Beyond allergy: Mast cells mediate brain-behavior-immune interactions.

除了过敏：肥大细胞介导大脑-行为-免疫相互作用。

• 批准号: 7929482
• 负责人: Katherine M Nautiyal
• 金额: $ 2.2万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7929482
• 关键词: Affect; Antidepressive Agents; Anxiety; Behavior; Behavioral; Behavioral Assay; Brain; Brain region; Brain-Derived Neurotrophic Factor; Cell Degranulation; Cell Proliferation; Cells; Characteristics; Clinical Sciences; Cromoglicic Acid; Data; Disease Management; Figs - dietary; Fright; Genetic; Hippocampus (Brain); Hypersensitivity; Immune; Immune system; In Vitro; Investigation; Limbic System; Link; Literature; Location; Maintenance; Marshal; Mediating; Mediation; Mediator of activation protein; Mental Depression; Mental Health; Mental disorders; Modeling; Mus; Nerve Growth Factors; Neuraxis; Neurons; Pain; Pharmaceutical Preparations; Pharmacologic Substance; Physiology; Reflex action; Regulation; Research; Role; Selective Serotonin Reuptake Inhibitor; Sensory; Serotonin; Signal Transduction; Site; System; Time; TimeLine; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Work; behavior test; brain behavior; candidate identification; dentate gyrus; depressive symptoms; emergency service responder; in vivo; loss of function; mast cell; nerve stem cell; neurogenesis; neurotrophic factor; new therapeutic target; olfactory bulb; research study; response; sensory stimulus; serotonin receptor; subventricular zone

DESCRIPTION (provided by applicant):There are dynamic bidirectional interactions between the immune and central nervous systems that affect behavior and mental health. The current proposal joins a growing literature investigating the role of immune cells in the brain. The focus here is on mast cells because of their unique granular and mobile characteristics and their ability to release neuroactive and neurotrophic mediators. Mast cells in the brain have a direct effect on the regulation of anxiety (Nautiyal et al, 2008). Both genetic and pharmacological models (using mast cell-deficient mice and a drug that blocks mast cell degranulation, respectively) of mast cell loss-of-function show that a lack of mast cells or their products result in increased anxiety-like behavior, with no effects on homecage behavior or sensory responsiveness. This proposal explores the mechanism for mast cell modulation of anxiety. The likely site of mast cell impact on the limbic system is the hippocampus. Hippocampal signaling regulates depression and anxiety, brain mast cells are located within and near the hippocampus, and a number of mast cell mediators can affect hippocampal physiology. For example, serotonin (a major mast cell mediator) in the hippocampus influences neurogenesis in the dentate gyrus and results in changes in anxiety and depression. Additionally, increases in neurogenesis are thought to be responsible for the effects of serotonin acting (SSRI) anti-depressants on depressive and anxious behaviors. Preliminary data shows that mast cell deficient sash-/- mice have decreased cell proliferation and survival in the dentate gyrus suggesting that mast cells contribute to the maintenance of hippocampal neurogenesis. Experiments here will extend this research using a pharmacological model of mast cell loss-of-function and will also explore the behavioral consequences of a lack of mast cell mediated neurogenesis. Subsequent experiments will focus on delineating which mast cell mediators affect cell proliferation. This will include in vivo experiments assessing mast cell contribution to the hippocampal milieu, as well as in vitro experiments exploring the direct mechanisms of mast cell influence on neural stem cells. Finally, behavioral and histochemical experiments will assess mast cell influences on the efficacy of SSRI antidepressants. Relevance: Psychiatric diseases, like anxiety and depression, are correlated with abnormalities in the immune system, which in turn has recently become a focus of new treatments for the management of these disorders. The research proposed will explore how immune cells in the brain can impact mental health, potentially contributing to new pharmaceutical targets.

描述（由申请人提供）：免疫系统和中枢神经系统之间存在动态的双向相互作用，影响行为和心理健康。目前的建议加入了越来越多的文献调查免疫细胞在大脑中的作用。这里的重点是肥大细胞，因为它们独特的颗粒和移动的特性和它们释放神经活性和神经营养介质的能力。大脑中的肥大细胞对焦虑的调节有直接影响（Nautiyal等人，2008）。肥大细胞功能丧失的遗传和药理学模型（分别使用肥大细胞缺陷小鼠和阻断肥大细胞脱粒的药物）表明，肥大细胞或其产物的缺乏导致焦虑样行为增加，对家居行为或感觉反应没有影响。该建议探讨了肥大细胞调节焦虑的机制。肥大细胞影响边缘系统的可能部位是海马体。海马信号调节抑郁和焦虑，脑肥大细胞位于海马内和海马附近，许多肥大细胞介质可以影响海马生理。例如，海马体中的血清素（一种主要的肥大细胞介质）影响齿状回中的神经发生，并导致焦虑和抑郁的变化。此外，神经发生的增加被认为是5-羟色胺作用（SSRI）抗抑郁药对抑郁和焦虑行为的影响的原因。初步数据显示，肥大细胞缺陷型sash-/-小鼠齿状回中的细胞增殖和存活减少，表明肥大细胞有助于维持海马神经发生。这里的实验将使用肥大细胞功能丧失的药理学模型来扩展这项研究，并且还将探索缺乏肥大细胞介导的神经发生的行为后果。随后的实验将集中在描绘肥大细胞介质影响细胞增殖。这将包括评估肥大细胞对海马环境的贡献的体内实验，以及探索肥大细胞对神经干细胞影响的直接机制的体外实验。最后，行为和组织化学实验将评估肥大细胞对SSRI抗抑郁药疗效的影响。相关性：精神疾病，如焦虑和抑郁，与免疫系统的异常有关，这反过来又成为最近管理这些疾病的新疗法的焦点。这项研究将探索大脑中的免疫细胞如何影响心理健康，可能有助于新的药物靶点。