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• W4367175273 abstract "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 M1 muscarinic acetylcholine receptor (mAChR) subtype. Understanding how M1 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 M1 mAChR positive allosteric modulator (PAM) VU0453595 affects visual search and flexible reward learning in nonhuman primates. We found that allosteric potentiation of M1 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 M1 mAChR positive allosteric modulation enhances cognitive flexibility without affecting attentional filtering of distraction, consistent with M1 activity boosting the effective salience of relevant over irrelevant objects specifically during learning. These results suggest that M1 PAMs are versatile compounds for enhancing cognitive flexibility in disorders spanning schizophrenia and Alzheimer's diseases." @default.
• W4367175273 created "2023-04-28" @default.
• W4367175273 creator A5020165662 @default.
• W4367175273 creator A5028518404 @default.
• W4367175273 creator A5044383039 @default.
• W4367175273 creator A5049402792 @default.
• W4367175273 creator A5051209585 @default.
• W4367175273 date "2023-04-27" @default.
• W4367175273 modified "2023-09-23" @default.
• W4367175273 title "M ₁ -selective muscarinic allosteric modulation enhances cognitive flexibility and effective salience in nonhuman primates" @default.
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