Cholinergic and dopaminergic modulation of cognitive flexibility and stability

在一个不断变化的环境中，个体必须能够在任务相关表征的稳定性和这些表征的灵活更新之间取得平衡，以应对不断变化的需求。前额叶皮层和基底神经节是这些过程的关键区域。遗传变异和多巴胺能神经传递的药理学操作调节灵活性和稳定性之间的平衡。然而，多巴胺能药物的作用很小，并表现出个体差异，这表明其他神经递质也可能起作用。我们之前提供的证据表明，尼古丁胆碱能调节认知稳定性，这是由多巴胺能受体基因的个体差异调节的。大量的动物数据为前额叶皮层和基底神经节中的胆碱能-多巴胺能相互作用提供了证据，然而，关于人脑中神经递质相互作用的研究很少，也没有研究胆碱能-多巴胺能相互作用如何促进认知的灵活性和稳定性。目前的拨款提案旨在通过健康年轻志愿者的功能磁共振成像（fMRI）研究胆碱能和多巴胺能神经递质系统如何在健康的人类大脑中相互作用，以实现认知稳定性和灵活性之间的动态平衡。我们将进行三个心理药理学实验，并使用胆碱能激动剂尼古丁和氨基酸l -酪氨酸（多巴胺和去甲肾上腺素合成的前体）操纵胆碱能或胆碱能和多巴胺能神经传递。所有的实验将采用相同的，先前建立的范式，这是一个持续的注意力任务与切换和分心试验，分别评估认知的灵活性和稳定性。该提案的第一个目的是为烟碱乙酰胆碱受体在灵活和稳定行为之间的平衡中的关键作用提供进一步的证据，并分离潜在的神经机制。由于多巴胺能受体基因的变化调节了胆碱能尼古丁刺激的行为和神经效应，第二个目的是测试l -酪氨酸对基线多巴胺能功能的实验操作是否会影响尼古丁的行为和神经效应，从而为胆碱能-多巴胺能相互作用提供因果证据。第三个目标是研究多巴胺能受体基因变异的作用，这是胆碱能药物作用的核心，以及多巴胺能脑区域结构连通性的变化。总的来说，该项目将提供关于胆碱能-多巴胺能相互作用在执行功能中的作用的新的人类数据，这也与理解在许多精神疾病（如多动症和精神分裂症）中共存的不灵活行为和增加的分心和冲动有关。

In a constantly changing environment, individuals must be able to balance between the stabilization of task relevant representations and flexible updating of these representations in response to changing demands. The prefrontal cortex and basal ganglia are key regions to these processes. Genetic variations and pharmacological manipulations of dopaminergic neurotransmission modulate the balance between flexibility and stability. Effects of dopaminergic drugs are however small and show individual variation, which suggests that other neurotransmitters may also play a role. We previously provided evidence for a nicotinic cholinergic modulation of cognitive stability, which was modulated by individual differences in dopaminergic receptor genes. A wealth of animal data provides evidence for cholinergic-dopaminergic interactions in prefrontal cortex and basal ganglia, there is however a paucity of studies on neurotransmitter interactions in the human brain and none has investigated how cholinergic-dopaminergic interactions contribute to cognitive flexibility and stability. The current grant proposal aims to investigate with functional magnetic resonance imaging (fMRI) in healthy young volunteers how cholinergic and dopaminergic neurotransmitter systems interact in the healthy human brain to achieve this dynamic balance between cognitive stability and flexibility. We will perform three psychopharmacological experiments and manipulate cholinergic or cholinergic and dopaminergic neurotransmission with the cholinergic agonist nicotine and the amino acid L-Tyrosine, a precursor to dopamine and noradrenaline synthesis. All experiments will employ the same, previously established paradigm, which is a sustained attention task with switch and distractor trials to assess cognitive flexibility and stability respectively. The first aim of the proposal is to provide further evidence for a crucial role of nicotinic acetylcholine receptors in the balance between flexible and stable behaviour and to isolate the underlying neural mechanisms. Because variations in dopaminergic receptor genes modulate behavioural and neural effects of cholinergic nicotinic stimulation, a second aim is to test whether experimental manipulations of baseline dopaminergic function with L-Tyrosine impact behavioural and neural effects of nicotine, providing causal evidence for a cholinergic-dopaminergic interaction. A third objective is to study the role of variations in dopaminergic receptor genes which are central to cholinergic drug effects as well as variations in structural connectivity of dopaminergic brain regions. Overall, the project will provide novel human data on the role of cholinergic-dopaminergic interactions in executive function, which is also of relevance for understanding the inflexible behaviour and increased distraction and impulsivity that co-exist in many psychiatric disorders such as ADHD and schizophrenia.