Brain Mast Cells in Sleep and Behavioral Regulation

 描述（由申请人提供）：本修订提案的目标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粒细胞的异质群体，并且它们含有许多介质，例如组胺和5-羟色胺、细胞因子、趋化因子和脂质衍生因子。肥大细胞不仅定位于外周，而且也存在于大脑中。大脑中的肥大细胞 具有组成性活性，通过过敏性脱粒逐渐或快速释放其内容物。它们的活性也通过广泛的刺激增加，包括免疫和非免疫信号。因此，脑肥大细胞神经调节可能涉及各种神经和精神疾病。然而，肥大细胞在大脑中调节神经行为的功能在很大程度上是未知的。使用Kit突变型肥大细胞缺陷小鼠（KitW/KitW-V），我们有初步的结果表明，脑肥大细胞调节睡眠/觉醒和其他行为表型，脑肥大细胞的组胺促进觉醒。然而，Kit突变小鼠在色素形成细胞、生殖细胞、RBC和肥大细胞中具有多效性缺陷，因此可能缺乏特异性。东京理科大学的Kubo博士的实验室最近产生了一种新的诱导型和Kit非依赖性肥大细胞缺陷型Mas-TRECK（毒素受体敲除）小鼠。注射白喉毒素（DT）选择性地消耗肥大细胞和嗜碱性粒细胞在Mas-TRECK小鼠，而其他造血细胞群的数量没有表现出变化。我们还预计，脑肥大细胞可以在这些Mas-TRECK小鼠中特异性耗尽，如果DT脑室内给药。尽管一系列实验证据表明神经免疫相互作用对睡眠和神经行为控制以及某些精神疾病是重要的，但肥大细胞在控制睡眠和神经行为中的作用仍有待进一步研究。 睡眠和其他行为尚未得到系统的评估。我们的研究结果首次表明，脑肥大细胞可能参与生理觉醒和各种行为操纵的唤醒反应。我们还发现肥大细胞的可用性影响普遍的精神症状，包括焦虑和抑郁样症状。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发挥重要作用。因此，在本修订提案中，我们将使用Mas-TRECK小鼠进一步研究脑肥大细胞在生理和病理条件下的睡眠/觉醒和行为控制中的作用。从拟议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，睡眠和行为是如何由非神经元细胞调节的。由于肥大细胞释放的已知化学物质和物质可能参与了这些作用的介导，因此这些系统可以通过药物治疗来靶向治疗各种睡眠和行为障碍，并且拟议研究的结果将对进一步的翻译研究非常有用。

 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.