Brain Mast Cells in Sleep and Behavioral Regulation

睡眠和行为调节中的脑肥大细胞

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：本修订提案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的异质粒细胞群，它们含有许多介质，例如组胺。血清素、细胞因子、趋化因子和脂质衍生因子不仅存在于哺乳动物的外周细胞中，而且也存在于哺乳动物的大脑中。它们是组成性活性的，通过过敏性脱粒逐渐或快速释放其内容物，它们的活性也会因包括免疫和非免疫信号在内的多种刺激而增加。，大脑中肥大细胞介导神经行为的功能很大程度上未知，使用 Kit 突变型肥大细胞缺陷小鼠 (KitW/KitW-v)，我们得到初步结果表明大脑肥大细胞具有调节作用。然而，Kit 突变小鼠在色素形成细胞、生殖细胞、红细胞和肥大细胞中具有多效性缺陷，因此可能缺乏特异性。东京理科大学实验室最近培育出一种新的可诱导且独立于 Kit 的肥大细胞缺陷型 Mas-TRECK（毒素受体敲除）小鼠，选择性注射白喉毒素 (DT)。尽管在脑室内给予 DT，但 Mas-TRECK 小鼠中的肥大细胞和嗜碱性粒细胞被耗尽，而其他造血细胞群的数量没有变化。实验证据表明，神经免疫相互作用对于睡眠和神经行为控制以及某些精神疾病很重要，肥大细胞在控制睡眠和神经行为方面发挥着重要作用。睡眠和其他行为尚未得到系统评估，我们的研究结果首次表明，大脑肥大细胞可能参与各种行为操作的生理觉醒和唤醒反应。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发挥着重要作用，因此，我们将进一步研究脑肥大细胞在睡眠/觉醒和行为中的作用。生理控制从所提出的实验中获得的知识可能会带来关于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的新概念，因为已知肥大细胞释放的化学物质和物质。可能参与了效应的调节，这些系统可以通过针对各种睡眠和行为障碍的药物治疗来靶向，并且拟议研究的结果对于进一步的转化研究将非常有用。