Neuroimmune Mechanisms of Risk and Resilience to Maladaptive Responses to Stress

描述（由申请人提供）：长期以来，人们一直认为心理社会压力与躯体健康之间的关系是双向的：心理社会压力影响总体健康状况，躯体疾病影响对压力的应对反应。然而，这种关系的机制仍然知之甚少。我们的实验室和其他研究表明，免疫系统是中枢神经系统和外周器官系统之间的纽带。最近对小鼠的研究表明，T淋巴细胞对应激不良行为反应的发展具有保护作用。这些研究结果与我们的初步结果一致，表明T细胞缺陷的RAG2-/-小鼠在急性或慢性应激暴露后更容易发生对应激的不适应行为反应，并且野生型小鼠的CD4+ T细胞重建可以恢复对应激的适应性反应。此外，我们之前的研究也表明，CD4+ T细胞功能的缺失，如在慢性炎症性疾病中看到的，会导致适应性不良的行为应激反应。本应用的目的是进一步确定CD4+ T细胞在应激反应中发挥的双向作用，并增强对心理社会和其他应激相关疾病的恢复或易感性机制的认识。核心假设是T细胞在压力暴露后会短暂地进入大脑，在那里它们会刺激神经营养因子和细胞因子的产生，最终导致对压力的行为应对反应的保护或加剧。我们进一步假设CD4+ T细胞活化的机制将决定神经营养因子或细胞因子的表达模式。我们将采用RAG2-/-缺陷小鼠模型，缺乏功能性T细胞和B细胞。我们将通过过继性转移重建这些小鼠的T细胞，并在急性和慢性应激模型中评估它们的行为。在体外，T细胞对环境抗原的激活将被用于测试不同的激活机制。用T细胞重组的BALB/c野生型、RAG2-/-和RAG2-/-小鼠将在习得性无助范式或应激的社会隔离模型中进行评估。免疫组织化学和原位杂交组织化学将分析脑内CD4+ T细胞的存在和神经营养因子的表达。Real-time RT-PCR将用于比较脑内细胞因子mRNA的表达，以评估脑炎症反应和T细胞治疗的效果。最后，通过给药RU486来阻断应激暴露后的糖皮质激素受体功能，将被用来评估激素对应激反应的作用，已知其介导应激的稳态或有害影响。这些研究将提供对心理压力恢复的细胞机制的见解，当受到刺激时，可能会在大脑中提供再生和修复功能，并恢复正常的应激反应和行为。

DESCRIPTION (provided by applicant): It has been long recognized that the relationship between psychosocial stress and somatic health is bi-directional: psychosocial stress affects general health status and somatic disease influences coping responses to stress. However, the mechanisms of this relationship remain poorly understood. Research from our laboratories and others has shown that the immune system is a nexus, interfacing between the central nervous systems and peripheral organ systems. Recent studies in mice indicate that T lymphocytes are protective against the development of maladaptive behavioral responses to stress. These studies are in agreement with our preliminary results suggesting that the T cell deficient RAG2-/- mice is more susceptible to the development of maladaptive behavioral responses to stress after acute or chronic stress exposure, and that reconstitution with CD4+ T cells from wild type mice restore adaptive responses to stress. Furthermore, our previous studies also indicates that miss-directed CD4+ T cell function, such as those seen in chronic inflammatory diseases, results in maladaptive behavioral stress responses. The objective of the present application is to further establish the bi-directional role played by CD4+ T cells in stress responsiveness and to enhance knowledge regarding mechanisms conferring resilience or susceptibility to psychosocial and other stress related disorders. The central hypothesis is that T cells will transiently traffic to the brain after stress exposure where they will stimulate the production of neurotrophic factors and cytokines, ultimately resulting in protection or aggravation of behavioral coping responses to stress. We further hypothesize that the mechanism of CD4+ T cell activation will determine the pattern of neurotrophic factor or cytokine expression. We will employ the RAG2-/- deficient mouse model, which lack functional T and B cells. We will reconstitute these mice with T cells by adoptive transfer and assess their behavior in models of acute and chronic stress. In vitro activation of T cells against environmental antigens will be applied to test differential mechanisms of activation. BALB/c wild type, RAG2-/-, and RAG2-/- mice reconstituted with T cells will be evaluated in the learned helplessness paradigm or in the social isolation model of stress. Immunohistochemistry and in situ hybridization histochemistry will be employed to analyze the presence of CD4+ T cells in the brain and the expression of neurotrophic factors. Real-time RT-PCR will be used to compare cytokine mRNA expression in the brain to evaluate brain inflammatory responses and the effects of T cell treatment. Lastly, blockade of glucocorticoid receptor function after stress exposure by administration of RU486 will be employed to evaluate the role of hormonal responses to stress known to mediate either homeostatic or deleterious effects of stress. These studies will provide insight into cellular mechanisms of resilience to psychogenic stress that when stimulated may provide regenerative and repair functions in the brain and restore normal stress responses and behaviors.