Brain Mast Cells in Sleep and Behavioral Regulation

睡眠和行为调节中的脑肥大细胞

• 批准号: 9000177
• 负责人: SEIJI NISHINO
• 金额: $ 20.43万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9000177
• 关键词: Agent 48-80; Animals; Anxiety; Arousal; Behavior; Behavior Control; Behavior Disorders; Behavioral; Brain; Cells; Chemicals; Defect; Diphtheria Toxin; Exhibits; Fasting; Food deprivation (experimental); Functional disorder; Genes; Germ Cells; Goals; Health; Hematopoietic; Histamine; Histamine Release; Hypothalamic structure; Immune; Immune system; Injection of therapeutic agent; Knockout Mice; Knowledge; Lipids; Lipopolysaccharides; Measures; Mediating; Mediation; Mediator of activation protein; Mental Depression; Mental disorders; Mus; Mutant Strains Mice; Neuroglia; Pattern; Pharmacological Treatment; Phenotype; Physiological; Pigments; Play; Population; Population Heterogeneity; Receptor Protein-Tyrosine Kinases; Recovery; Regulation; Role; Science; Series; Serotonin; Signal Transduction; Sleep; Sleep Deprivation; Sleep Disorders; Slow-Wave Sleep; Specificity; Stem cells; Stimulus; Symptoms; System; Testing; Time; Tokyo; Toxin; Translational Research; Universities; Wakefulness; Wild Type Mouse; cell growth; chemokine; cytokine; experience; granulocyte; mast cell; mutant; nervous system disorder; neurobehavior; neuropsychiatric disorder; neuroregulation; psychiatric symptom; receptor; research study; response; sleep regulation; Agent 48-80; Animals; Anxiety; Arousal; Behavior; Behavior Control; Behavior Disorders; Behavioral; Brain; Cells; Chemicals; Defect; Diphtheria Toxin; Exhibits; Fasting; Food deprivation (experimental); Functional disorder; Genes; Germ Cells; Goals; Health; Hematopoietic; Histamine; Histamine Release; Hypothalamic structure; Immune; Immune system; Injection of therapeutic agent; Knockout Mice; Knowledge; Lipids; Lipopolysaccharides; Measures; Mediating; Mediation; Mediator of activation protein; Mental Depression; Mental disorders; Mus; Mutant Strains Mice; Neuroglia; Pattern; Pharmacological Treatment; Phenotype; Physiological; Pigments; Play; Population; Population Heterogeneity; Receptor Protein-Tyrosine Kinases; Recovery; Regulation; Role; Science; Series; Serotonin; Signal Transduction; Sleep; Sleep Deprivation; Sleep Disorders; Slow-Wave Sleep; Specificity; Stem cells; Stimulus; Symptoms; System; Testing; Time; Tokyo; Toxin; Translational Research; Universities; Wakefulness; Wild Type Mouse; cell growth; chemokine; cytokine; experience; granulocyte; mast cell; mutant; nervous system disorder; neurobehavior; neuropsychiatric disorder; neuroregulation; psychiatric symptom; receptor; research study; response; sleep regulation

