Meninges-to-astrocyte communication in cognitive function

认知功能中的脑膜与星形胶质细胞的通讯

• 批准号: 8279364
• 负责人: Jonathan Kipnis
• 金额: $ 30.06万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8279364
• 关键词: AIDS Dementia Complex; Acute; Address; Adoptive Transfer; Affect; Age; Astrocytes; Behavior; Binding; Biological Models; CXCL9 gene; CXCR3 gene; Clinical Data; Cognition; Cognition Disorders; Cognitive; Communication; Data; Dementia; Deterioration; Development; Disease; Event; Exhibits; Genetic; Goals; Hippocampus (Brain); Immigration; Immune; Immune system; Immunity; Immunologic Deficiency Syndromes; Impaired cognition; In Vitro; Inflammatory; Infusion procedures; Injury; Interleukin-4; Lead; Learning; Ligands; Literature; Mediating; Memory; Meningeal; Meninges; Mental disorders; Molecular; Molecular Mechanisms of Action; Mus; Myeloid Cells; Nature; Neuraxis; Neuronal Plasticity; Neurons; Pathogenesis; Pathway interactions; Patients; Pattern; Performance; Pharmaceutical Preparations; Phenotype; Physiological; Play; Population; Process; Production; Proteins; Recruitment Activity; Relative (related person); Research Project Grants; Role; SCID Mice; Symptoms; Synapses; T-Cell Immunodeficiency; T-Lymphocyte; Task Performances; Testing; Therapeutic; Thrombospondin 1; Time; Tissues; Tumor Necrosis Factor Suppression; Tumor Necrosis Factor-alpha; Up-Regulation; adaptive immunity; age related; biological adaptation to stress; cell motility; chemobrain; cognitive function; cytokine; design; functional decline; improved; migration; new therapeutic target; novel therapeutic intervention; protective effect; public health relevance; relating to nervous system; repaired; research study; response; senescence; synaptogenesis

DESCRIPTION (provided by applicant): Critical roles for T cells in regulating physiological and pathological events in the central nervous system have been defined in recent years. T cells modulate the post-injury survival and repair of neural tissue. In addition, T cells play an important role in neuronal plasticity, an essential substrate for spatial learning and memory. We showed that cognitive performance of immune-deficient mice is impaired relative to that of their wild-type counterparts, and is improved by passive transfer of T cells. These findings are consistent with the concept that the decline in immune activity associated with several mental disorders, such as age- and HIV-related dementia, "chemo-brain" symptoms, contributes to cognitive dysfunction observed in these patients. The mechanism(s) underlying the beneficial T cell-mediated effect on cognition is (are) not fully understood. We hypothesize that cognitive task performance (or its associated stress response) results in migration and accumulation of T cells in the meningeal spaces. We posit that recruited T cells regulate meningeal myeloid cell phenotype and thus define the cytokine composition of the meninges. These cytokines, in turn, influence cognition either directly or through astrocyte-mediated synaptogenesis, regulating the astrocyte-derived synaptogenic factor, TSP1. This hypothesis predicts that the loss or inactivity of T cells would result in impaired synaptogenesis and lead to cognitive decline, whereas an enrichment of T cell-derived cytokines (primarily IL- 4) would improve cognitive function and conceivably circumvent the need for T cell activity. In the proposed project, we will address the types of T cells that affect learning and memory (aim #1), how do T cells get into the meninges (aim #2), and how do meningeal cytokines, controlled and produced by T cells, affect learning and memory (aim #3). Experiments in specific aim #1 are designed to determine which sub- populations of T cells are responsible for the mediated effect and how soon and for how long T cells mediate their protective effect on learning and memory. Experiments in specific aim #2 will examine the nature and the function of T cells that migrate to the meningeal spaces and accumulate there during performance of a cognitive task. The mechanism of T cell migration, their activation pattern and phenotype will be addressed. Experiments in specific aim #3 will aim to elucidate the mechanism underlying the beneficial role of T cell- derived IL-4 on learning and memory through either suppression of TNF, induction of TSP1, or though alternative pathway. Elucidation of the role of T cells in cognition and in their underlying cellular and molecular mechanism(s) of action will advance our understanding of cognitive deterioration in disorders characterized by impaired immune-system function. This enhanced understanding has the potential to define novel therapeutic targets for the improvement of several forms of cognitive decline. PUBLIC HEALTH RELEVANCE: T cells modulate the post-injury survival and repair of neurons in the central nervous system. In addition, T cells play an important role in learning and memory. The aim of this project is to elucidate cellular and molecular mechanism(s) underlying the role of T cells in cognitive function. This understanding has the potential to define novel therapeutic targets for several forms of cognitive decline.

描述（由申请人提供）：近年来定义了T细胞在调节中枢神经系统中的生理和病理事件中的关键作用。 T细胞调节伤害后的存活和神经组织的修复。此外，T细胞在神经元可塑性中起重要作用，这是空间学习和记忆的必不可少的底物。我们表明，相对于其野生型对应物的认知性能的认知性能受到了损害，并且通过T细胞的被动转移得到改善。这些发现与以下概念一致：与几种精神疾病相关的免疫活性下降，例如与年龄和HIV相关的痴呆，“化学脑”症状的“化学脑”症状有助于在这些患者中观察到的认知功能障碍。有益T细胞介导的认知作用的基础机制尚未完全了解。我们假设认知任务表现（或其相关的压力反应）会导致脑膜空间中T细胞的迁移和积累。我们认为，募集T细胞调节脑膜髓样细胞表型，从而定义脑膜的细胞因子组成。这些细胞因子又直接或通过星形胶质细胞介导的突触发生影响认知，从而调节星形胶质细胞衍生的突触因子TSP1。该假设预测，T细胞的损失或不活动将导致突触发生受损并导致认知能力下降，而T细胞衍生的细胞因子（主要是IL-4）的富集将改善认知功能，并可以想象可以避免对T细胞活性的需求。在拟议的项目中，我们将解决影响学习和记忆的T细胞的类型（AIM＃1），T细胞如何进入脑膜（AIM＃2）以及T细胞控制和产生的脑膜细胞因子如何影响学习和记忆（AIM＃3）。特定目标＃1中的实验旨在确定哪些T细胞的子群负责介导的效果，以及T细胞多久和多长时间介导其对学习和记忆的保护作用。特定目标2中的实验将检查迁移到脑膜空间并在认知任务执行期间堆积的T细胞的性质和功能。 T细胞迁移的机制，其激活模式和表型将被解决。特定目标＃3的实验将旨在阐明通过抑制TNF，TSP1的诱导或替代途径，从而阐明T细胞衍生的IL-4在学习和记忆中的有益作用的机制。阐明T细胞在认知及其潜在的细胞和分子机制中的作用（s）的作用将提高我们对以免疫系统功能受损为特征的疾病认知恶化的理解。这种增强的理解有可能定义新的治疗靶标，以改善几种形式的认知能力下降。 公共卫生相关性：T细胞调节中枢神经系统中神经元的伤害后生存和修复。此外，T细胞在学习和记忆中起着重要作用。该项目的目的是阐明T细胞在认知功能中作用的基础细胞和分子机制。这种理解有可能为多种形式的认知下降定义新的治疗靶标。