Department of Psychology, Vanderbilt University, Nashville, TN 37240.
Department of Pharmacology, Vanderbilt University, Nashville, TN 37240.
Proc Natl Acad Sci U S A. 2023 May 2;120(18):e2216792120. doi: 10.1073/pnas.2216792120. Epub 2023 Apr 27.
Acetylcholine (ACh) in cortical neural circuits mediates how selective attention is sustained in the presence of distractors and how flexible cognition adjusts to changing task demands. The cognitive domains of attention and cognitive flexibility might be differentially supported by the M muscarinic acetylcholine receptor (mAChR) subtype. Understanding how M mAChR mechanisms support these cognitive subdomains is of highest importance for advancing novel drug treatments for conditions with altered attention and reduced cognitive control including Alzheimer's disease or schizophrenia. Here, we tested this question by assessing how the subtype-selective M mAChR positive allosteric modulator (PAM) VU0453595 affects visual search and flexible reward learning in nonhuman primates. We found that allosteric potentiation of M mAChRs enhanced flexible learning performance by improving extradimensional set shifting, reducing latent inhibition from previously experienced distractors and reducing response perseveration in the absence of adverse side effects. These procognitive effects occurred in the absence of apparent changes of attentional performance during visual search. In contrast, nonselective ACh modulation using the acetylcholinesterase inhibitor (AChEI) donepezil improved attention during visual search at doses that did not alter cognitive flexibility and that already triggered gastrointestinal cholinergic side effects. These findings illustrate that M mAChR positive allosteric modulation enhances cognitive flexibility without affecting attentional filtering of distraction, consistent with M activity boosting the effective salience of relevant over irrelevant objects specifically during learning. These results suggest that M PAMs are versatile compounds for enhancing cognitive flexibility in disorders spanning schizophrenia and Alzheimer's diseases.
乙酰胆碱 (ACh) 在皮质神经回路中介导选择性注意如何在存在干扰物的情况下保持，以及认知灵活性如何适应不断变化的任务需求。注意力和认知灵活性的认知领域可能由 M 毒蕈碱型乙酰胆碱受体 (mAChR) 亚型不同程度地支持。了解 M mAChR 机制如何支持这些认知子领域对于推进治疗注意力改变和认知控制降低的新型药物治疗具有至关重要的意义，包括阿尔茨海默病或精神分裂症。在这里，我们通过评估选择性 M mAChR 正变构调节剂 (PAM) VU0453595 如何影响非人类灵长类动物的视觉搜索和灵活奖励学习来检验这个问题。我们发现，M mAChR 的变构增强增强了灵活的学习表现，通过改善额外维度的转移，减少先前经历过的干扰物的潜伏抑制，并减少在没有不良反应的情况下的反应坚持。这些促认知作用发生在视觉搜索过程中注意力表现没有明显变化的情况下。相比之下，使用乙酰胆碱酯酶抑制剂 (AChEI) 多奈哌齐的非选择性 ACh 调节在不改变认知灵活性且已经引发胃肠道胆碱能副作用的剂量下改善了视觉搜索期间的注意力。这些发现表明，M mAChR 正变构调节增强了认知灵活性，而不影响注意力对分心的过滤，这与 M 活动增强相关物体相对于不相关物体的有效显着性一致，特别是在学习期间。这些结果表明，M PAMs 是增强跨越精神分裂症和阿尔茨海默病的各种疾病认知灵活性的多功能化合物。
