Mesocortical neuromodulation in punishment-resistant alcohol drinking

项目摘要 长期存在的假说已经假定了多巴胺能神经调节失调的关键作用， 前额叶皮层在酒精使用障碍（AUD）的发展。尽管人们对大脑皮层中膜 多巴胺系统，技术挑战已经排除了直接的，时间分辨的多巴胺观察 前额叶皮层的释放模式。因此，关于基本职能的问题 中皮层多巴胺以及它在AUD中的作用已经众所周知地难以解决。在此，我们建议 使用最近开发的遗传编码荧光多巴胺传感器，它允许直接评估 以前所未有的特异性和时间分辨率研究体内多巴胺动力学， 内侧前额叶皮层（mPFC）的释放模式与酒精自我管理行为相关。 在雄性和雌性小鼠中，我们将首先测试mPFC的多巴胺神经支配对一系列 刺激，包括酒精，以确定其对基本行为过程的贡献。接下来我们将评估如何 这些释放模式在酒精自我给药和重复酒精暴露期间发生变化， 确定该系统的缺陷是否与饮酒量增加有关， 寻找最后，我们将通过以下方法从机制上研究中皮层对饮酒行为的控制： 在体内操纵这个系统的活动，并确定酒精对突触前多巴胺的直接作用， 使用离体成像的mPFC中的末端。完成这项提案将提供前所未有的洞察力， 了解失调的皮质神经调节在听觉诱发障碍相关行为中的作用。

Project Summary Long-standing hypotheses have posited a critical role for dysregulated dopaminergic neuromodulation of prefrontal cortex in the development of alcohol use disorder (AUD). Despite intense interest in the mesocortical dopamine system, technical challenges have precluded direct, temporally resolved observation of dopamine release patterns in the prefrontal cortex until recently. Accordingly, questions regarding the basic function of mesocortical dopamine as well as its role in AUD have been notoriously difficult to address. Here we propose to use a recently developed genetically-encoded fluorescent dopamine sensor, which allows for direct assessment of dopamine dynamics in vivo with unprecedented specificity and temporal resolution, to dissect dopamine release patterns in the medial prefrontal cortex (mPFC) associated with alcohol self-administration behaviors. In male and female mice, we will first test the responsiveness of dopamine innervation of mPFC to a range of stimuli including alcohol to determine its contribution to basic behavioral processes. Next we will assess how these release patterns evolve during initiation of alcohol self-administration and repeated alcohol exposure to determine if deficits in this system are associated with the emergence of heightened alcohol drinking and seeking. Finally, we will mechanistically investigate mesocortical control of alcohol drinking behaviors by manipulating the activity of this system in vivo and determine alcohol’s direct actions on presynaptic dopamine terminals in the mPFC using ex vivo imaging. Completion of this proposal will provide unprecedented insight and understanding as to the contribution of dysregulated cortical neuromodulation in AUD-relevant behaviors.