Medullary Control of REM Sleep
快速眼动睡眠的髓质控制
基本信息
- 批准号:10447718
- 负责人:
- 金额:$ 39.81万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-08-05 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:AffectAreaAxonBiological MarkersBrainBrain StemCorticotropin-Releasing HormoneDataDevelopmentDorsalDreamsElectroencephalogramFiberGoalsKnowledgeLightLinkMaintenanceMediatingMental DepressionMethodsModelingMolecularMood DisordersMusNeuronsParalysedPathway interactionsPatternPhotometryPontine structurePopulationREM SleepRabies virusRegulationRoleSkeletal MuscleSleepSleep DisordersSleep disturbancesSynapsesTestingTherapeutic InterventionViralWakefulnessbaseexpectationexperimental studyin vivoin vivo calcium imaginginnovationmood symptommouse modelneuromechanismnew therapeutic targetnon rapid eye movementnoveloptogeneticspostsynapticrapid eye movementrelating to nervous systemsleep regulationtool
项目摘要
PROJECT SUMMARY
Rapid eye movement (REM) sleep is characterized by activated electroencephalogram (EEG) and skeletal
muscle paralysis and is associated with vivid dreaming. Disturbances in REM sleep are symptomatic of mood
disorders and are considered as a biomarker for depression. Core circuits generating REM sleep are located in
two brainstem areas, the pons and medulla. The role of the pons in REM sleep regulation is well studied, while
the importance of the medulla has only recently been appreciated. Previous studies, including our preliminary
data, suggest an important role of neurons in the dosomedial medulla (dmM) in REM sleep control. However,
little is known about the molecular identity of neurons in the dmM that promote REM sleep, about their activity
during sleep and their downstream targets. To fill this gap, we will employ state-of-the-art tools for circuit
mapping and methods for recording and perturbing neural activity in the mouse model.
Our long-term objective is to unravel the circuit mechanisms controlling REM sleep. Our preliminary results
show that a genetically defined population of neurons in the dmM that express corticotropin-releasing hormone
(CRH) promotes REM sleep. The central objective of this proposal is to understand how the activity of dmM
CRH neurons controls REM sleep and identify the downstream targets in the pons through which they induce
REM sleep. In Aim 1, we will manipulate the activity of CRH neurons using opto- and chemogenetic
approaches and examine how activation and inhibition affect the initiation and maintenance of REM sleep.
Using optrodes, we will record the activity of dmM CRH neurons in freely moving mice across multiple periods
of wakefulness, NREM, and REM sleep and test whether their activity pattern supports a role in initiating and
maintaining REM sleep. In Aim 2, we will investigate whether the axonal projections from the dmM to
downstream areas in the pons mediate the effects on REM sleep. We will use pseudo-typed rabies viruses for
circuit mapping and employ in vivo calcium imaging and optogenetic perturbations to examine the role of this
pathway. The proposed studies are innovative, as they will reveal the role of an unexplored brainstem circuit in
REM sleep control, and the results will extend existing models of how neurons in the medulla interact with
post-synaptic areas in the pons to regulate REM sleep. The capability to manipulate REM sleep by targeting a
genetically defined population of medullary neurons will provide a powerful tool to understand the pervasive
link between REM sleep and mood disorders.
项目摘要
快速眼动(REM)睡眠的特征是激活脑电图(EEG)和骨骼肌运动。
肌肉麻痹,并与生动的梦想。快速眼动睡眠的紊乱是情绪的症状
被认为是抑郁症的生物标志物。产生REM睡眠的核心电路位于
两个脑干区域脑桥和延髓脑桥在REM睡眠调节中的作用已经得到了很好的研究,
髓质的重要性直到最近才被认识到。以前的研究,包括我们的初步研究,
数据表明,在REM睡眠控制中,延髓内侧区(domedial medulla,DMM)的神经元起着重要作用。然而,在这方面,
对于促进REM睡眠的DMM中神经元的分子特性、它们的活动,
和下游的目标。为了填补这一空白,我们将采用最先进的电路工具,
用于在小鼠模型中记录和干扰神经活动的映射和方法。
我们的长期目标是解开控制REM睡眠的电路机制。我们的初步结果
显示在表达促肾上腺皮质激素释放激素的dmM中,
(CRH)促进快速眼动睡眠该提案的中心目标是了解DMM的活性如何影响其生物学特性。
CRH神经元控制REM睡眠,并识别脑桥中的下游靶点,
快速眼动睡眠。在目的1中,我们将使用光和化学遗传学方法操纵CRH神经元的活性。
方法和研究如何激活和抑制影响的启动和维持快速眼动睡眠。
使用光电管,我们将记录自由活动小鼠在多个时期的dmM CRH神经元的活动
觉醒,NREM和REM睡眠,并测试他们的活动模式是否支持启动和
维持快速眼动睡眠在目标2中,我们将研究从DMM到DMM的轴突投射是否与DMM的轴突投射有关。
脑桥中的下游区域介导对REM睡眠的影响。我们将使用假狂犬病毒
电路映射,并采用体内钙成像和光遗传学扰动来检查这一作用。
通路这项研究是创新性的,因为它们将揭示一个未被探索的脑干回路在
快速眼动睡眠控制,结果将扩展现有的模型,如何在延髓神经元相互作用,
突触后区域来调节快速眼动睡眠。通过瞄准目标来操纵快速眼动睡眠的能力
遗传定义的髓神经元群体将提供一个强大的工具来理解广泛的
快速眼动睡眠和情绪障碍之间的联系。
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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Franz L Weber其他文献
Franz L Weber的其他文献
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