Cholinergic and dopaminergic modulation of cognitive flexibility and stability

在不断变化的环境中，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，以响应不断变化的需求。前额叶皮质和基底节是这些过程的关键区域。多巴胺能神经传递的遗传变异和药物操作调节了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，并显示出个体差异，这表明其他神经递质也可能发挥作用。我们之前提供了尼古丁胆碱能调节认知稳定性的证据，这种调节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和基底节的胆碱能-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，也没有人研究胆碱能-多巴胺能相互作用如何有助于认知的灵活性和稳定性。目前的拨款方案旨在利用功能磁共振成像(FMRI)在健康的年轻志愿者中研究胆碱能和多巴胺能神经递质系统如何在健康的人脑中相互作用，以实现认知稳定性和灵活性之间的动态平衡。我们将进行三个精神药理学实验，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)来操纵胆碱能或胆碱和多巴胺能神经传递。所有实验都将采用相同的先前建立的范式，这是一项持续的注意力任务，通过转换和分心试验分别评估认知灵活性和稳定性。该提案的第一个目的是提供进一步的证据，证明烟碱型乙酰胆碱受体在灵活和稳定行为之间的平衡中发挥关键作用，并分离潜在的神经机制。由于多巴胺能受体基因的变异调节胆碱能尼古丁刺激的行为和神经效应，第二个目标是测试L酪氨酸对基线多巴胺能功能的实验操纵是否影响尼古丁的行为和神经效应，为胆碱能和多巴胺能相互作用提供因果证据。第三个目标是研究对胆碱能药物效应至关重要的多巴胺能受体基因变异的作用，以及多巴胺能脑区结构连接性的变异。总体而言，该项目将提供有关胆碱能-多巴胺能相互作用在执行功能中的作用的新的人类数据，这对于理解许多精神障碍(如ADHD和精神分裂症)中共存的僵硬行为、更多的分心和冲动也是相关的。

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.