Neural and Behavioral Impact of T Cell Activation

描述：相当多的神经精神问题是由细胞因子引起的 免疫疗法(如白介素2：白介素2)，这可能反映了 大脑对外源性细胞因子的反应方式，而不是内源性 由抗原激发的细胞因子，是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是如何对 葡萄球菌肠毒素B(SEB)诱导内源性细胞因子的产生 这个模型涉及到一种自然的免疫事件的激活。 这不仅用来调节免疫反应，而且还用来调节生物体应该如何 进行适应性行为调整(例如，在生病期间)。行政管理 SEB在体内刺激T细胞产生高水平IL-2和肿瘤 肿瘤坏死因子-α(TNF-a)，这与增加 中枢促肾上腺皮质激素释放激素(CRH)在中枢的转录 杏仁核(CEA)和室旁核(PVN) 下丘脑，这与新的恐惧症反应增加有关。 系统IL-2的免疫中和显著减弱了 SEB对杏仁中央核神经元激活的影响 大脑中相邻的边缘区域。因此，在具体目标1中，我们将测试 SEB挑战是否促进对引发焦虑的反应增强 刺激物。这些将包括焦虑和/或恐惧的行为学测试(即， 开阔的田野和高架的迷宫)在熟悉和新颖的语境下 条件。此外，受SEB挑战的动物将接受后天恐惧测试 恐惧等反应会增强惊吓反应，这是一种 与杏仁核紧密相连。具体目标2将决定IL-2的作用 和TNF-a在SEB的行为效应中的作用。研究将涉及抗免疫 细胞因子单抗治疗，并在研究IL-2、SEB的情况下 具有IL-2基因突变的小鼠的挑战。《特定目标2》也将进行测试 SEB诱导的CRH mRNA在杏仁核和其他脑组织中是否增加 这些区域是由上述细胞因子调控来调节的。最后，在 特定目的3促肾上腺皮质激素释放激素在促进SEB Will行为效应中的作用 通过部位特异性地将CRH受体拮抗剂注射到 CEA和蓝斑，这两个已知的区域介导了一些引起焦虑的 促性腺激素释放激素的作用。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，这反过来可能促进努力 了解T细胞衍生的细胞因子(如IL-2和TNF-a)如何支持和/或 影响对压力的行为适应。鉴于人们越来越重视 关于免疫系统在影响激励系统中的作用 临床抑郁症的改变，这项研究将有助于理解 情感性疾病的病因和治疗策略。

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.