Role of the locus coeruleus and basal forebrain in arousal and attention

Abstract

Experimental evidence has implicated multiple neurotransmitter systems in either the direct or indirect modulation of cortical arousal and attention circuitry. In this review, we selectively focus on three such systems: 1) norepinephrine (NE)-containing neurons of the locus coeruleus (LC), 2) acetylcholine (ACh)-containing neurons of the basal forebrain (BF), and 3) parvalbumin (PV)-containing gamma-aminobutyric acid neurons of the BF. Whereas BF-PV neurons serve as a rapid and transient arousal system, LC-NE and BF-ACh neuromodulation are typically activated on slower but longer-lasting timescales. Recent findings suggest that the BF-PV system serves to rapidly respond to even subtle sensory stimuli with a microarousal. We posit that salient sensory stimuli, such as those that are threatening or predict the need for a response, will quickly activate the BF-PV system and subsequently activate both the BF-ACh and LC-NE systems if the circumstances require longer periods of arousal and vigilance. We suggest that NE and ACh have overlapping psychological functions with the main difference being the precise internal/environmental sensory situations/contexts that recruit each neurotransmitter system - a goal for future research to determine. Implications of dysfunction of each of these three attentional systems for our understanding of neuropsychiatric conditions are considered. Finally, the contemporary availability of research tools to selectively manipulate and measure the activity of these distinctive neuronal populations promises to answer longstanding questions, such as how various arousal systems influence downstream decision-making and motor responding.

Keywords: Acetylcholine; GABA; Norepinephrine; Parvalbumin; Vigilance; Wakefulness.

Fig. 1.

Simplified circuit diagram showing interactions between ascending norepinephrinergic, cholinergic, and gamma-Aminobutyric (GABA)-ergic pathways and their effects on cortical arousal- and attention-relevant neurons. Both norepinephrine (NE) from the locus coeruleus (LC) and acetylcholine (ACh) from the basal forebrain (BF) enhance sensitivity of pyramidal (PYR) excitatory neurons to incoming salient sensory inputs, exerting a slower but longer-lasting effect through volume transmission and actions at G protein-coupled NE and ACh receptors. LC norepinephrinergic neurons also project to and increase the output of BF nuclei. BF corticopetal parvalbumin (PV)-positive GABAergic neurons evoke a rapid yet excitatory effect through the suppression of PYR-innervating cortical GABAergic interneurons. Though not discussed in depth in this review, BF glutamate (Glu) neurons promote cortical activity by exciting BF-ACh and BF-PV neurons (Yang et al., 2017).