Project 2- Scammell

项目2-Scammell

基本信息

批准号：
9096141
负责人：
THOMAS E SCAMMELL
金额：
$ 42.02万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-01 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9096141
关键词：
Acetylcholine Acute Address Affect American Anatomy Arousal Behavior Behavioral Brain Carbon Dioxide Cells Data Electroencephalography Electrophysiology (science)Frequencies Glutamates Goals Hour Hypercapnia Hypertension Impaired cognition In Situ Hybridization Knowledge Lateral Lead Life Maps Mediating Methods Midline Thalamic Nuclei Modeling Nerve Neurons Obstructive Sleep Apnea Pathway interactions Patients Pedunculopontine Tegmental Nucleus Play Population REM Sleep Research Personnel Resources Respiration Role Sleep Sleep Apnea Syndromes Sleep Disorders Substantia Innominata Synapses Techniques Wakefulness adeno-associated viral vector basal forebrain base behavioral response benefit sharing cholinergic designer receptors exclusively activated by designer drugs experience gamma-Aminobutyric Acid improved medical complication mouse model multidisciplinary neurochemistry neuromechanism novel therapeutics optogenetics parabrachial nucleus programs research study respiratory response therapy development

项目摘要

Scammell Project Summary In patients with obstructive sleep apnea (OSA), arousals play a life-saving role, and we hypothesize that neurons in the laterodorsal and pedunculopontine tegmental nuclei (LDT/PPT) play an essential role in many aspects of arousal, including arousals from sleep in OSA. Our goals are to determine the specific functions of the LDT/PPT neurons producing acetylcholine, glutamate and GABA; to map the anatomic projections of these cells; and to examine how they influence the activity of key target regions that regulate sleep/wake behavior and respiration. We will pursue these goals using optogenetics to examine acute, brief increases or decreases in neuronal activity within a behavioral state, and pharmacosynthetics using Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to examine changes lasting hours. As a model of OSA, many experiments will use the Repetitive CO2 Arousal (RCA) method to examine responses to hypercapnia during sleep. To determine if specific LDT/PPT neurons are sufficient for wakefulness, EEG activation, and the response to RCA, we will activate each class of neurons using the hM3 DREADD or channelrhodopsin (ChR2). To determine if specific LDT/PPT neurons are necessary for wakefulness, EEG activation, and the response to RCA, we will inhibit each class of neurons using the hM4 DREADD or ArchT, an inhibitory archaerhodopsin. To define the key LDT/PPT target regions mediating these behavioral responses, we will map projections of specific LDT/PPT neurons using conditional anterograde and retrograde tracing; determine which projections form functional synapses using ChR2- Assisted Circuit Mapping (CRACM); and determine which target regions are functionally most important by focally stimulating or inhibiting glutamatergic and cholinergic nerve terminals in each target region using ChR2 or ArchT. Collectively, these multidisciplinary experiments will define the neural mechanisms through which specific types of LDT/PPT neurons promote wakefulness, cortical activation, and arousals in a mouse model of OSA. The results of these experiments should substantially improve our scientific knowledge of the neural mechanisms that generate wakefulness and arousals due to hypercapnia, and ultimately lead to better treatments for obstructive sleep apnea.

斯卡梅尔项目摘要对于阻塞性睡眠呼吸暂停 (OSA) 患者，觉醒起着挽救生命的作用，我们假设外侧背侧和桥脚被盖神经元细胞核（LDT/PPT）在唤醒的许多方面发挥着重要作用，包括唤醒从 OSA 睡眠中恢复。我们的目标是确定LDT/PPT的具体功能产生乙酰胆碱、谷氨酸和 GABA 的神经元；绘制解剖投影图这些细胞；并研究它们如何影响关键目标区域的活动调节睡眠/觉醒行为和呼吸。我们将利用以下方式实现这些目标光遗传学检查神经元活动的急性、短暂的增加或减少行为状态和仅使用设计受体的药物合成由设计药物 (DREADD) 激活，以检查持续数小时的变化。作为模特 OSA 的许多实验将使用重复 CO2 唤醒 (RCA) 方法来检查睡眠期间对高碳酸血症的反应。为了确定特定的 LDT/PPT 神经元是否足以保持清醒，脑电图激活，以及对 RCA 的反应，我们将使用以下方法激活每一类神经元 hM3 DREADD 或视紫红质通道 (ChR2)。确定特定的 LDT/PPT 神经元对于觉醒、脑电图激活和对 RCA 的反应是必要的，我们将抑制每一类神经元都使用 hM4 DREADD 或 ArchT（一种抑制性古视紫红质）。为了定义调节这些行为反应的关键 LDT/PPT 目标区域，我们将使用条件顺行和特定 LDT/PPT 神经元的地图投影逆行追踪；使用 ChR2- 确定哪些投射形成功能性突触辅助电路测绘（CRACM）；并确定哪些目标区域具有功能最重要的是通过局部刺激或抑制谷氨酸能和胆碱能神经使用 ChR2 或 ArchT 的每个目标区域中的终端。总的来说，这些多学科实验将定义神经网络特定类型的 LDT/PPT 神经元促进觉醒的机制， OSA 小鼠模型中的皮质激活和唤醒。这些结果实验应该大大提高我们对神经网络的科学知识由于高碳酸血症而产生觉醒和唤醒的机制，最终导致阻塞性睡眠呼吸暂停的更好治疗方法。