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：
9054105
负责人：
STEPHEN RAYPORT
金额：
$ 60.86万
依托单位：
NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
依托单位国家：
美国
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：
https://reporter.nih.gov/project-details/9054105
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 Health 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 connectome dopamine transporter dopaminergic neuron experience gamma-Aminobutyric Acid indexing insight motivated behavior neurotransmission optogenetics postsynaptic preempt psychostimulant

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.

描述（由适用提供）：心理刺激剂靶向多巴胺神经元，主要作用于多巴胺转运蛋白。在突触后纹状体回路中随之而来的作用介导了对药物的急性行为反应以及与成瘾有关的长期神经塑性变化。广泛的工作集中在多巴胺释放和多巴胺的作用上，但直到最近，随着光遗传学的发展，多巴胺神经元突触作用才能直接进行研究。光遗传学可以实现一种功能连接方法来确定多巴胺神经元突触作用。在这种方法中，通道Rhodopsin 2在确定的神经元群体中进行了全面表达，以及神经元与确定靶神经元的连接总和的总和，以确定功能连通性指数，以编译连接的事件及其强度。确定纹状体棘投射神经元的功能连接组（多巴胺神经元的主要突触后靶标）提供了功能连通性的定量测量，超越了解剖学数据，可以直接测量突触强度的测量。虽然棘投射神经元似乎仅通过GABA发出信号，但多巴胺以及谷氨酸和GABA的多巴胺神经元信号以及不同纹状体区域的型纹状体神经元的靶向不同。多巴胺神经元与腹纹状体中的胆碱能中间神经元，特别是在伏隔核的内侧壳中与胆碱能中间神经元进行稳健的突触连接，这似乎与急性行为对氨菲胺的反应有关。单一的低剂量苯丙胺产生了摩托车刺激，可显着和选择性地减弱这些谷氨酸能连接。相比之下，产生刻板印象行为的高苯丙胺剂量会大致减弱整个纹状体的多巴胺能连接。这激发了以下假设，即苯丙胺诱导的多巴胺神经元突触的可塑性对于驱动纹状体至关重要向上的状态的电路。为了解决这一假设，三个特定的目的是：<1>确定纹状体中多巴胺神经元功能连接组，绘制多巴胺神经元跨纹状体的突触作用。 <2>确定单次暴露后如何调节多巴胺神经元功能连接组，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，作为苯丙胺电路的关键介体和行为效应。用功能连接的术语表达苯丙胺诱导的动作，使系统突触到行为至行为的方法，以阐明苯丙胺作用的突触底物和成瘾的启动。