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

• 批准号: 8174102
• 负责人: Leonardo H Tonelli
• 金额: $ 37.5万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 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/8174102
• 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

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. PUBLIC HEALTH RELEVANCE: Mechanisms underlying the bi-directional relationship between psychological stress and organ systems are poorly understood. The present application will employ a genetically engineered mice model to study the role played by the CD4+ T lymphocyte subtype as key cellular entities conferring susceptibility or resilience to psychogenic stress and emotional behaviors. This information will significantly advance our understanding of the mind-body connection, and its role in mediating susceptibility to somatic disease.

描述（由申请人提供）：人们早已认识到社会心理压力与躯体健康之间的关系是双向的：社会心理压力影响一般健康状况，躯体疾病影响对压力的应对反应。然而，人们对这种关系的机制仍知之甚少。我们实验室和其他实验室的研究表明，免疫系统是中枢神经系统和周围器官系统之间的纽带。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的行为反应。这些研究与我们的初步结果一致，表明 T 细胞缺陷的 RAG2-/- 小鼠在急性或慢性应激暴露后更容易对应激产生适应不良的行为反应，并且用来自野生型小鼠的 CD4+ T 细胞进行重建恢复对压力的适应性反应。此外，我们之前的研究还表明，定向错误的 CD4+ T 细胞功能（例如慢性炎症性疾病中的功能）会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CD4+T细胞在应激反应中发挥的双向作用，并增强关于赋予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。中心假设是，在压力暴露后，T 细胞会短暂地流入大脑，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细胞激活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 RAG2-/- 缺陷型小鼠模型，该模型缺乏功能性 T 细胞和 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。针对环境抗原的 T 细胞体外激活将用于测试不同的激活机制。用 T 细胞重建的 BALB/c 野生型、RAG2-/- 和 RAG2-/- 小鼠将在习得性无助范例或压力的社会隔离模型中进行评估。将采用免疫组织化学和原位杂交组织化学来分析大脑中 CD4+ T 细胞的存在以及神经营养因子的表达。实时RT-PCR将用于比较大脑中细胞因子mRNA的表达，以评估大脑炎症反应和T细胞治疗的效果。最后，通过施用 RU486 来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影响的激素对应激反应的作用。这些研究将深入了解心理应激的细胞机制，当受到刺激时，可能会在大脑中提供再生和修复功能，并恢复正常的应激反应和行为。 公共卫生相关性：心理压力与器官系统之间双向关系的潜在机制尚不清楚。本申请将采用基因工程小鼠模型来研究CD4+ T淋巴细胞亚型作为赋予对心因性压力和情绪行为的易感性或恢复力的关键细胞实体所发挥的作用。这些信息将极大地增进我们对身心联系及其在介导躯体疾病易感性中的作用的理解。