Tonic and phasic dopamine-mediated modulation of prefrontal cortex neurons

多巴胺（DA）是影响纹状体和前额叶皮层（PFC）行为的重要神经调节剂。DA信号的时间动态强烈地限制了关于DA功能的理论。在PFC中，DA的释放是缓慢的，即使是短暂的DA应用也会对PFC神经元的生物物理特性产生持续的影响，持续数分钟至数小时。基于PFC DA系统的已知特征，我们提出了“双态理论”，假设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种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，数据挖掘编码暂时精确的奖励预测误差（RPEs），这是强化学习的基础。这一理论是基于数据表明，奖励预测线索或结果与DA神经元的短暂尖峰爆发（<100ms）和纹状体的短暂DA升高有关。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释放太慢，而且暂时不精确，并且不能区分意外的好“和坏”结果。***然而，准确表征PFC中瞬态DA信号所需的工具当时还不可用。在过去的5年里，新技术已经出现，可以解决这个问题。本研究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。目的1是表征pfc中阶段性DA释放的时间动态。使用快速扫描循环伏安法测量DA水平的变化，并使用光遗传学技术精确控制DA释放。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是确定目的1中表征的光遗传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。这将包括激发PFC中DA的光遗传学释放，同时对行为动物的多个PFC神经元进行光四极记录或对脑切片中的突触电流进行膜片钳记录。***提出的实验建立在我们研究外源性DA对PFC神经元生物物理特性影响的研究历史的基础上。我们建议采用强大的新技术来唤起PFC轴突精确定时释放DA，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对PFC的影响可能对我们理解整个大脑的PFC和DA信号传导有重要影响。

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.