CRCNS: Alcohol modulation of dopamine-GABA dynamics in the ventral tegmental area

CRCNS：酒精调节腹侧被盖区多巴胺-GABA 动力学

• 批准号: 8644394
• 负责人: Alexey S Kuznetsov
• 金额: $ 18.38万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8644394
• 关键词: Accounting; Actins; Acute; Alcohol abuse; Alcoholism; Alcohols; Attention; Behavioral; Biological; Biological Availability; Biophysics; Boxing; Brain region; Cells; Cessation of life; Chronic; Collaborations; Comorbidity; Computer Simulation; Data; Development; Disease; Dopamine; Equilibrium; France; Funding; Goals; In Vitro; Institution; Lead; Mediating; Medical; Modeling; Neurobiology; Neurons; Neurotransmitters; Nicotine; Opiates; Outcome; Pattern; Pharmaceutical Preparations; Phase; Phenotype; Physiological; Play; Population; Process; Property; Rewards; Role; Science; Signal Transduction; Simulate; Site; Staging; Structure; Study models; Synapses; System; Techniques; Testing; Training; Ventral Tegmental Area; Work; addiction; alcohol effect; alcohol research; alcohol use disorder; base; computerized tools; data modeling; dopamine system; dopaminergic neuron; drug of abuse; gamma-Aminobutyric Acid; graduate student; improved; in vivo; learned behavior; motivated behavior; neural circuit; neuroadaptation; neurotransmission; novel; optogenetics; programs; psychostimulant; relating to nervous system; research study; scale up; theories; therapeutic target; tool; translational approach; undergraduate student

DESCRIPTION (provided by applicant): Understanding how drugs of abuse alter the computational properties of neural populations has been characterized as a "necessary intermediary" to identify how cellular-level changes in neurobiology, induced by the drug, manifest altered behavioral phenotypes commonly observed in addiction (Kalivas, 2005). While numerous neurotransmitter systems play a role in encoding reward-related information and guiding motivated behavior, overwhelming evidence identifies the mesocorticolimbic dopamine system as particularly important in these processes. Furthermore, multiple drugs of abuse, including alcohol, evoke persistent neuroadaptations in the dopamine system that are thought to be a primary biological feature that underlies the expression of the addicted phenotype. Drugs of abuse, such as opiates and psychostimulants, have received considerable attention in modeling studies as their clear pharmacological mechanism of action on ventral tegmental area dopamine (DA) neurons provides a computationally tractable target. An understanding of alcohols pharmacological and physiological effects on the DA system are improving, but understanding the specific mechanisms by which alcohol modulates ventral tegmental area microcircuits and specifically GABA-DA dynamics are still largely a mystery. Considering alcohol use disorders are the most pervasive of all addiction spectrum disorders and alcohol abuse is estimated to be responsible to 2.5 million deaths world-wide annually, understanding how alcohol alters DA signaling represents a currently unmet and critical medical need. The immediate goal of this France-USA collaboration is to quantify the acute effects of alcohol on the dynamics of GABA-DA crosstalk and ultimately the integrative and computational properties of this neural system. A balance between intrinsic conductances and synaptic inputs mediates both pacemaking and burst firing in the DA neuron, which ultimately controls tonic and phasic release of DA. Our hypothesis is 1) alcohol modifies intrinsic conductances, which have the net effect of increasing the dynamic range of DA neuron activity and 2) in parallel, this is boosted by changes in GABA release onto DA neurons allowing for increased bursting. To test these hypotheses, we will combine single cell and network biophysical models of DA and GABA neurons to motivate in vitro and in vivo experiments to assess synaptic and network function. Our goal is to build a toolbox able to drive and predict experimental approaches that allow for the changes induced by alcohol on DA dynamics to be quantified. The models will be developed together by the USA and French theoretical teams. The French and USA experimental teams will perform in vitro and in vivo experiments, respectively, using cutting edge electrophysiological techniques. Our overall goal is to clarify the key biophysical mechanisms by which alcohol usurps the function of dopaminergic circuits in the ventral tegmentum and thus motivational signals. Intellectual merit: This proposal aims to model and characterize alcohol-induced effects in the dopamine system, notably the ventral tegmental area. As such, our work will provide experimental data and computational tools to understand the neuronal and circuit level effects of alcohol on DA and GABA neuronal circuits. Notably, the models of DA and GABA neuron spiking and their local circuit interactions proposed herein are not currently available. Developing these model have application beyond this project and would be easily incorporated into high-level models of reward-based learning and behavior. Furthermore, the tools developed can be used to study the biophysics of reward signaling for other drugs of abuse and understand the basic biological mechanisms of motivated behavior. Broader Impact: Our project will provide data and modeling tools that can potentially identify the key site of actin and mechanism for alcohols initial effects on motivational signaling. These data will also provide the necessary framework to understand how alcohol's actions on motivational circuits are altered in populations genetically vulnerable to alcohol use disorders. Moreover, these data will provide a critical first step to develop computational models that trace the progressive changes in cellular and circuit level signaling by chronic alcohol. Potential therapeutic targets to treat alcoholism could be modeled, leading to the discovery or development of novel translational approaches to treat this disease. Furthermore, the computational tools developed will set the stage to understand the biophysics of co-morbidity between alcohol and nicotine, another highly addictive substance. In summary we believe the outcomes of this project will have a broad translational impact. In terms of educational impact, this project initiates a consortium between US and French institutions and provides funding for two postdoctoral trainees, will provide training opportunities for at least one graduate student, and three undergraduate students. Moreover, this project will stimulate a robust collaborative program between the participating institutions that is certain to stimulate novel projects and collaborative science beyond the currently proposed studies.

