Neuron-astrocyte interactions mediating ethanol and noradrenergic modulation of wake-promoting vPAG dopamine neurons
神经元-星形胶质细胞相互作用介导促醒 vPAG 多巴胺神经元的乙醇和去甲肾上腺素能调节
基本信息
- 批准号:10463298
- 负责人:
- 金额:$ 3.2万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-07-01 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:AcuteAdenosineAdenosine TriphosphateAdrenergic AgonistsAdrenergic ReceptorAgonistAlcohol consumptionAlcohol withdrawal syndromeAmericanArousalAstrocytesBehavioralBrainBrain regionCalciumCalcium SignalingCellsChronicDevelopmentDoseElectrophysiology (science)EthanolFiberFluorescence MicroscopyG alpha q ProteinGoalsHumanIndividualInvestigationMeasuresMediatingMental disordersMidbrain structureModelingMusNeurogliaNeuronsNorepinephrinePathologicPeriodicityPharmacologyPhenylephrinePhotometryPhysiologyPopulationPurinesPurinoceptorReceptor ActivationRelapseReportingRoleSeriesSignal TransductionSignaling ProteinSleepSleep DisordersSleep disturbancesSleeplessnessSliceStressSynapsesSynaptic TransmissionSynaptic plasticitySystemTestingTimeViralWakefulnessWithdrawalWorkalcohol abstinencealcohol exposurealcohol use disorderalertnessalpha-1 adrenergic receptorsantagonistchronic alcohol ingestioncomorbiditydisorder later incidence preventiondopaminergic neuronexcitatory neuronexperienceexperimental studyextracellularfluorescence imaginggenetic approachin vivolocus ceruleus structuremidbrain central gray substancemouse modelnew therapeutic targetnoradrenergicnovelnovel therapeuticspatch clamppreventpromoterreceptor expressionrelapse riskresponsesensorsleep difficultysleep regulationtherapeutic targettransmission processvirus genetics
项目摘要
PROJECT SUMMARY
An estimated 50-70 million Americans suffer from a sleep disorder, which is commonly comorbid with many
psychiatric illnesses, such as alcohol use disorder (AUD). Individuals with AUD frequently report insomnia, and
sleep difficulty significantly increases the likelihood of relapse. Despite the overwhelming need to control sleep
disturbances to aid in the prevention of relapse, the underlying physiology of wakefulness, particularly in the
context of acute and chronic alcohol use, is not well understood. The brain’s noradrenergic system mediates
many behavioral states, such as arousal, alertness, and stress. Acute and chronic alcohol exposure
differentially alter the activity of noradrenergic neurons as well as the release, synthesis, and turnover of
norepinephrine (NE) in the brain. Recently, our lab alongside collaborators delineated a novel arousal circuit
from the noradrenergic locus coeruleus (LC) to dopaminergic neurons in the ventral periaqueductal gray
(vPAGDA), where stimulation of this circuit promotes wakefulness. Acute ethanol exposure also increases
excitatory drive and the activity of wake-promoting vPAGDA neurons; however, the mechanism is unknown.
Specific activation of alpha1-adrenergic receptors (α1ARs) increases excitatory drive onto vPAGDA neurons and
subsequently causes arousal. Interestingly, α1AR expression is particularly enriched on vPAG astrocytes, and
activation of astrocytic Gq signaling is sufficient to promote wakefulness. While astrocytes are essential in
mediating synaptic transmission in other brain regions through purinergic signaling, the role of neuron-
astrocyte interactions in the vPAG during ethanol exposure requires further investigation. This F30 aims to
test the central hypothesis that purinergic transmission from neighboring astrocytes mediates the
noradrenergic modulation of vPAGDA neurons, and that ethanol potentiates this signaling. The goal is to
elucidate the mechanistic details mediating the increase in excitatory drive onto the wake-promoting vPAGDA
neurons by activation of α1ARs and the pathologic changes to the noradrenergic system following acute and
chronic alcohol exposure. In Specific Aim 1 I will utilize pharmacological and viral genetic approaches
combined with ex vivo fluorescence imaging and whole cell patch-clamp electrophysiology to examine the
neuron-astrocyte interactions underlying noradrenergic modulation of vPAGDA neurons. In Specific Aim 2 I will
use similar approaches in addition to a mouse model of chronic intermittent ethanol exposure to determine the
changes in synaptic transmission onto vPAGDA neurons following acute and chronic ethanol exposure. The
results of these studies will allow our lab, our collaborators, and others to further investigate the role of neuron-
astrocyte physiology related to sleep dysfunction in alcohol use disorder. This will further the work towards
identifying possible therapeutic targets for the development of novel therapies to alleviate disordered sleeping
and aid in relapse prevention.
项目总结
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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Nicholas Petersen其他文献
Nicholas Petersen的其他文献
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{{ truncateString('Nicholas Petersen', 18)}}的其他基金
Neuron-astrocyte interactions mediating ethanol and noradrenergic modulation of wake-promoting vPAG dopamine neurons
神经元-星形胶质细胞相互作用介导促醒 vPAG 多巴胺神经元的乙醇和去甲肾上腺素能调节
- 批准号:
10588136 - 财政年份:2022
- 资助金额:
$ 3.2万 - 项目类别:
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