M1 selective muscarinic allosteric modulation enhances cognitive flexibility and effective salience in nonhuman primates

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 cholinergic sub-receptor. Understanding how M1 mechanisms support these cognitive subdomains is of highest importance for advancing novel drug treatments for conditions with altered attention and reduced cognitive control including Alzheimers disease or schizophrenia. Here, we tested this question by assessing how the subtype selective M1-receptor specific positive allosteric modulator (M1 PAM VU0453595) affects visual search and flexible reward-learning in nonhuman primates. We found that allosteric potentiation of the M1 receptor enhanced flexible learning performance by improving extra-dimensional set shifting, by reducing latent inhibition of previously experienced distractors, and by reducing response perseveration in the absence of adverse side effects. These pro-cognitive effects occurred in the absence of apparent changes of attentional performance during visual search. In contrast, non-selective ACh modulation using the acetylcholinesterase inhibitor 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 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. These results suggest that M1 PAMs are versatile compounds for enhancing cognitive flexibility in disorders spanning schizophrenia and Alzheimers diseases. Statement of significanceMuscarinic receptors mediate the pro-cognitive effects of acetylcholine, but it has remained unclear whether they differentially affect the cognitive subfunctions of attentional filtering, set shifting, and learning. To clarify the functional specificity of M1 receptors, we assessed these diverse functions using a recently developed, highly selective M1 PAM. This M1 PAM caused domain-specific cognitive improvement of flexible learning and extra-dimensional set shifting, reduced perseverations and enhanced target recognition during learning without altering attentional filtering functions. These domain-specific improvement contrasted to effects of a non-selective acetylcholinesterase inhibitor that primarily enhanced attention and caused dose limiting adverse side effects. These results demonstrate domain-specific improvements of cognitive flexibility suggesting M1 PAMs are versatile compounds for treating cognitive deficits in schizophrenia and Alzheimers disease.