Neuroimmune Mechanisms of Risk and Resilience to Maladaptive Responses to Stress

压力适应不良反应的风险和复原力的神经免疫机制

基本信息

批准号：
8546252
负责人：
Leonardo H Tonelli
金额：
$ 36.38万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-26 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8546252
关键词：
Adoptive Transfer Affect Agonistic Behavior Agreement Animal Model Animals Antigen Receptors Antigens Anxiety B-Lymphocytes Back Behavior Behavioral Brain Brain region Brain-Derived Neurotrophic Factor CD4 Positive T Lymphocytes Cell physiology Chronic Chronic stress Data Development Disease Disease susceptibility Emotional Emotional Disturbance Emotional Stress Exposure to Feeds Gap Junctions Genetic Genetic Transcription Genetically Engineered Mouse Glucocorticoid Receptor Goals Health Health Status Histocytochemistry Hormonal Human Immune system Immunity Immunohistochemistry In Situ Hybridization In Vitro Inbred BALB C Mice Individual Inflammatory Inflammatory Response Interferons Interleukin-2 Knowledge Laboratories Learned Helplessness Link Lung diseases Lymphocyte Lymphocyte Function Mediating Mental Depression Modeling Mus Neuraxis Neuroimmunomodulation Outcome Ovalbumin Pathology Pattern Peripheral Play Population Predisposition Process Production Psychological Stress Psychosocial Stress RU-486 Research Reverse Transcriptase Polymerase Chain Reaction Risk Role Saline Social Behavior Social isolation Stress T-Cell Activation T-Lymphocyte TNF gene Testing Time Transgenic Mice Wild Type Mouse acute stress arm base behavior test biological adaptation to stress body system body-mind coping cytokine experience insight mRNA Expression mortality mouse model neurobehavioral neurotrophic factor prevent protective effect psychosocial receptor function reconstitution regenerative repaired research study resilience response showing emotion social social stress stress related disorder stressor trafficking

项目摘要

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.

描述（由申请人提供）：长期以来，人们已经认识到，社会心理压力与躯体健康之间的关系是双向的：社会心理压力会影响一般健康状况，躯体疾病影响应对压力的应对反应。但是，这种关系的机制仍然很少理解。我们实验室和其他实验室的研究表明，免疫系统是一种联系，在中枢神经系统和外围器官系统之间接口。对小鼠的最新研究表明，T淋巴细胞可防止适应性行为对压力的不良反应。这些研究与我们的初步结果一致，表明缺乏T细胞RAG2 - / - 小鼠更容易受到急性或慢性应激暴露后压力的不良行为反应的发展，并且可以从野生型小鼠中与CD4+ T细胞重新建立，从而恢复适应性的压力。此外，我们以前的研究还表明，未指导的CD4+ T细胞功能（例如在慢性炎症性疾病中看到的）导致了适应性的行为应力反应。本应用的目的是进一步建立CD4+ T细胞在压力反应性中所起的双向作用，并增强有关赋予弹性或对心理社会和其他与压力相关疾病的机制的知识。中心假设是，在压力暴露后，T细胞将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细胞活化的机制将确定神经营养因子或细胞因子表达的模式。我们将采用缺乏功能性T和B细胞的RAG2 - / - 缺陷小鼠模型。我们将通过收养转移来重构T细胞，并评估其在急性和慢性压力模型中的行为。 T细胞对环境抗原的体外激活将用于测试激活的差异机制。 BALB/C野生型，RAG2 - / - 和RAG2 - / - 与T细胞重构的小鼠将在学习的无助范式或应力的社会隔离模型中评估。免疫组织化学和原位杂交组织化学将用于分析大脑中CD4+ T细胞的存在以及神经营养因子的表达。实时RT-PCR将用于比较大脑中的细胞因子mRNA表达，以评估脑炎症反应和T细胞治疗的作用。最后，将采用RU486的压力暴露后的糖皮质激素受体功能来评估荷尔蒙反应对已知的压力的荷尔蒙反应的作用，以介导压力的稳态或有害影响。这些研究将洞悉对心理压力的韧性的细胞机制，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。