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

描述（由申请人提供）：了解滥用药物如何改变神经群体的计算特性已被描述为“必要的中介”，以确定药物诱导的神经生物学细胞水平变化如何表现出成瘾中常见的行为表型改变（Kalivas，2005）。虽然许多神经递质系统在编码奖励相关信息和指导动机行为中发挥作用，但压倒性的证据表明，中皮质边缘多巴胺系统在这些过程中特别重要。此外，包括酒精在内的多种滥用药物引起多巴胺系统的持续神经适应，这被认为是成瘾表型表达的主要生物学特征。滥用药物，如阿片类药物和精神兴奋剂，已受到相当大的关注，在建模研究中，其明确的药理学作用机制腹侧被盖区多巴胺（DA）神经元提供了一个计算易处理的目标。酒精对DA系统的药理学和生理学影响的理解正在改善，但了解酒精调节腹侧被盖区微电路的具体机制，特别是GABA-DA动力学仍然是一个谜。考虑到酒精使用障碍是所有成瘾谱系障碍中最普遍的，并且酒精滥用估计每年导致全球250万人死亡，了解酒精如何改变DA信号传导代表了目前未满足的关键医疗需求。这项法国-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，并最终确定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DA神经元中的起搏和爆发放电，其最终控制DA的紧张性和阶段性释放。我们的假设是：1）酒精改变内在电导，其具有增加DA神经元活动的动态范围的净效应; 2）并行地，这被 GABA释放到DA神经元上的变化允许增加的爆发。为了验证这些假设，我们将结合联合收割机单细胞和网络生物物理模型的DA和GABA神经元，激励在体外和体内实验，以评估突触和网络功能。我们的目标是建立一个工具箱，能够驱动和预测的实验方法，允许由酒精引起的DA动力学的变化进行量化。这些模型将由美国和法国的理论团队共同开发。法国和美国的实验团队将使用尖端的电生理技术分别进行体外和体内实验。我们的总体目标是澄清酒精篡夺腹侧被盖多巴胺能回路功能的关键生物物理机制，从而激发信号。智力优点：该提案旨在模拟和描述多巴胺系统中酒精诱导的效应，特别是腹侧被盖区。因此，我们的工作将提供实验数据和计算工具，以了解神经元和回路水平的影响，酒精对DA和GABA神经元回路。值得注意的是，本文提出的DA和GABA神经元尖峰及其局部回路相互作用的模型目前不可用。开发这些模型的应用超出了这个项目，将很容易纳入奖励为基础的学习和行为的高层次模型。此外，开发的工具可用于研究其他滥用药物的奖励信号的生物物理学，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，可以潜在地确定肌动蛋白的关键位点和酒精对动机信号的初始影响机制。这些数据还将提供必要的框架，以了解酒精对动机回路的作用如何在遗传上易受酒精使用障碍影响的人群中改变。此外，这些数据将为开发计算模型提供关键的第一步，该模型可以追踪慢性酒精引起的细胞和回路水平信号传导的渐进变化。可以模拟治疗酒精中毒的潜在治疗靶点，从而发现或开发治疗这种疾病的新的翻译方法。此外，开发的计算工具将为理解酒精和尼古丁（另一种高度成瘾物质）之间的共同发病的生物物理学奠定基础。总之，我们相信该项目的成果将产生广泛的转化影响。在教育影响方面，该项目发起了美国和法国机构之间的联盟，并为两名博士后学员提供资助，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有力的合作计划，这肯定会刺激新的项目和合作科学超越目前提出的研究。

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.