Abstract: The locus coeruleus-norepinephrine (LC-NE) system is a central neuromodulatory system in the brain that orchestrates attentional processes across the brain through its widespread neural projections and norepinephrine (NE) release mechanisms. According to classical attentional theories, attention comprises three subsystems: alerting, orienting, and executive control. Although extensive studies have highlighted the LC-NE system's significant involvement across these subsystems, its specific neural mechanisms regulating attention remain incompletely elucidated. Therefore, this review aims to systematically explore the neurophysiological mechanisms underlying LC-NE modulation of attention, summarize physiological indicators reflecting its activity, and integrate current advances on its functional roles across attentional subsystems and its implications for attention-related disorders.
The locus coeruleus (LC) is a vertebrate-specific NE nucleus and the primary site for NE synthesis and release in the brain. LC neurons project widely to regions critical for attention and executive control, including the prefrontal cortex (PFC), anterior cingulate cortex (ACC), parietal cortex, thalamus, and amygdala, forming the anatomical basis of LC-NE-mediated attentional regulation. NE released by LC neurons exerts excitatory or inhibitory effects via receptors with varying affinities, dynamically influencing attention. Furthermore, LC neurons exhibit two firing patterns: tonic and phasic. Tonic activity reflects the baseline firing state, while phasic activity, triggered by salient or goal-relevant stimuli, enhances selective processing and suppresses irrelevant input. When tonic activity is maintained at moderate levels, phasic responses are most pronounced, demonstrating optimal attentional control. Both excessively low and high tonic activity attenuate phasic responses, leading to distraction and impaired task performance. These dynamic activity patterns enable adaptive gain modulation, balancing exploitation and exploration to optimize behavioral flexibility. This reflects the complex neural basis of attention regulation within the LC-NE system.
The functional dynamics of the LC-NE system can also be reflected through behavioural and neurophysiological indicators. Pupil dilation, which reflects arousal levels and cognitive effort, correlates strongly with LC firing patterns and serves as a reliable proxy for LC-NE activity. Event-related potentials (ERPs), particularly the P3 and N2 components, also provide indirect indicators of LC modulation of attention. Multimodal studies combining pupillometry, electrophysiology, and functional magnetic resonance imaging (fMRI) have revealed dynamic LC-cortical interactions, validated the link between LC-NE activity and attention, and highlighted population differences in LC-NE function and potential attentional deficits.
Functionally, the LC-NE system regulates cortical gain across multiple attentional subsystems. In alerting, LC-mediated NE release modulates global arousal and cortical baseline activity, contributing to sustained readiness through its widespread projections. In orienting, phasic LC activation triggers a “network reset,” facilitating rapid attentional shifts by coordinating interactions between the dorsal and ventral attention networks. In executive control, broad NE projections to the PFC and related control networks enhance conflict monitoring, inhibitory control, and flexible cognitive strategy adjustment. Notably, dysfunction within the LC-NE system has been closely associated with attention-related disorders such as attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), suggesting that it may represent a potential neural target for therapeutic intervention.
Despite significant progress in recent years, key challenges remain in elucidating LC-NE modulation of attention. Future research should prioritize three directions: (1) Observational precision—integrating pupillometry, ERPs, intracranial electrophysiology, and high-resolution neuroimaging to achieve temporally and spatially precise tracking of LC-NE activity during attentional processes; (2) Causal mechanisms—employing causal perturbation methods such as pharmacological manipulations, transcranial magnetic stimulation, and deep brain stimulation to validate the LC-NE system’s role in attentional processing, complemented by multimodal measures to capture its dynamic effects; and (3) Network and modeling approaches—further investigating dynamic LC connectivity with key attentional nodes (e.g., PFC, parietal cortex, temporoparietal junction) across developmental stages, and integrating predictive coding and gain control frameworks to construct unified computational models of LC-NE-driven attentional regulation. This review contributes by integrating receptor-level mechanisms, firing patterns, and attentional subsystems into a unified framework, and by synthesizing multimodal evidence to highlight complementary approaches to investigating the mechanisms of the LC-NE system in attention.

Key words: LC-NE, attention, alerting, orienting, executive control