Changing behavior by shifting Th1/Th2 balance in the brain

描述（由申请人提供）：本申请涉及广泛的挑战领域（01）行为，行为改变和预防，以及特定的挑战主题，01- aa -102*：神经免疫因子在调节行为中的功能作用。在理解神经免疫和不良行为条件方面，一个关键的未解决的挑战是，是否可以调节神经免疫系统的激活，从而消除或改善神经炎症的发展及其生物行为后果。正如我们所展示和回顾的那样，IL-1¿/IL-1RA平衡对于神经免疫系统激活过程中发生的生物行为并发症的发展和持续至关重要。我们已经在小鼠模型中证明，神经免疫激活的严重程度增加和恢复延迟是由于IL-1反调节失败，可以通过给予IL-1RA （IL-1的天然拮抗剂）来纠正。重要的是，我们已经证明，IL-4是T辅助1/T辅助2 （Th1/Th2）平衡的重要调节因子和替代巨噬细胞激活的诱导剂，是脂多糖（LPS）依赖的IL-1RA上调的关键，并且在2型糖尿病等疾病中发生的IL-4耐药性导致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可以偏斜Th2保护它免受th1驱动的免疫反应。为了支持这一目标，我们有令人兴奋的新初步数据表明，喂食含有10%可溶性纤维的饮食的小鼠明显抵抗并从lps诱导的社交退缩中恢复得更快，这是一种生物行为，与基于大脑的促炎细胞因子IL-1， TNFa和IL-6的上调直接相关。这些可溶性纤维喂养的小鼠Th2偏斜，具有可选择性激活的外周巨噬细胞，并显示出脑IL-4和IL-1RA的明显增加。值得注意的是，IL-4敲除小鼠对可溶性纤维饮食的免疫行为影响具有抗性。这些发现首次表明，一种现成的饮食成分有利于神经免疫和激活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用于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？这个项目的成功完成将确定新的目标和潜在的治疗方法，以减轻或改善各种行为状况的神经免疫功能，包括那些与过度饮酒、焦虑和抑郁有关的行为。一个关键的未解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新的饮食策略，使用可溶性纤维，有可能阻止神经免疫系统的不良激活和与脑部炎症相关的疾病症状。因此，一个重要而富有成果的新研究领域是研究神经免疫系统是否可以通过饮食干预从促炎状态重定向到抗炎状态。成功完成我们的目标将为减轻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。

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.