Abstract
Neuromodulation by acetylcholine plays a vital role in shaping the physiology and functions of cerebral cortex. Cholinergic neuromodulation influences brain-state transitions, controls the gating of cortical sensory stimulus responses, and has been shown to influence the generation and maintenance of persistent activity in prefrontal cortex. Here we review our current understanding of the role of muscarinic cholinergic receptors in primate prefrontal cortex during its engagement in the performance of working memory tasks. We summarize the localization of muscarinic receptors in prefrontal cortex, review the effects of muscarinic neuromodulation on arousal, working memory and cognitive control tasks, and describe the effects of muscarinic M1 receptor stimulation and blockade on the generation and maintenance of persistent activity of prefrontal neurons encoding working memory representations. Recent studies describing the pharmacological effects of M1 receptors on prefrontal persistent activity demonstrate the heterogeneity of muscarinic actions and delineate unexpected modulatory effects discovered in primate prefrontal cortex when compared with studies in rodents. Understanding the underlying mechanisms by which muscarinic receptors regulate prefrontal cognitive control circuitry will inform the search of muscarinic-based therapeutic targets in the treatment of neuropsychiatric disorders.
Highlights
The ability to maintain and manipulate information about the sensory world, motor actions, and previously learned experience is central to cognition and flexible behavior
Given the pervasiveness of scopolamine-induced suppression of prefrontal cortex (PFC) neurons described above (Major et al, 2015), and that some or all of the effects of PFC carbachol stimulation were mediated by muscarinic receptors (Major et al, 2018), the question arises as to which muscarinic receptor subtypes contributed to the various physiological effects on persistent activity and task-selectivity changes caused by these cholinergic manipulations
This study found that high doses of the same allosteric M1 receptors (M1Rs) agonist, VU0357017, suppressed PFC working memory” (WM) activity, but in contrast with Vijayraghavan et al (2018), low doses of the allosteric agonist enhanced PFC persistent activity (Figures 6A,C)
Summary
The ability to maintain and manipulate information about the sensory world, motor actions, and previously learned experience is central to cognition and flexible behavior. Persistent, short-term elevated activity in cortical circuits has been proposed to Fuster and Alexander (1971) and Goldman-Rakic (1995) underlie the capacity to actively maintain such knowledge, or “working memory” (WM). The prefrontal cortex (PFC) in primates plays a pivotal role in the neural circuitry that processes such behaviorally relevant mental representations that are deployed to guide imminent choices and actions (Fuster and Alexander, 1971; Fuster, 1992, 1993; Miller and Cohen, 2001)
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