Dopaminergic circuitry underlying cognitive flexibility

灵活利用信息和执行适当的适应性行为以应对不断变化的环境条件的能力对所有物种的生存都至关重要。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，在奖励偶发变化时促进不同形式的认知灵活性方面起着至关重要的作用。然而，关于多巴胺调节这些功能的精确方式，以及接收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的改变，仍然存在重要的问题。本研究将以大鼠为模型系统，探索大脑奖赏回路中的不同节点如何促进认知灵活性。在三个主要目标上，我们将；1)利用药理学和脑刺激技术，阐明多巴胺活动的短暂、“阶段性”增加和减少是如何促进不同策略之间的转变的，多巴胺活动表明了奖励和非奖励事件；2)阐明当生物体必须根据既定规则的变化调整行为时，腹侧纹状体（一个关键的多巴胺输入区域）的神经元如何改变其放电模式；3)使用各种脑失活和药理学方法，探索当奖励传递不确定/概率时调节认知灵活性的神经回路。这一信息将为了解大脑的奖励系统如何促进与奖励相关的学习和习得行为的修改的不同方面提供重要的见解。鉴于啮齿类动物和灵长类动物大脑在解剖连接上的相似性，这些研究将对脑成像和人类调节这些过程的神经机制的神经心理学研究方向产生重大影响。此外，由于许多精神疾病都与认知灵活性受损有关，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，这条研究路线最终将导致对大脑中的分布式神经网络如何处理其环境中的意外变化以促进生存的更好理解。

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.