免疫系统中发挥作用，改变行为。我们现在有数据表明，TNFpha也可以与经典的神经递质一起作用，改变行为。在这两种情况下，人们对调节大脑中促炎症细胞因子活动的内源性保护分子知之甚少，因此他们的行为影响也很少。我们在体内有令人兴奋的新的初步证据表明，IGF-1以TNFpha依赖的方式抑制由TNFpha诱导的疾病行为和由谷氨酸/海人藻酸诱导的空间记忆障碍。我们扩展了这些体内的发现，表明只有在谷氨酸和海人藻酸存在的情况下，肿瘤坏死因子α才会加剧神经元的应激，而IGF-I在体外可以保护神经元免受这些侮辱。在目标1中，我们将进一步评估IGF-I改善TNFpha的情感和认知效果的可能性。缺乏肿瘤坏死因子受体和一种关键的细胞内肿瘤坏死因子受体信号蛋白FAN的小鼠将被使用。社会探索、不动和养育活动的变化将被用来量化疾病行为在i.c.v，注射TNFpha目标2将使用TNFpha和肿瘤坏死因子受体缺陷的小鼠来确定在体内TNFpha对红藻氨酸诱导的空间记忆丧失的贡献。这一目标将证实IGF-I在预防这种形式的认知障碍中的作用。目的探讨胰岛素样生长因子-I(IGF-I)诱导的信号蛋白直接靶向谷氨酸受体，增加存活蛋白表达以减轻兴奋诱导的神经元应激的可能性。目标4中的实验将通过使用缺乏肿瘤坏死因子受体或FAN的小鼠，并确定肿瘤坏死因子α是否增加谷氨酸受体的激活，来描绘肿瘤坏死因子α促进神经元功能障碍和空间记忆丧失的分子信号。这一目标也将决定IGF-I如何抵消TNFpha诱导的神经元应激。这些研究是了解TNFpha如何与大脑中的内源性保护因子相互作用所必需的。这些创新的实验将促进我们对大脑和免疫通讯系统的理解，这些系统控制着行为障碍的神经生物学基础

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