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: 8913460
• 负责人: STEPHEN RAYPORT
• 金额: $ 59.42万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/8913460
• 关键词: Acute; Adaptive Behaviors; Address; Affect; Amphetamines; Attenuated; Automobile Driving; Behavior; Behavioral; Biology; Brain; Cocaine; Corpus striatum structure; Cues; Data; Development; Dopamine; Dose; Drug Addiction; Drug Exposure; Drug effect disorder; Drug usage; Epigenetic Process; Glutamates; Guide prevention; Heterogeneity; Incidence; Interneurons; Link; Maps; Measures; Medial; Mediating; Mediator of activation protein; Mental disorders; Molecular; Molecular Target; Mus; Neuronal Plasticity; Neurons; Neurotransmitters; Nucleus Accumbens; Pharmaceutical Preparations; Population; Presynaptic Terminals; Psychostimulant dependence; Psychotropic Drugs; Reporting; Research; Role; Self Administration; Signal Transduction; Sum; Synapses; Synaptic plasticity; System; Time; Ventral Striatum; Work; addiction; approach behavior; base; behavioral response; cholinergic; dopamine transporter; dopaminergic neuron; experience; gamma-Aminobutyric Acid; indexing; insight; motivated behavior; neurotransmission; optogenetics; postsynaptic; preempt; psychostimulant; public health relevance

 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.

 描述（由申请人提供）：精神兴奋剂靶向多巴胺神经元，主要作用于多巴胺转运蛋白。突触后纹状体回路中的后续作用介导了对药物的急性行为反应以及与成瘾相关的长期神经可塑性变化。大量的工作集中在多巴胺的释放和多巴胺的作用上，但直到最近随着光遗传学的出现，多巴胺神经元突触作用才成为直接研究的对象。光遗传学使功能性连接体方法能够确定多巴胺神经元突触作用。在该方法中，通道视紫红质2在识别的神经元群体中全面表达，并且测量神经元群体到识别的靶神经元上的连接的总和以确定包括连接的发生率及其强度的功能连接指数。确定纹状体棘状投射神经元（多巴胺神经元的主要突触后靶点）的功能连接组提供了功能连接的定量测量，超越了解剖学数据，直接测量突触强度。虽然多刺投射神经元似乎仅通过GABA发出信号，但多巴胺神经元通过多巴胺以及谷氨酸和GABA发出信号，并且在不同的纹状体区域中差异地靶向纹状体神经元。多巴胺神经元与腹侧纹状体中的胆碱能中间神经元建立了强大的多巴胺能突触连接，特别是在内侧壳的延髓核中，这些神经元似乎与介导对苯丙胺的急性行为反应密切相关。一个单一的低剂量的安非他明，它产生运动刺激，显着和选择性地减弱这些兴奋性连接。相反，高剂量的安非他明会产生刻板行为，广泛地减弱整个纹状体的多巴胺能连接。这激发了一种假设，即安非他明诱导的多巴胺神经元突触特定群体的可塑性对于驱动纹状体神经元突触的形成至关重要。 向上瘾状态的方向发展为了解决这个假设，三个具体的目标是：<1>确定纹状体中多巴胺神经元的功能连接体，绘制纹状体中多巴胺神经元的突触活动。<2>确定安非他明如何调节多巴胺神经元功能连接体后，单次曝光，检查区域异质性，以及调制的时间和持久性。<3>确定最受影响的连接的作用，作为安非他明回路和行为影响的关键介质。表达安非他明诱导的行动在功能连接体方面，使系统的突触电路行为的方法，阐明安非他明的行动和成瘾的开始突触基板。