Optical Isolation of Dopamine Signals and Regulation by Ethanol
Optical Isolation of Dopamine Signals and Regulation by Ethanol
批准号:
8718204
负责人:
James Melchior
金额:
$4.27万
依托单位国家:
美国
项目类别:
财政年份:
2014
资助国家:
美国
项目状态:
已结题
起止时间:
2014-08-01 至 2017-07-31
关键词:
Action PotentialsAcuteAddressAffectAffectiveAgonistAirAlcohol abuseAlcohol consumptionAlcohol dependenceAlcoholsAnhedoniaAreaBackBathingBehaviorBrainBrain regionBreathingBuffersCellsChronicConfocal MicroscopyCorpus striatum structureDataDevelopmentDiseaseDopamineDynorphinsElectric StimulationElectrical Stimulation of the BrainEthanolExcisionGoalsHealthHeterogeneityHumanImmunohistochemistryIn VitroIncentivesInvestigationLightMeasuresMediatingMethodsModelingMusNegative ReinforcementsNeuromodulatorNeuronsNeurotransmittersNucleus AccumbensOpioid ReceptorOpticsPrevalencePreventionProcessProgressive DiseaseReceptor ActivationReceptor InhibitionRegulationRewardsRodentScanningShapesSignal PathwaySignal TransductionSliceSpecificityStimulusSystemTechniquesTestingTetrodotoxinTissuesTransgenic MiceTyrosineTyrosine 3-MonooxygenaseUnited StatesUp-RegulationVentral Tegmental AreaViralVirusWithdrawalWithdrawal Symptomaddictionalcohol exposurebasecalmodulin-dependent protein kinase IIcell typedopaminergic neurondrug of abuseeconomic costimprovedin vitro Modelinhibitor/antagonistinsightmouse modelneurotransmitter releasenoveloptogeneticspostsynapticpromoterreceptorreceptor sensitivityrecombinaseresponseuptakevaporvesicular monoamine transporter
中文摘要
项目总结/文摘
英文摘要
Project Summary/Abstract
Dopamine (DA) signaling in the nucleus accumbens (NAc) increases in response to natural reward and is
thought to encode the incentive salience of environmental stimuli, which motivates goal-directed behaviors. All
drugs of abuse, including alcohol, increase DA signaling in the NAc, implicating this system in the development
of addiction. In contrast to acute effects, DA signaling is reduced during withdrawal from chronic alcohol
exposure. It has been proposed that the endogenous kappa opioid receptor (KOR)/dynorphin system is
upregulated in the NAc during chronic alcohol administration, and may contribute to reduced DA signaling via
inhibitory KORs located on DA terminals. Modulation of DA release through various heteroreceptors (including
KOR) located on DA terminals has been investigated in NAc slices using fast scan cyclic voltammetry (FSCV)
to measure DA release and application of electrical stimulation to excite DA terminals. However, electrical
stimulation of the tissue results in simultaneous excitation of all neuronal processes in the stimulation field. The
NAc integrates inputs from multiple brain regions, resulting in a high level of neuronal heterogeneity in the
tissue. Release of neurotransmitters from non-DAergic processes provide, individually and together, local
regulation of DA terminal release. Thus, pharmacological effects on DA terminal release may occur through
direct (receptors on DA terminals) and/or indirect (receptors on other terminals or cells) mechanisms. This level
of complexity confounds analysis of KOR effects on DA terminals. In this proposal we introduce a novel model
for in vitro investigations of DA terminal function by optogenetically targeting DA neuron stimulation in the NAc
and measuring release using FSCV. We will inject the ventral tegmental area with a viral construct encoding
expression of channelrhodopsin-2 (ChR2) to induce ChR2 expression in DA neurons. This will allow selective
stimulation of DA terminals in NAc slices using blue light. We propose to develop this technique by targeting
ChR2 expression specifically to DA neurons utilizing a Cre-inducible viral construct in TH:Cre transgenic mice.
We will assess the specificity of expression using immunohistochemistry and confocal microscopy. Also, we
will characterize the evoked signal to validate its identity as DA and demonstrate that release is action potential
dependent. Furthermore, we will use the model's improved sensitivity for measures of direct actions of KOR on
DA terminal release. Finally, we will assess the changes in DA terminal KOR sensitivity following chronic
ethanol administration in mice.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Dopaminergic Modulation of Excitatory Transmission in BNST and Regulation by Ethanol
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批准号:9793987
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项目类别:
-
资助金额:$5.28万
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财政年份:2018
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负责人:James Melchior
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依托单位:
Dopaminergic Modulation of Excitatory Transmission in BNST and Regulation by Ethanol
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批准号:10264772
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项目类别:
-
资助金额:$3.37万
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财政年份:2018
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负责人:James Melchior
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依托单位:
Dopaminergic Modulation of Excitatory Transmission in BNST and Regulation by Ethanol
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批准号:9679116
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项目类别:
-
资助金额:$5.87万
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财政年份:2018
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负责人:James Melchior
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依托单位:
海外基金