Functional connectome analysis of amphetamine action at dopamine neuron synapses
安非他明对多巴胺神经元突触作用的功能连接组分析
基本信息
- 批准号:8913460
- 负责人:
- 金额:$ 59.42万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-05-01 至 2020-02-29
- 项目状态:已结题
- 来源:
- 关键词:AcuteAdaptive BehaviorsAddressAffectAmphetaminesAttenuatedAutomobile DrivingBehaviorBehavioralBiologyBrainCocaineCorpus striatum structureCuesDataDevelopmentDopamineDoseDrug AddictionDrug ExposureDrug effect disorderDrug usageEpigenetic ProcessGlutamatesGuide preventionHeterogeneityIncidenceInterneuronsLinkMapsMeasuresMedialMediatingMediator of activation proteinMental disordersMolecularMolecular TargetMusNeuronal PlasticityNeuronsNeurotransmittersNucleus AccumbensPharmaceutical PreparationsPopulationPresynaptic TerminalsPsychostimulant dependencePsychotropic DrugsReportingResearchRoleSelf AdministrationSignal TransductionSumSynapsesSynaptic plasticitySystemTimeVentral StriatumWorkaddictionapproach behaviorbasebehavioral responsecholinergicdopamine transporterdopaminergic neuronexperiencegamma-Aminobutyric Acidindexinginsightmotivated behaviorneurotransmissionoptogeneticspostsynapticpreemptpsychostimulantpublic health relevance
项目摘要
DESCRIPTION (provided by applicant): Psychostimulants target dopamine neurons, acting principally at the dopamine transporter. Ensuing actions in the postsynaptic striatal circuitry mediate both the acute behavioral response to the drug as well as longer-term neuroplastic changes associated with addiction. Extensive work has focused on dopamine release and on the actions of dopamine, but only recently with the advent of optogenetics have dopamine neuron synaptic actions become directly accessible to study. Optogenetics enables a functional connectome approach to determining dopamine neuron synaptic actions. In this approach, channelrhodopsin 2 is expressed comprehensively in an identified population of neurons and the sum total of the connections of the population of neurons onto identified target neurons measured to determine a functional connectivity index comprising the incidence of connections and their strength. Determining the functional connectome of striatal spiny projection neurons - the principal postsynaptic targets of dopamine neurons - has provided quantitative measures of functional connectivity, going beyond anatomical data to direct measures of synaptic strength. While spiny projection neurons appear to signal solely via GABA, dopamine neurons signal via dopamine as well as glutamate and GABA, and differentially target striatal neurons in different striatal regions. Dopamine neurons make robust glutamatergic synaptic connections with cholinergic interneurons in the ventral striatum, specifically in the medial shell of the nucleus accumbens that appear to be critically involved in mediating the acute behavioral response to amphetamine. A single low dose of amphetamine, which engenders motoric stimulation, significantly and selectively attenuates these glutamatergic connections. In contrast, a high amphetamine dose, which engenders stereotypic behavior, broadly attenuates dopaminergic connections throughout the striatum. This motivates the hypothesis that amphetamine-induced plasticity of specific populations of dopamine neuron synapses is critical for driving the striatal
circuitry towards the addicted state. To address this hypothesis, the three specific aims are to: <1> Determine the dopamine neuron functional connectome in the striatum, mapping the synaptic actions of dopamine neurons across the striatum. <2> Determine how amphetamine modulates the dopamine neuron functional connectome following a single exposure, examining regional heterogeneity, and the timing and persistence of the modulation. <3> Determine the role of the most affected connections, as crucial mediators of amphetamine circuit and behavioral effects. Expressing amphetamine-induced actions in functional connectome terms enables a systematic synapses-to-circuits-to-behavior approach to elucidating the synaptic substrate of amphetamine action and the inception of addiction.
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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STEPHEN RAYPORT其他文献
STEPHEN RAYPORT的其他文献
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{{ truncateString('STEPHEN RAYPORT', 18)}}的其他基金
Synaptic Actions of Amphetamine in the Striatum
安非他明在纹状体中的突触作用
- 批准号:
10668662 - 财政年份:2023
- 资助金额:
$ 59.42万 - 项目类别:
Targeting cotransmission for circuit-specific pharmacotherapy
针对回路特异性药物治疗的共传输
- 批准号:
10410440 - 财政年份:2018
- 资助金额:
$ 59.42万 - 项目类别:
Targeting cotransmission for circuit-specific pharmacotherapy
针对回路特异性药物治疗的共传输
- 批准号:
10212915 - 财政年份:2018
- 资助金额:
$ 59.42万 - 项目类别:
Targeting cotransmission for circuit-specific pharmacotherapy
针对回路特异性药物治疗的共传输
- 批准号:
9769150 - 财政年份:2018
- 资助金额:
$ 59.42万 - 项目类别:
Mapping dopamine neuron cotransmission by proximity detection
通过邻近检测绘制多巴胺神经元共传递
- 批准号:
8985749 - 财政年份:2015
- 资助金额:
$ 59.42万 - 项目类别:
Functional connectome analysis of amphetamine action at dopamine neuron synapses
安非他明对多巴胺神经元突触作用的功能连接组分析
- 批准号:
9231430 - 财政年份:2015
- 资助金额:
$ 59.42万 - 项目类别:
Functional connectome analysis of amphetamine action at dopamine neuron synapses
安非他明对多巴胺神经元突触作用的功能连接组分析
- 批准号:
9054105 - 财政年份:2015
- 资助金额:
$ 59.42万 - 项目类别:
Therapeutic potential of GLS1 inhibition for the pharmacotherapy of schizophrenia
GLS1 抑制在精神分裂症药物治疗中的治疗潜力
- 批准号:
7767107 - 财政年份:2010
- 资助金额:
$ 59.42万 - 项目类别:
Therapeutic potential of GLS1 inhibition for the pharmacotherapy of schizophrenia
GLS1 抑制在精神分裂症药物治疗中的治疗潜力
- 批准号:
8403407 - 财政年份:2010
- 资助金额:
$ 59.42万 - 项目类别:
Therapeutic potential of GLS1 inhibition for the pharmacotherapy of schizophrenia
GLS1 抑制在精神分裂症药物治疗中的治疗潜力
- 批准号:
8210963 - 财政年份:2010
- 资助金额:
$ 59.42万 - 项目类别:
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