Tonic and phasic dopamine-mediated modulation of prefrontal cortex neurons

前额皮质神经元的强直性和阶段性多巴胺介导的调节

• 批准号: RGPIN-2017-05979
• 负责人: Seamans, Jeremy
• 金额: $ 2.33万
• 依托单位: University of British Columbia
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=664635
• 关键词: Tonic; phasic; dopamine; mediated; modulation

Dopamine (DA) is an important neuromodulator that affects behaviors involving the striatum and prefrontal cortex (PFC). The temporal dynamics of DA signaling strongly constrain proposed theories about DA function. In the PFC, DA release is slow and even a brief application of DA exerts sustained effects on the biophysical properties of PFC neurons recorded in vitro and in vivo that lasts minutes to hours. Based on the known characteristics of the PFC DA system, we proposed the ‘dual-state theory', positing that the DA modulation of ionic currents in PFC neurons causes networks to switch into one of two distinct states or modes over prolonged periods. ***In contrast, another more prominent theory posits that DA encodes temporally precise ‘Reward Prediction Errors' (RPEs) that are proposed to underlie ‘reinforcement' learning. This theory is based on data showing that reward predictive cues or outcomes are associated with brief bursts of spikes in DA neurons (<100ms) and transient DA elevations in the striatum. In 2007 we argued that the RPE-based reinforcement learning model is not feasible for the PFC because PFC DA release is far too slow and temporally imprecise and does not differentiate between unexpectedly ‘good' and ‘bad' outcomes. ***However, the tools necessary to accurately characterize transient DA signaling in PFC were not available at that time. New technologies have emerged within the last 5 years that can now address this issue. The present proposal will utilize these new technologies to investigate the effects of fast and slow DA signaling in the PFC. ***Specific Aims***1. Aim 1 is to characterize the temporal dynamics of phasic DA release in the PFC. Changes in DA levels will be measured using fast-scan cyclic voltammetry and DA release will be precisely controlled using optogenetic technology. We will quantify the specific DA concentrations in PFC produced by different optical stimulation parameters. ***2. Aim 2 is to determine how optogenetic DA release characterized in Aim 1 affects the firing of PFC neurons in vivo and synaptic interactions between neurons in vitro. This will involve evoking optogenetic release of DA in PFC while simultaneously performing opto-tetrode recordings of multiple PFC neurons in behaving animals or patch-clamp recordings of synaptic currents in brain slices.***The proposed experiments build on a history of studies where we have characterized the effects of exogenous DA on the biophysical properties of PFC neurons. We propose to incorporate powerful new technologies to evoke precisely timed release of DA from axons in PFC and determine its effects on PFC neurons and circuits. Understanding the temporal dynamics of DA release and its effects in the PFC could have significant impact on our understanding of the PFC and DA signaling throughout the brain.

多巴胺(DA)是影响纹状体和前额叶皮质(PFC)行为的重要神经调节剂。DA信号的时间动力学特性强烈地制约了已有的DA功能理论。在PFC中，DA的释放是缓慢的，即使是短暂的DA应用也会对体外和体内记录的PFC神经元的生物物理性质产生持续的影响，持续几分钟到几个小时。基于PFC DA系统的已知特性，我们提出了双态理论，认为PFC神经元离子电流的DA调制导致网络在较长时间内切换到两种截然不同的状态或模式之一。*相反，另一个更突出的理论假设DA编码时间上精确的“奖励预测误差”(RPE)，这些误差被认为是“强化”学习的基础。这一理论基于的数据表明，奖赏预测线索或结果与纹状体DA神经元的短暂尖峰爆发(100毫秒)和短暂的DA升高有关。2007年，我们认为基于RPE的强化学习模型对于PFC是不可行的，因为PFC DA的发布太慢，在时间上不准确，并且没有区分出人意料的好结果和坏结果。*然而，当时还没有准确描述PFC中瞬时DA信号特征所需的工具。在过去的5年里，出现了新的技术，现在可以解决这个问题。本提案将利用这些新技术来研究快速和慢速DA信号在PFC中的影响。*特定目标*1.目标1描述PFC中阶段DA释放的时间动力学。DA水平的变化将使用快速扫描循环伏安法进行测量，DA的释放将使用光遗传技术进行精确控制。我们将量化不同光刺激参数产生的PFC中特定的DA浓度。*2.目的2是为了确定Aim 1所描述的光遗传DA释放如何影响体内PFC神经元的放电和体外神经元之间的突触相互作用。这将涉及在PFC中诱发DA的光遗传释放，同时进行行为动物多个PFC神经元的光四极记录或脑片中突触电流的膜片钳记录。*拟议的实验建立在我们表征外源性DA对PFC神经元生物物理性质的影响的研究历史的基础上。我们建议结合强大的新技术来激发PFC轴突中DA的精确定时释放，并确定其对PFC神经元和电路的影响。了解DA释放的时间动态及其在PFC中的作用，对于我们理解PFC和整个大脑中的DA信号具有重要的影响。