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: 8663780
• 负责人: Jonathan Kipnis
• 金额: $ 30.04万
• 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/8663780
• 关键词: AIDS Dementia Complex; Acute; Address; Adoptive Transfer; Affect; Age; Astrocytes; 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; learned behavior; migration; new therapeutic target; novel therapeutic intervention; protective effect; 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.

描述（由申请人提供）：近年来，T 细胞在调节中枢神经系统生理和病理事件中的关键作用已被确定。 T 细胞调节神经组织损伤后的存活和修复。此外，T 细胞在神经元可塑性中发挥着重要作用，神经元可塑性是空间学习和记忆的重要基础。我们发现，与野生型小鼠相比，免疫缺陷小鼠的认知能力受到损害，但通过 T 细胞的被动转移而得到改善。这些发现与以下概念一致：与多种精神疾病相关的免疫活性下降，例如与年龄和艾滋病毒相关的痴呆症、“化学脑”症状，导致这些患者观察到的认知功能障碍。 T 细胞介导的有益认知作用的机制尚不完全清楚。我们假设认知任务表现（或其相关的应激反应）导致 T 细胞在脑膜间隙中迁移和积累。我们假设招募的 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。这些细胞因子反过来直接或通过星形胶质细胞介导的突触发生影响认知，调节星形胶质细胞衍生的突触发生因子 TSP1。该假设预测，T 细胞的丢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，并可能避免对 T 细胞活性的需求。在拟议的项目中，我们将讨论影响学习和记忆的 T 细胞类型（目标 #1）、T 细胞如何进入脑膜（目标 #2）以及 T 细胞如何控制和产生脑膜细胞因子，影响学习和记忆（目标#3）。具体目标#1 中的实验旨在确定哪些 T 细胞亚群负责介导作用，以及 T 细胞介导其对学习和记忆的保护作用的时间和持续时间。具体目标#2 的实验将检查 T 细胞的性质和功能，这些 T 细胞在执行认知任务期间迁移到脑膜空间并在那里积累。 T 细胞迁移的机制、它们的激活模式和表型将得到解决。具体目标#3 的实验旨在阐明 T 细胞衍生的 IL-4 通过抑制 TNF、诱导 TSP1 或通过替代途径对学习和记忆产生有益作用的机制。阐明 T 细胞在认知中的作用及其潜在的细胞和分子作用机制将促进我们对以免疫系统功能受损为特征的疾病中认知恶化的理解。这种增强的理解有可能确定新的治疗靶点，以改善多种形式的认知衰退。