Muscarinic M1 Receptor Overstimulation Disrupts Working Memory Activity for Rules in Primate Prefrontal Cortex

Authors

Susheel Vijayraghavan, Department of Physiology and Pharmacology, The University of Western Ontario, London, ON N6A 5B7, Canada; Robarts Research Institute, The University of Western Ontario, London, ON N6A 5B7, Canada.
Alex James Major, Graduate Program in Neuroscience, The University of Western Ontario, London, ON N6A 5B7, Canada.
Stefan Everling, Department of Physiology and Pharmacology, The University of Western Ontario, London, ON N6A 5B7, Canada; Robarts Research Institute, The University of Western Ontario, London, ON N6A 5B7, Canada; Graduate Program in Neuroscience, The University of Western Ontario, London, ON N6A 5B7, Canada. Electronic address: severlin@uwo.ca.

Document Type

Article

Publication Date

6-27-2018

Journal

Neuron

Volume

98

Issue

6

First Page

1256

Last Page

1268.e4

URL with Digital Object Identifier

10.1016/j.neuron.2018.05.027

Abstract

Acetylcholine release in the prefrontal cortex (PFC), acting through muscarinic receptors, has an essential role in regulating flexible behavior and working memory (WM). General muscarinic receptor blockade disrupts PFC WM representations, while selective stimulation of muscarinic receptor subtypes is of great interest for the treatment of cognitive dysfunction in Alzheimer's disease. Here, we tested selective stimulation and blockade of muscarinic M1 receptors (M1Rs) in macaque PFC, during performance of a cognitive control task in which rules maintained in WM specified saccadic responses. We hypothesized that M1R blockade and stimulation would disrupt and enhance rule representation in WM, respectively. Unexpectedly, M1R blockade did not consistently affect PFC neuronal rule selectivity. Moreover, M1R stimulation suppressed PFC activity, and at higher doses, degraded rule representations. Our results suggest that, in primates, the deleterious effects of general muscarinic blockade on PFC WM activity are not mediated by M1Rs, while their overstimulation deteriorates PFC rule maintenance.