 DESCRIPTION (provided by applicant): The goal of this revised proposal is to dissect the role of brain mast cells in sleep and behavioral controls. Mast cells are a heterogeneous population of granulocytic cells of the immune system and they contain numerous mediators, such as histamine and serotonin, cytokines, chemokines, and lipid- derived factors. Mast cells localize not only in the periphery but are also resident in the brain of mammalians. Mast cells in the brain are constitutively active, releasing their contents gradually or rapidly by anaphylactic degranulation. Their activity is also increased by a wide range of stimuli including both immune and non-immune signals. Brain mast cell neuromodulation may thus be involved in various neurological and psychiatric diseases. However, the function of mast cells in the brain for the mediation of neurobehavior is largely unknown. Using Kit mutant mast cell deficient mice (KitW/KitW-v), we have preliminary results indicating that brain mast cells regulate sleep/wake and other behavioral phenotypes and that histamine from brain mast cells promote wakefulness. However, Kit mutant mice possess pleiotropic defects in pigment-forming cells, germ cells, RBC`s and mast cells, and thus may lack specificity. Dr. Kubo's lab at Tokyo University of Science, recently produced a new inducible and Kit- independent mast cell deficient, Mas-TRECK (toxin receptor knockout) mouse. Injections of diphtheria toxin (DT) selectively deplete mast cell and basophiles in Mas-TRECK mice, whereas the numbers of other hematopoietic cell populations exhibit no changes. We also anticipate brain mast cells can be specifically depleted in these Mas-TRECK mice, if DT is administered intracerebroventricularly. Although a series of experimental evidence has suggested that neuroimmune interaction is important for sleep and neurobehavior control and for some psychiatric disorders, the roles of mast cells in the control of sleep and other behaviors has not yet been systematically evaluated. Our results showed for the first time that brain mast cells are likely involved in physiological wakefulness and arousal responses to various behavioral manipulations. We also found that the availability of mast cells influences prevalent psychiatric symptoms, including anxiety and depression-like symptoms. It is therefore conceivable that brain mast cells play a significant role in the pathophysiology of some neuropsychiatric diseases. In this revised proposal, we will therefore further examine the role of brain mast cells in sleep/wake and behavioral control in physiological and pathological conditions using Mas-TRECK mice. The knowledge obtained from the proposed experiments will likely bring a new concept about how sleep and behavior is regulated by non-neuronal cells in normal and pathophysiological conditions. Since known chemical and substances released from the mast cell is likely involved in the mediation of the effects, these systems can be targeted by pharmacological treatments for various sleep and behavioral disorders, and results from the proposed study will be very useful for further translation research.

 描述（由适用提供）：该修订建议的目的是剖析脑肥大细胞在睡眠和行为控制中的作用。肥大细胞是免疫系统粒细胞的异质群，它们包含许多介质，例如组胺和5-羟色胺，细胞因子，趋化因子和脂质衍生因子。肥大细胞不仅将其定位在外围，而且是哺乳动物大脑中的居民。大脑中的肥大细胞 它们始终保持活跃，通过过敏性脱粒逐渐或快速释放其内容物。它们的活性也通过包括免疫和非免疫信号在内的广泛刺激增加。因此，脑肥大细胞神经调节可能与各种神经系统疾病有关。然而，大脑中肥大细胞在神经行为的介导的功能在很大程度上是未知的。使用KIT突变肥大细胞缺乏小鼠（KITW/KITW-V），我们的初步结果表明脑肥大细胞调节睡眠/唤醒和其他行为表型，并且来自脑肥大细胞的组胺会促进唤醒。然而，盒子突变小鼠潜在的多效细胞，生殖细胞，rbc和肥大细胞中的多效性缺陷，因此可能缺乏特异性。东京科学大学的Kubo博士实验室最近生产了一种新的诱导且独立的肥大细胞缺乏Mas-Treck（毒素受体敲除）小鼠。在Mas-Treck小鼠中选择性地重复肥大细胞和寄生虫，注射白喉毒素（DT）的注射，而其他造血细胞群体的数量却没有变化。我们还预计，如果DT室内室内施用DT，则可以在这些Mas-Treck小鼠中特别耗尽脑肥大细胞。尽管已经提出了一系列的实验证据，即神经免疫相互作用对于睡眠和神经行为控制和某些精神病疾病很重要，但肥大细胞在控制中的作用 睡眠和其他行为尚未系统评估。我们的结果首次表明，脑肥大细胞可能参与了物理清醒和对各种行为操纵的唤醒反应。我们还发现，肥大细胞的可用性会影响普遍的精神症状，包括焦虑和抑郁症状。因此，可以想象，脑肥大细胞在某些神经精神疾病的病理生理学中起着重要作用。因此，在这项修订的建议中，我们将进一步研究使用Mas-Treck小鼠在身体和病理状况中脑肥大细胞在睡眠/唤醒和行为控制中的作用。从提出的实验中获得的知识可能会带来一个新的概念，即在正常和病理生理条件下非神经元细胞如何调节睡眠和行为。由于从肥大细胞中释放出已知的化学物质和物质可能参与了效果的介导，因此这些系统可以通过药物治疗的各种睡眠和行为障碍来瞄准，而拟议研究的结果将非常有用。