Brain Mast Cells in Sleep and Behavioral Regulation

 描述(申请人提供)：这项修订提案的目标是剖析大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中粒细胞的异质性群体，它们含有许多介质，如组胺和5-羟色胺、细胞因子、趋化因子和脂类衍生因子。肥大细胞不仅定位于哺乳动物的外周，也存在于哺乳动物的大脑中。大脑中的肥大细胞 具有结构性活性，通过过敏性脱颗粒逐渐或迅速释放其内容物。它们的活性也被广泛的刺激所增强，包括免疫和非免疫信号。因此，脑肥大细胞的神经调节可能与各种神经和精神疾病有关。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。利用Kit突变的肥大细胞缺陷小鼠(KitW/KitW-v)，我们有了初步的结果，表明大脑肥大细胞调节睡眠/觉醒和其他行为表型，来自大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、红细胞和肥大细胞上存在多向性缺陷，因此可能缺乏特异性。久保博士在东京科学大学的实验室最近培育出了一种新的可诱导和非依赖Kit的肥大细胞缺陷小鼠，Mas-treck(毒素受体基因敲除)小鼠。注射白喉毒素(DT)选择性地耗尽Mas-treck小鼠的肥大细胞和嗜碱性细胞，而其他造血细胞群的数量没有变化。我们还预计，如果脑室内注射DT，这些Mas-treck小鼠的脑部肥大细胞可以特异性地被耗尽。尽管一系列实验证据表明，神经免疫相互作用对于睡眠和神经行为控制以及一些精神障碍是重要的，但肥大细胞在控制睡眠和神经行为障碍中的作用 睡眠和其他行为还没有得到系统的评估。我们的结果首次表明，大脑肥大细胞可能参与了生理觉醒和对各种行为操作的唤醒反应。我们还发现，肥大细胞的可获得性会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扮演着重要的角色。因此，在这项修订后的提案中，我们将利用Mas-treck小鼠进一步研究大脑肥大细胞在生理和病理条件下睡眠/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，非神经细胞如何调节睡眠和行为。由于已知的化学物质和从肥大细胞释放的物质可能参与了这些影响的中介，这些系统可以作为各种睡眠和行为障碍的药物治疗的靶点，拟议的研究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.