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和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。我们实验室和其他机构的研究表明，免疫系统是中枢神经系统和外周器官系统之间的一个连接点。最近对小鼠的研究表明，T淋巴细胞可以防止对压力产生适应不良行为反应。这些研究与我们的初步结果一致，表明T细胞缺陷型RAG 2-/-小鼠在急性或慢性应激暴露后更容易发展对应激的适应不良行为反应，并且用来自野生型小鼠的CD 4 + T细胞重建恢复对应激的适应性反应。此外，我们以前的研究也表明，错误定向的CD 4 + T细胞功能，如慢性炎症性疾病中所见，导致适应不良的行为应激反应。本申请的目的是进一步确定CD 4 + T细胞在应激反应中所起的双向作用，并增强关于赋予对心理社会和其他应激相关障碍的恢复力或易感性的机制的知识。核心假设是，T细胞在应激暴露后会短暂地运输到大脑，在那里它们会刺激神经营养因子和细胞因子的产生，最终导致对应激的行为应对反应的保护或加重。我们进一步假设，CD 4 + T细胞活化的机制将决定神经营养因子或细胞因子表达的模式。我们将采用RAG 2-/-缺陷小鼠模型，其缺乏功能性T和B细胞。我们将通过过继转移用T细胞重建这些小鼠，并评估它们在急性和慢性应激模型中的行为。T细胞对环境抗原的体外活化将被应用于测试活化的差异机制。将在习得性无助范例或应激的社会隔离模型中评估用T细胞重建的BALB/c野生型、RAG 2-/-和RAG 2-/-小鼠。免疫组织化学和原位杂交组织化学将被用来分析CD 4 + T细胞在脑中的存在和神经营养因子的表达。实时RT-PCR将用于比较脑中细胞因子mRNA的表达，以评价脑炎症反应和T细胞治疗的效果。最后，通过施用RU 486阻断应激暴露后的糖皮质激素受体功能将用于评估已知介导应激的稳态或有害作用的激素对应激的反应的作用。这些研究将提供对心因性压力恢复力的细胞机制的深入了解，当受到刺激时，可能会在大脑中提供再生和修复功能，并恢复正常的压力反应和行为。

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.