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: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=684469
• 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）是一种重要的神经调节剂，影响涉及纹状体和前额叶皮质（PFC）的行为。DA信号的时间动力学强烈约束提出的理论DA功能。在PFC中，DA的释放是缓慢的，即使是短暂的应用DA施加持续的影响PFC神经元的生物物理特性记录在体外和体内，持续数分钟至数小时。基于PFC DA系统的已知特性，我们提出了双态理论，假定PFC神经元中离子电流的DA调制导致网络在长时间内切换到两个不同的状态或模式之一。* 相比之下，另一个更突出的理论认为DA编码了时间上精确的奖励预测错误（RPE），这些错误被提出来作为强化学习的基础。该理论基于数据显示奖励预测线索或结果与DA神经元中的短暂尖峰脉冲（<100 ms）和纹状体中的短暂DA升高相关。在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的释放太慢，时间上不精确，并且不能区分意外的好结果和坏结果。* 然而，当时还没有准确表征PFC中瞬时DA信号传导所需的工具。 在过去的五年里，新技术已经出现，现在可以解决这个问题。本提案将利用这些新技术来研究PFC中快速和慢速DA信号的影响。* 具体目标 *1。目的1是表征PFC中阶段性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测量，DA释放将使用光遗传学技术精确控制。我们将量化特定的DA浓度在PFC产生不同的光刺激参数。*2。目的2是确定目的1中表征的光遗传学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。这将涉及唤起PFC中DA的光遗传学释放，同时在行为动物中进行多个PFC神经元的光四极记录或脑切片中突触电流的膜片钳记录。拟议的实验建立在历史的研究，我们的特点是外源性DA的生物物理特性的PFC神经元的影响。我们建议将强大的新技术，以唤起精确定时释放DA从PFC的轴突，并确定其对PFC神经元和电路的影响。了解DA释放的时间动力学及其在PFC中的作用可能对我们理解PFC和整个大脑中的DA信号产生重大影响。