描述（由申请人提供）：了解滥用药物如何改变神经种群的计算特性已被描述为“必要的中介”，以确定该药物诱导的细胞级变化如何在成瘾中经常观察到的行为表型改变了行为表型（Kalivas，2005年）。尽管许多神经递质系统在编码与奖励相关的信息和指导动机行为方面发挥作用，但压倒性的证据表明，在这些过程中，中皮质胶多巴胺系统在这些过程中尤为重要。此外，多种滥用药物（包括酒精）在多巴胺系统中引起了持续的神经适应，这被认为是上瘾表型表达的主要生物学特征。滥用药物（例如阿片类药物和精神刺激物）在建模研究中受到了极大的关注，因为它们对腹侧换段区域多巴胺（DA）神经元的清晰药理作用机理提供了一个可计算触觉的靶标。对酒精对DA系统的药理和生理影响的理解正在改善，但是了解酒精调节腹侧段盖区微电路的特定机制，尤其是GABA-DA动力学仍然很大程度上是一个谜。考虑到饮酒障碍是所有成瘾谱系中最普遍的一种，并且估计酒精滥用是每年在全球范围内250万人死亡的原因，因此了解酒精如何改变DA信号代表当前未满足和关键的医疗需求。法国 - 美国合作的直接目标是量化酒精对GABA-DA串扰动力学的急性影响，并最终量化该神经系统的综合和计算特性。内在电导和突触输入之间的平衡介导了DA神经元中的起搏和爆发，这最终控制了DA的滋补和阶段性释放。我们的假设是1）酒精修饰固有电导，其具有增加DA神经元活性动态范围的净效果，并且2）并行，这是通过 GABA释放到DA神经元的变化允许增加爆发。为了检验这些假设，我们将结合DA和GABA神经元的单细胞和网络生物物理模型，以激励体外和体内实验，以评估突触和网络功能。我们的目标是构建一个能够驱动和预测实验方法的工具箱，以量化酒精对DA动力学的变化。这些模型将由美国和法国理论团队一起开发。法国和美国实验团队将使用尖端电生理技术分别在体外和体内实验。我们的总体目标是阐明酒精在腹侧teggementum中篡夺多巴胺能电路功能的关键生物物理机制，从而激励信号。知识分子的优点：该提案旨在建模和表征饮酒诱导的多巴胺系统的影响，尤其是腹侧段区域。因此，我们的工作将提供实验数据和计算工具，以了解酒精对DA和GABA神经元电路的神经元和电路水平的影响。值得注意的是，目前尚不可用DA和GABA神经元尖峰及其本地电路相互作用的模型。开发这些模型超出了该项目的应用，并且很容易被纳入基于奖励的学习和行为的高级模型中。此外，开发的工具可用于研究其他滥用药物的奖励信号传导的生物物理学，并了解动机行为的基本生物学机制。更广泛的影响：我们的项目将提供数据和建模工具，这些工具可以潜在地识别肌动蛋白的关键部位和酒精机制的初始影响对动机信号的影响。这些数据还将提供必要的框架，以了解酒精对动机电路的行为如何改变了遗传易于酒精饮酒障碍的人群。此外，这些数据将为开发计算模型提供关键的第一步，以追踪慢性酒精的细胞和电路水平信号的进行性变化。可以对治疗酒精中毒的潜在治疗靶标进行建模，从而导致或开发新的翻译方法来治疗这种疾病。此外，开发的计算工具将奠定阶段，以了解酒精和尼古丁（另一种高度上瘾的物质）之间合并症的生物物理学。总而言之，我们认为该项目的结果将产生广泛的翻译影响。在教育影响方面，该项目启动了美国与法国机构之间的财团，并为两名博士后学员提供资金，将为至少一名研究生和三名本科生提供培训机会。此外，该项目将刺激参与机构之间的强大协作计划，这肯定会激发新的项目和合作科学，而不是当前建议的研究。