Elsevier

Neuropharmacology

Volume 64, January 2013, Pages 294-304
Neuropharmacology

Invited review
Leveraging the cortical cholinergic system to enhance attention

https://doi.org/10.1016/j.neuropharm.2012.06.060Get rights and content

Abstract

Attentional impairments are found in a range of neurodegenerative and neuropsychiatric disorders. However, the development of procognitive enhancers to alleviate these impairments has been hindered by a lack of comprehensive hypotheses regarding the circuitry mediating the targeted attentional functions. Here we discuss the role of the cortical cholinergic system in mediating cue detection and attentional control and propose two target mechanisms for cognition enhancers: stimulation of prefrontal α4β2* nicotinic acetylcholine receptors (nAChR) for the enhancement of cue detection and augmentation of tonic acetylcholine levels for the enhancement of attentional control.

This article is part of a Special Issue entitled ‘Cognitive Enhancers’.

Highlights

► Cue detection and top-down attentional control represent key attentional functions. ► Agonism of specific nicotinic receptor subtypes aids cue detection. ► Augmentation of tonic acetylcholine levels aids attentional control. ► Development of cognition enhancers should focus on these aspects of attention.

Introduction

Attentional functions are often parsed into “bottom-up” processes, including processes associated with the detection and processing of relevant cues, and “top-down” processes associated with selecting relevant inputs, ignoring irrelevant inputs, and maintaining the appropriate task set over time in the face of competing internal or external demands (Kastner and Ungerleider, 2000; Sarter et al., 2001, 2006; Treisman and Gelade, 1980). Converging evidence from numerous animal model studies, including lesion and pharmacological manipulations, and human psychopharmacological and pharmaco-fMRI studies demonstrates the importance and necessity of the cortical cholinergic input system for attention (e.g., Robbins et al., 1989; Muir et al., 1994; McGaughy et al., 1996; Sarter et al., 2005; Giocomo and Hasselmo, 2007; Hahn et al., 2007; Deco and Thiele, 2009; Hasselmo and Sarter, 2011). The cortical cholinergic system exerts its effects on attention via sensory, prefrontal, and parietal regions and interactions among those regions (e.g., Sato et al., 1987; Golmayo et al., 2003; Nelson et al., 2005). Prefrontal cortex, particularly right prefrontal cortex, is a key site for cortical cholinergic mediation of both cue detection and top-down attentional control processes, including the enhancement of control in response to challenging or distracting conditions (e.g., Parikh et al., 2007; Gill et al., 2000; Sarter et al., 2006; see also Cabeza and Nyberg, 2000 for a review of neuroimaging studies of attention supporting the involvement of a right-lateralized frontoparietal network, particularly for selective and sustained attention).

Given the cortical cholinergic system's importance in mediating attentional functions, this system is a frequent target of drug development programs aimed at improving cognition. Here, we propose two target mechanisms for cognition enhancers, cue detection and attentional control. To this end, we describe these attentional functions in healthy individuals and impairments in these functions in patient populations, review the literature on the use of acetylcholinesterase inhibitors and agonists at muscarinic acetylcholine receptors (mAChRs) and nicotinic acetylcholine receptors (nAChRs) to enhance cognition and attention, and detail recent data indicating tonic cholinergic activity mediates top-down attentional control functions while phasic cholinergic activity mediates cue detection. Collectively, the available evidence and literature supports the use of cholinergic drugs, particularly agonists targeting α4β2* nAChRs, for enhancing attentional and cognitive functions and capacities.

Section snippets

Cue detection and attentional control in healthy and patient populations

A critical aspect of attention is the ability to detect relevant environmental cues and discriminate these cues from noise. Detection is defined as a cognitive process which consists of “…the entry of information concerning the presence of a signal into a system that allows the subject to report the existence of the signal by an arbitrary response indicated by the experimenter” (Posner et al., 1980). Behaviorally relevant stimuli, particularly unexpected or salient stimuli, are detected by the

Enhancement of attention via acetylcholinesterase inhibitors

The interest in acetylcholinesterase inhibitors like donepezil or galantamine for the enhancement of attention stems largely from their use clinically to treat the cognitive impairments associated with dementia (e.g., Rogers and Friedhoff, 1996; Rogers et al., 1998; Raskind et al., 2000). In animal model studies, selective lesions to the basal forebrain cortical cholinergic system in attention task-performing animals result in a severe and lasting impairment in signal detection, while the

Effects of nonselective mAChR antagonists

In mammals, there are five mAChR subtypes, M1–M5 (Wess, 1996; Caulfield and Birdsall, 1998). Nonselective mAChR antagonists such as scopolamine impair attention and the encoding of new memories in animal models (Aigner et al., 1991; McGaughy et al., 1994) and in healthy humans (e.g., Ghoneim and Mewaldt, 1975, 1977; Wesnes and Warburton, 1984), and exacerbate the cognitive impairments seen in healthy aged individuals and patients with Alzheimer's disease (e.g., Molchan et al., 1992; Sunderland

Effects of nicotine and nonspecific nAChR agonists

Overall, much more is known about the effects of nAChR agonists than mAChR agonists. While only a few animal model studies have assessed the effects of nicotine on attentional performance, nicotine's effects on attention have been extensively studied in smoker and nonsmoker healthy and patient populations (see Levin, 2002; Kassel, 1997; Bentley et al., 2011 for reviews). In general, the available evidence indicates nicotine improves basic attentional functions, but these beneficial effects are

Tonic and phasic cholinergic activity mediates attention

As described above, selective lesions of cholinergic neurons in the basal forebrain demonstrate the necessity of the cortical cholinergic system for attentional performance (McGaughy et al., 1996; Turchi & Sarter, 1997). Much of our own work on the cortical cholinergic system's role in mediating attention utilizes the sustained attention task (SAT), a task developed for use in, and validated for, mice, rats, and humans (St. Peters et al., 2011a; McGaughy and Sarter, 1995; Demeter et al., 2008).

Target mechanism for enhancing cue detection and attentional switching

The evidence concerning the phasic component of the cortical cholinergic system and its role in cue detection has evolved rapidly in the past few years. Below we describe how transient increases in prefrontal ACh release mediates the detection of cues and how these transient ACh increases are dependent, but not sufficiently, upon prefrontal glutamatergic activity. We also explain a complex pattern of data on when increases in transient ACh are seen and reconcile these findings by describing a

Target mechanism for enhancing top-down control

In addition to the second-based phasic component of the cortical cholinergic system that is theorized to mediate attentional switching and hence the detection of external, task-relevant cues, the cortical cholinergic system also operates via another, minutes-based component (“tonic” ACh release). Importantly, the tonic component of the cholinergic system cannot be fully explained by simply summing the cholinergic transients described above over time (Parikh et al., 2007). Tonic cholinergic

Conclusions

Here, we propose two target mechanisms for the development of procognitive enhancers: stimulation of α4β2* nAChRs on prefrontal glutamatergic neurons in order to facilitate attentional switching and cue detection, and augmentation of the tonic levels of ACh in order to improve attentional control functions. While cholinesterase inhibitors and nAChR agonists have been intensely studied in regards to their putative pro-attentional effects, the recent mechanistic evidence on the circuitry

Acknowledgements

The authors would like to thank David Cron for assistance with preparation of this manuscript.

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