Dopaminergic circuitry underlying cognitive flexibility

灵活使用信息和执行适当的适应行为以应对不断变化的环境条件的能力，对于所有物种的生存至关重要。我们之前的工作已经揭示了神经化学物质多巴胺，大脑奖励回路的关键组成部分，在奖励偶然性变化时促进不同形式的认知灵活性方面发挥着至关重要的作用。然而，关于多巴胺调节这些功能的精确方式，以及接受多巴胺输入的大脑区域的神经活动如何处理信息以促进行为改变，仍然存在重要的问题。本研究将以大鼠为模型系统，探讨大脑奖赏回路中的不同节点如何促进认知灵活性。在三个主要目标，我们将; 1）阐明多巴胺活动的短暂“阶段性”增加和减少是如何利用药理学和脑刺激技术促进不同策略之间的转换的，2）阐明腹侧纹状体中的神经元如何（一个关键的多巴胺输入区域）改变他们的发射模式时，有机体必须调整行为的变化，在完善的规则和3）探索神经回路，调节认知灵活性时，奖励交付是不确定的/概率，使用各种大脑失活和药理学方法。这些信息将提供关键的洞察力，了解大脑的奖励系统如何有助于奖励相关学习和学习行为的修改的不同方面。鉴于啮齿类动物和灵长类动物大脑解剖学连接的相似性，这些研究将对大脑成像和调节人类这些过程的神经机制的神经心理学研究方向产生相当大的影响。此外，由于许多精神疾病与认知灵活性障碍有关，这项基础研究可能会对这些类型的认知缺陷背后的大脑功能障碍产生重要的见解。因此，这一研究方向最终将使人们更好地理解大脑中的分布式神经网络如何应对环境中的意外变化，以促进生存。

The ability to use information flexibly and execute appropriate adaptive behaviours in response to changing environmental conditions is essential for survival in all species. Our previous work has revealed the neurochemical dopamine, a key component of the brain's reward circuitry, plays a crucial role in facilitating different forms of cognitive flexibility when reward contingencies change. Yet, important questions remain regarding the precise manner in which dopamine may regulate these functions, as well as how neural activity in brain regions that receive dopamine input process information to facilitate alterations in behaviour. The present proposal will explore how different nodes in the brain reward circuitry contribute to cognitive flexibility using rats as a model system. Over three primary aims, we will; 1) clarify how brief, "phasic" increases and decreases in dopamine activity that signal rewarded and non-rewarded events facilitate shifts between different strategies, using pharmacological and brain stimulation techniques, 2) clarify how neurons in the ventral striatum (a key dopamine input region) change their firing patterns when an organism must adjust behaviour upon changes in well-established rules and 3) explore the neural circuits that regulate cognitive flexibility when reward delivery is uncertain/probabilistic, using a variety of brain inactivation and pharmacological approaches. This information will provide crucial insight into how the brain's reward system contributes to different aspects of reward-related learning and modification of learned behaviours. Given the similarities in the anatomical connectivity of the rodent and primate brain, these studies will have considerable impact on the direction of brain imaging and neuropsychological studies of the neural mechanisms that regulate these processes in humans. Moreover, as a number of psychiatric disorders are associated with impairments in cognitive flexibility, this basic research may yield important insight into the brain dysfunction that underlies these types of cognitive deficits. Thus, this line of research ultimately will lead to a greater understanding of how distributed neural networks in the brain deals with unexpected changes in its environment to promote survival.