Neural and Behavioral Impact of T Cell Activation

细胞因子引起相当多的神经精神问题 免疫疗法（例如，白细胞介素-2：IL-2），这可能反映了不同的， 大脑对外源性细胞因子的反应方式， 由抗原引发的细胞因子作为动态细胞因子网络的一部分。 因此，目前的项目旨在了解大脑如何对 葡萄球菌肠毒素B（SE B）诱导的内源性细胞因子产生。 该模型涉及免疫事件的天然库的激活 它不仅调节免疫反应，而且调节生物体如何 执行自适应行为调整（例如，生病期间）。管理 SEB在体内刺激T细胞产生高水平的IL-2和肿瘤 坏死因子-α（TNF-α），这与增加 中枢促肾上腺皮质激素释放激素（CRH）的转录 杏仁核（ceA）和室旁核（PVN） 下丘脑，这与增加neophobic反应。 全身性IL-2的免疫中和显著减弱了 SEB激发对杏仁核中央核神经元活化的影响， 大脑的边缘区域因此，在具体目标1中，我们将测试 SEB激发是否促进对焦虑激发的反应性增强 刺激。这些将包括焦虑和/或恐惧的行为学测试（即， 开放领域和高架加迷宫）在熟悉和新颖的背景下 条件此外，将测试SEB激发的动物的习得性恐惧 反应，如恐惧增强惊吓反应，这是一种 与杏仁核紧密相连特异性目的2将决定IL-2的作用 和TNF-α在SEB的行为效应中的作用。研究将涉及抗免疫 细胞因子单克隆抗体治疗，在研究IL-2的情况下，SEB 对具有IL-2基因突变的小鼠进行攻击。第2章还将测试 SEB诱导的CRH mRNA是否在杏仁核和其他大脑中增加 区域由前述细胞因子操纵介导。最后在 具体目的3 CRH在促进SEB行为效应中的作用， 通过将CRH受体拮抗剂位点特异性施用至 ceA和蓝斑，已知介导一些焦虑的区域， CRH的影响。这些研究将证实免疫激活是否会改变 中枢神经系统对心理应激源的反应性，这反过来又可能促进 了解T细胞衍生的细胞因子（如IL-2和TNF-α）如何支持和/或 影响对压力的行为适应。鉴于日益强调 免疫系统在影响动机系统中的作用， 临床抑郁症的改变，这项研究将有助于了解 情感性疾病的病因及治疗策略。

DESCRIPTION: Considerable neuropsychiatric problems result from cytokine immunotherapy (eg., interleukin-2: IL-2), which may reflect differences in the way the brain responds to exogenous cytokines as opposed to endogenous cytokines elicited by antigens as part of a dynamic cytokine network. Therefore, the current project aims to understand how the brain reacts to endogenous cytokine production induced by Staphyloccocal enterotoxin B (SEB). This model involves activation of a natural repertoire of immunological events that serves to regulate not only immune responses, but how the organism should perform adaptive behavioral adjustments (eg., during sickness). Administration of SEB in vivo stimulates T cells to produce high levels of IL-2 and tumor necrosis factor-alpha (TNF-a), and this has been associated with increased transcription of central corticotropin releasing hormone (CRH) in the central nucleus of the amygdala, (ceA) and paraventricular nucleus (PVN) of the hypothalamus, which was associated with increased neophobic reactivity. Immunoneutralization of systemic IL-2 significantly attenuated the impact of SEB challenge on neuronal activation in the central nucleus of the amygdala and adjacent limbic regions of the brain. Therefore, in Specific Aim 1 we will test whether SEB challenge promotes enhanced reactivity to anxiety-provoking stimuli. These will include ethological tests of anxiety and/or fear (viz., open field and elevated plus maze) under familiar and novel contextual conditions. In addition, SEB challenged animals will be tested for learned fear responses, such as fear potentiated startle reactivity, a behavior that is strongly linked to the amygdala. Specific Aim 2 will determine the role of IL-2 and TNF-a in the behavioral effects of SEB. Studies will involve anti-immune cytokine monoclonal antibody treatment, and in the case of studying IL-2, SEB challenge of mice possessing IL-2 gene mutations. Specific Aim 2 will also test whether the SEB-induced CRH mRNA increases in the amygdala and other brain regions are mediated by the aforementioned cytokine manipulations. Finally, in Specific Aim 3 the role of CRH in promoting the behavioral effects of SEB will be tested by site-specific administration of CRH receptor antagonists into the ceA and locus coeruleus, regions known to mediate some of the anxiogenic effects of CRH. These studies will confirm if immunological activation modifies CNS reactivity to psychological stressors, which in turn may promote efforts to understand how T cell derived cytokines (such as IL-2 and TNF-a) support and/or influence behavioral adaptation to stress. In view of the increasing emphasis on the role of the immune system in affecting motivational systems typically altered in clinical depression, this research will contribute to understanding the aetiology and strategies for treatment of affective illness.