Intersections of Sleep and Coma: Neural Pathways of Alpha-2 Adrenergic Hypnosis
睡眠与昏迷的交叉点:Alpha-2 肾上腺素催眠的神经通路
基本信息
- 批准号:9293823
- 负责人:
- 金额:$ 19.66万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-05-01 至 2021-04-30
- 项目状态:已结题
- 来源:
- 关键词:AcuteAddressAdrenergic AgentsAdrenergic AgonistsAdrenergic ReceptorAffectAmericanAnesthesia proceduresAnestheticsAnimalsAreaArousalBehavioralBindingBiological Neural NetworksChronicClinicalComaCritical PathwaysDataDevelopment PlansDexmedetomidineDirect CostsDiseaseDrug effect disorderEngineeringEnsureEnterobacteria phage P1 Cre recombinaseFutureGeneticGenetic studyGoalsHeadHypnosisHypothalamic structureInstitutionInvestigationKnock-outKnockout MiceLightMedetomidineMediatingMentorsMicroinjectionsModelingMusNeural PathwaysNeuronsNeurosciencesOpsinPatternPharmacologyPontine structurePopulationPropertyPublic HealthPublishingReceptor GeneResearchResistanceRoleSiteSleepSleep DisordersSleep Disorders TherapySleeplessnessSlow-Wave SleepStructureStudy modelsTestingTransgenic MiceUncertaintyViralalpha 2 agonistawakebasebehavioral studybrain pathwaycareercareer developmentexperiencehypnoticinsightknowledge baselife time costlocus ceruleus structuremultidisciplinaryneural circuitnoveloptogeneticspresynapticreceptorsedative
项目摘要
Disorders of sleep or arousal will affect up to a third of all Americans at some point in their lives, with
upwards of 50 million of those experiencing chronic issues. To understand and treat these disorders, we
must first understand the neural circuits and networks responsible for arousal and sleep. We propose to
study the hypnotic action of α2 adrenergic agonists, which activate endogenous sleep-active circuits and
produce a hypnosis that appears similar to slow-wave sleep. Our data corroborates earlier behavioral
studies showing the neuronal population(s) producing α2 agonist hypnosis lies in the rostral pons in a
region that includes the locus coeruleus. However, adrenergic neurons of the locus coeruleus alone do
not appear to be sufficient. The proposed investigation will determine the role of adrenergic and rostral
pontine neurons in hypnotic actions of α2 adrenergic agonists through addressing these questions:
Can discrete and localized actions of α2 agonists targeting the rostral pons produce and maintain
hypnosis? Previously published together with our preliminary data support the idea that local delivery
of α2 agonists to pons including the locus coeruleus is sufficient for hypnosis. We will use novel α2
adrenergic agonist photolabels to locally modulate neuronal activity and rigorously test this hypothesis.
Are adrenergic neurons of the locus coeruleus necessary for α2-mediated hypnosis? We will
perform adrenergic-specific knockouts of α2A adrenergic receptors in the rostral pons, looking for
resistance to α2 adrenergic agonist hypnosis. We will also optogenetically drive adrenergic neurons of the
rostral pons to determine if their activity can reverse α2 mediated hypnosis.
Is the neuronal firing pattern in the rostral pons around the LC under α2-agonist hypnosis
primarily dependent on local or systemic effects? Can changing adrenergic neuron activity
reverse α2-agonist hypnosis? We will record unit-activity in the rostral pons with α2 agonist
administration in wild-type and adrenergic α2A receptor knockout mice. Using optogenetics and α2
photolabels, we will mechanistically dissect local presynaptic vs. systemic circuit effects of α2 agonists.
At the completion of this project, we will have determined the contribution of adrenergic neurons of the
rostral pons to α2 mediated hypnosis. This will give insight into the neural circuits common to sleep and
anesthesia—a door to future therapies for disorders of sleep and arousal. The proposed project will also
build upon the PI's base knowledge of anesthetic pharmacology, as well as providing expertise in new
areas of neuroscience and genetics. The strong, multi-disciplinary mentoring team, equally intellectually
diverse collaborators, a clear career development plan, and the phenomenal support of a department that
deeply values research at a world-class institution will ensure that the PI not only achieves the scientific
goals of this proposal, but is prepared for a successful career investigating sleep and anesthetic hypnosis.
