Project 2- Scammell

项目2-Scammell

• 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
• 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

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.

Scammell项目摘要 在阻塞性睡眠呼吸暂停（OSA）患者中，唤醒起着挽救生命的作用， 我们假设背外侧和脚桥被盖的神经元 核团（LDT/PPT）在觉醒的许多方面起着重要作用，包括觉醒 从睡眠中醒来我们的目标是确定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 研究这些细胞的活性，并研究它们如何影响关键靶区域的活性， 调节睡眠/觉醒行为和呼吸。我们将通过以下方式实现这些目标： 光遗传学检查急性，短暂的增加或减少神经元活动内， 行为状态和药物合成，仅使用设计者受体 由Designer Drugs（DREADDs）激活，以检查持续数小时的变化。为模特 许多实验将使用重复CO2唤醒（RCA）方法， 检查睡眠时对高碳酸血症的反应。 为了确定特定的LDT/PPT神经元是否足以用于觉醒，EEG 激活，以及对RCA的反应，我们将使用 hM 3 DREADD或通道视紫红质（ChR 2）。为了确定特定的LDT/PPT神经元是否 是清醒、脑电图激活和对RCA的反应所必需的，我们将抑制 每类神经元使用hM 4 DREADD或ArchT，一种抑制性古视紫红质。 为了定义介导这些行为反应的关键LDT/PPT靶区域，我们将 使用条件性顺行和逆行标记特定LDT/PPT神经元的映射投影， 逆行追踪;使用ChR 2确定哪些投射形成功能性突触- 辅助电路映射（CRACM）;并确定哪些目标区域在功能上 最重要的是通过局部刺激或抑制多巴胺能和胆碱能神经 在每个目标区域中使用ChR 2或ArchT。 总的来说，这些多学科的实验将定义神经 特定类型的LDT/PPT神经元促进觉醒的机制， 皮质激活和觉醒。的结果予以 实验应该大大提高我们的科学知识的神经 由于高碳酸血症而产生觉醒和觉醒的机制， 从而更好地治疗阻塞性睡眠呼吸暂停。