Changing behavior by shifting Th1/Th2 balance in the brain

通过改变大脑中 Th1/Th2 平衡来改变行为

• 批准号: 7937101
• 负责人: Gregory G Freund
• 金额: $ 49.53万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7937101
• 关键词: Address; Anti-Inflammatory Agents; Anti-inflammatory; Anxiety; Area; Base of the Brain; Behavior; Behavioral; Brain; Data; Desire for food; Development; Diet; Dietary Component; Dietary Fiber; Dietary Intervention; Disease; Encephalitis; Equilibrium; Failure; Goals; Heavy Drinking; Immune response; Interleukin-1; Interleukin-1 Receptors; Interleukin-4; Interleukin-6; Knockout Mice; Link; Lipopolysaccharides; Macrophage Activation; Mediating; Memory Loss; Mental Depression; Microglia; Mus; Non-Insulin-Dependent Diabetes Mellitus; Peripheral; Prevention; Production; Recovery; Regulation; Research; Research Project Grants; Resistance; Role; Severities; Symptoms; System; Up-Regulation; Withdrawal; arginase; base; behavior change; biobehavior; cytokine; feeding; immune activation; improved; macrophage; mannose receptor; mouse model; neuroinflammation; novel; prevent; research study; social; soluble fiber

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (01) Behavior, Behavioral Change, and Prevention and specific Challenge Topic, 01-AA-102*: Functional Roles of Neuroimmune Factors in Mediating Behavior. A critical unanswered challenge in understanding neuroimmunity and adverse behavioral conditions is whether activation of the neuroimmune system can be regulated so as to abrogate or ameliorate the development of neuroinflammation and its biobehavioral consequences. As we have shown and reviewed, IL-1¿/IL-1RA balance is vital to the development and persistence of biobehavioral complications that occur during activation of the neuroimmune system. We have demonstrated, in mouse models, that increased severity and delayed recovery from neuroimmune activation is due to a failure in IL-1¿ counter-regulation and can be rectified by administration of IL-1RA, the naturally occurring antagonist to IL-1. Importantly, we have shown that IL-4, an essential regulator of T helper 1/T helper 2 (Th1/Th2) balance and inducer of alternative macrophage activation is key to lipopolysaccharide (LPS)-dependent up- regulation of IL-1RA and that IL-4 resistance, which occurs in diseases such as type 2 diabetes, causes failure in appropriate IL-1RA production seriously prolonging biobehavioral recovery from neuroimmune system activation. Thus, the objective of this research project is to determine whether the neuroimmune system can be skewed Th2 protecting it from Th1-driven immune responses. In support of this goal, we have exciting new preliminary data that show mice fed a diet containing 10% soluble fiber are markedly resistant to and recover much faster from LPS-induced social withdrawal, a biobehavior directly tied to brain-based up-regulation of the proinflammatory cytokines IL-1¿, TNFa and IL-6. These soluble fiber-fed mice are skewed Th2, possess peripheral macrophages that are alternatively activated and show a distinct increase in brain IL-4 and IL-1RA. Significantly, IL-4 knockout mice are resistant to the immunobehavioral effects of a soluble fiber diet. These findings are the first to show that a readily available dietary component favorably impacts neuroimmunity and activated-neuroimmune system-associated biobehaviors. The most important question that will be answered by our proposed experiments is: Can soluble dietary fiber be used to block activation of the neuroimmune system and mitigate the biobehavioral consequences of brain-based innate immune activation? Successful completion of this project will identify new targets and potential therapies for alleviating or improving neuroimmune function for a variety of behavioral conditions including those tied to excessive drinking, anxiety and depression. A critical unanswered challenge is determining if neuroinflammation can be prevented or ameliorated. We have developed a novel dietary strategy using soluble fiber that has the potential to block adverse activation of the neuroimmune system and the sickness symptoms associated with brain inflammation. Therefore, a vital and fruitful new area of research is investigating whether the neuroimmune system can be redirected from a proinflammatory state and directed toward an anti-inflammatory state via dietary intervention. Successful completion of our objectives will provide new targets and potential therapies for alleviating or improving a variety of behavioral conditions including those tied to excessive drinking, anxiety and depression.

描述(由申请人提供)：本申请涉及广泛的挑战领域(01)行为，行为改变，以及预防和特定挑战主题，01-AA-102*：神经免疫因素在行为调节中的功能作用。在理解神经免疫和不良行为状况方面，一个关键的尚未回答的挑战是，是否可以调节神经免疫系统的激活，以消除或改善神经炎症及其生物行为后果的发展。正如我们已经证明和综述的那样，IL-1/IL-1RA平衡对于神经免疫系统激活期间发生的生物行为并发症的发展和持续至关重要。我们已经证明，在小鼠模型中，神经免疫激活的严重性增加和恢复延迟是由于IL-1的反调节失败，可以通过给予IL-1的天然拮抗剂IL-1RA来纠正。重要的是，我们已经证明，IL-4是T辅助细胞1/T辅助2(Th1/Th2)平衡的基本调节因子和巨噬细胞交替激活的诱导者，是脂多糖(LPS)依赖的IL-1RA上调的关键，而IL-4抵抗发生在2型糖尿病等疾病中，导致IL-1RA的适当产生失败，严重延长了神经免疫系统激活后的生物行为恢复。因此，本研究项目的目的是确定神经免疫系统是否会受到Th2的扭曲，以保护其免受Th1驱动的免疫反应的影响。为了支持这一目标，我们有令人兴奋的新的初步数据表明，喂食含有10%可溶性纤维的饮食的小鼠对内毒素诱导的社交退缩有明显的抵抗力，并从内毒素诱导的社交退缩中恢复得更快。内毒素诱导的社交退缩是一种生物行为，直接与促炎细胞因子IL-1、TNFa和IL-6的脑部上调有关。这些以可溶性纤维喂养的小鼠具有扭曲的Th2，拥有交替激活的外周巨噬细胞，并显示出脑内IL-4和IL-1RA的显著增加。值得注意的是，IL-4基因敲除的小鼠对可溶性纤维饮食的免疫行为影响具有抵抗力。这些发现首次表明，容易获得的饮食成分有利于影响神经免疫和激活的神经免疫系统相关的生物行为。我们提出的实验将回答的最重要的问题是：可溶性膳食纤维能否被用来阻断神经免疫系统的激活，并减轻基于大脑的先天免疫激活的生物行为后果？该项目的成功完成将确定新的目标和潜在的治疗方法，以缓解或改善各种行为状况的神经免疫功能，包括与酗酒、焦虑和抑郁有关的行为状况。一个关键的悬而未决的挑战是确定神经炎症是否可以预防或改善。我们已经开发了一种使用可溶性纤维的新饮食策略，它有可能阻止神经免疫系统的不利激活和与脑部炎症相关的疾病症状。因此，一个重要而富有成效的新研究领域是研究是否可以通过饮食干预将神经免疫系统从促炎状态重定向到抗炎状态。成功完成我们的目标将为缓解或改善各种行为状况提供新的目标和潜在的治疗方法，包括那些与过度饮酒、焦虑和抑郁有关的行为状况。