睡眠或觉醒障碍将影响多达三分之一的美国人在一生中的某个阶段,
为了了解和治疗这些疾病,我们有超过 5000 万人患有慢性疾病。
我们建议首先必须了解负责唤醒和睡眠的神经回路和网络。
研究 α2 肾上腺素能激动剂的催眠作用,它激活内源性睡眠活跃回路,
产生类似于慢波睡眠的催眠作用我们的数据证实了早期的行为。
研究表明,产生 α2 激动剂催眠作用的神经元群位于脑桥的嘴侧。
然而,仅蓝斑的肾上腺素能神经元就可以。
似乎还不够。拟议的研究将确定肾上腺素能和吻侧的作用。
通过解决以下问题,研究脑桥神经元在 α2 肾上腺素能激动剂催眠作用中的作用:
α2 激动剂针对脑桥头端的离散和局部作用能否产生并维持
催眠?之前与我们一起发布的初步数据支持本地交付的想法
α2 激动剂对脑桥(包括蓝斑)的作用足以进行催眠。
肾上腺素能激动剂光标签可局部调节神经元活动并严格检验这一假设。
蓝斑的肾上腺素能神经元是 α2 介导的催眠所必需的吗?
对脑桥头侧的 α2A 肾上腺素能受体进行肾上腺素能特异性敲除,寻找
对 α2 肾上腺素能激动剂催眠的抵抗 我们还将通过光遗传学驱动肾上腺素能神经元。
脑桥头端以确定其活性是否可以逆转 α2 介导的催眠。
α2 激动剂催眠下 LC 周围脑桥头侧的神经元放电模式是
主要取决于局部或全身效应?可以改变肾上腺素能神经元活性吗?
逆转α2激动剂催眠?我们将用α2激动剂记录脑桥头端的单位活动
使用光遗传学和 α2 对野生型和肾上腺素能 α2A 受体敲除小鼠进行给药。
通过照片标签,我们将机械地剖析 α2 激动剂的局部突触前与全身回路效应。
在该项目完成时,我们将确定肾上腺素能神经元的贡献
脑桥头端到 α2 介导的催眠这将深入了解睡眠和睡眠中常见的神经回路。
麻醉——未来治疗睡眠和觉醒障碍的大门。
以 PI 的麻醉药理学基础知识为基础,并提供新领域的专业知识
神经科学和遗传学领域强大的多学科指导团队,在智力上同样出色。
多元化的合作者、清晰的职业发展计划以及部门的大力支持
深深重视在世界一流机构的研究将确保 PI 不仅实现科学性
该提案的目标,但已为研究睡眠和麻醉催眠的成功职业做好准备。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Andrew Rich McKinstry-Wu其他文献
Andrew Rich McKinstry-Wu的其他文献
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{{ truncateString('Andrew Rich McKinstry-Wu', 18)}}的其他基金
Personalized Anesthesia: The Role of the Locus Coeruleus in Individual Anesthetic Responses
个性化麻醉:蓝斑在个体麻醉反应中的作用
- 批准号:
10274962 - 财政年份:2021
- 资助金额:
$ 19.66万 - 项目类别:
Personalized Anesthesia: The Role of the Locus Coeruleus in Individual Anesthetic Responses
个性化麻醉:蓝斑在个体麻醉反应中的作用
- 批准号:
10665091 - 财政年份:2021
- 资助金额:
$ 19.66万 - 项目类别:
Personalized Anesthesia: The Role of the Locus Coeruleus in Individual Anesthetic Responses
个性化麻醉:蓝斑在个体麻醉反应中的作用
- 批准号:
10799159 - 财政年份:2021
- 资助金额:
$ 19.66万 - 项目类别:
Intersections of Sleep and Coma: Neural Pathways of Alpha-2 Adrenergic Hypnosis
睡眠与昏迷的交叉点:Alpha-2 肾上腺素催眠的神经通路
- 批准号:
9906236 - 财政年份:2017
- 资助金额:
$ 19.66万 - 项目类别:
Intersections of Sleep and Coma: Neural Pathways of Alpha-2 Adrenergic Hypnosis
睡眠与昏迷的交叉点:Alpha-2 肾上腺素催眠的神经通路
- 批准号:
10361385 - 财政年份:2017
- 资助金额:
$ 19.66万 - 项目类别:
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