Cholinergic and dopaminergic modulation of cognitive flexibility and stability

认知灵活性和稳定性的胆碱能和多巴胺能调节

基本信息

批准号：
326561482
负责人：
Professorin Dr. Christiane M. Thiel
金额：
--
依托单位：
Abteilung Biologische Psychologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2016
资助国家：
德国
起止时间：
2015-12-31 至 2019-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/326561482?language=en
关键词：
Cholinergic dopaminergic modulation cognitive flexibility

项目摘要

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.

在不断变化的环境中，个人必须能够平衡与任务相关表示形式的稳定与这些表示形式的灵活更新，以响应不断变化的需求。前额叶皮层和基底神经节是这些过程的关键区域。多巴胺能神经传递的遗传变异和药理学操纵调节柔韧性和稳定性之间的平衡。但是，多巴胺能药物的作用很小，并且显示出个体变异，这表明其他神经递质也可能起作用。我们先前提供了证据表明认知稳定性的烟碱胆碱能调节，这是由多巴胺能受体基因的个体差异调节的。大量动物数据为前额叶皮质和基底神经节中的胆碱能 - 多巴胺能相互作用提供了证据，但是，关于人脑中神经递质相互作用的研究很少，没有人研究胆碱能 - 甲基氨基胺能如何有助于认知灵活性和稳定性。当前的赠款提案旨在通过健康的年轻志愿者中的功能磁共振成像（fMRI）研究胆碱能和多巴胺能神经递质系统如何在健康的人脑中相互作用，以实现认知稳定性和灵活性之间的这种动态平衡。我们将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）进行三个心理药物实验，并操纵胆碱能或胆碱能和多巴胺能神经传递。所有实验将采用相同的先前建立的范式，这是开关和分散试验的持续关注任务，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，证明烟碱乙酰胆碱受体在柔性和稳定行为之间的平衡并隔离基本的神经机制之间的平衡。由于多巴胺能受体基因的变化调节了胆碱能刺激的行为和神经效应，因此第二个目的是测试基线多巴胺能对L-酪氨酸影响行为的实验性操纵是否具有具有L-酪氨酸影响行为和尼古丁的神经作用，从而提供了胆碱能互动的因果关系。第三个目标是研究多巴胺能受体基因的变化的作用，这是胆碱能药物作用以及多巴胺能脑区域结构连通性的变化。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型人类数据，这也与理解不灵活的行为以及增加的分心和冲动性相关，这些分心和冲动性在许多精神病患者（如ADHD和Schizizophrenia）中共存。