Optogenetic Testing of Mechanims of Dopamine Action in Pavlovian Learning

描述（由申请人提供）：中边缘多巴胺被认为在巴甫洛夫奖励学习中起主要作用。巴甫洛夫奖励学习过程是药物寻求行为的许多方面的基础，并可能在药物复发中起关键作用。因此，我们的总体目标是更好地理解奖励学习的基本神经行为机制。在这里，我们试图使用光遗传学工具来更好地定义这一作用，这将允许在行为过程中精确控制多巴胺神经元的活动。我们将使用Th:Cre大鼠，这是一种在酪氨酸羟化酶（Th）启动子控制下表达Cre重组酶的转基因大鼠，在输注表达通道视紫红质或盐视紫红质的cree依赖病毒后，允许基因表达仅限于VTA中的多巴胺神经元。然后我们可以通过手术植入大鼠的VTA的光纤传送光来激活或抑制DA神经元的活动。提出的研究基于以下观点：1)在收到意外奖励时多巴胺神经元的活动推动了对预测奖励可用性的线索的新学习；2)在预期奖励期间多巴胺神经元活动的减少可能导致对奖励预测线索的反应消失。因此，我们建议扩展初步研究结果，以表明由光刺激引起的多巴胺神经元活动的增加是一种积极的预测误差，并可能导致学习。我们还将测试通过光刺激抑制多巴胺神经元活动作为负预测误差并减少学习反应的假设。此外，我们将验证这些影响是由投射到伏隔核的多巴胺神经元介导的假设。因此，利用特征明确的巴甫洛夫条件反射程序，结合最先进的行为光遗传学，目前的目标是扩大我们对VTA DA神经元活动在奖励学习中的因果作用的理解。

DESCRIPTION (provided by applicant): Mesolimbic dopamine is considered to have a major role in Pavlovian reward learning. Pavlovian reward learning processes underlie many aspects of drug seeking behavior and may play a critical role in drug relapse. Hence our overall goal is to better understand the basic neurobehavioral mechanisms of reward learning. Here we seek to better define that role using optogenetic tools that will allow precise control of dopamine neuron activity during behavior. We will use the Th:Cre rat, a transgenic rat expressing Cre recombinase under control of a tyrosine hydroxylase (Th) promoter that allows for gene expression limited to dopamine neurons in the VTA following infusion of cre-dependent viruses expressing either channelrhodopsin or halorhodopsin. We can then deliver light through optical fibers surgically implanted into the VTA in the behaving rat to activate or inhibit activity of DA neurons. The proposed studies are based upon the notion that 1) dopamine neuron activity during the receipt of unexpected reward drives new learning about cues that predict the availability that reward, and that 2) decreases in dopamine neuron activity during expected reward may contribute to extinction of responding to reward-predictive cues. Thus we propose to extend preliminary findings to show that increases in dopamine neuron activity induced by optical stimulation functions as a positive prediction error and can cause learning. We also will test the hypothesis that suppression of dopamine neuron activity by optical stimulation functions as a negative prediction error and decreases learned responding. Additionally, we will test the hypothesis that these effects are mediated by dopamine neurons that project to the nucleus accumbens. Hence, using well-characterized Pavlovian conditioning procedures in combination with state-of- the-art behavioral optogenetics, the current aims are designed to expand our understanding of causal roles for VTA DA neuron activity in reward learning.