Neural Circuit Connections and Functions of Locus Coeruleus–Norepinephrine System

The locus coeruleus-norepinephrine (LC-NE) system is a phylogenetically conserved neuromodulatory hub that regulates fundamental brain states and behaviors, including arousal, cognition, emotion, and pain. This review integrates two critical perspectives to provide a unified framework for understanding this system. First, we synthesize the evolutionary trajectory of the LC from non-mammalian to mammalian vertebrates, highlighting conserved properties and changes in cell number, anatomical projections, and physiological functions. Second, we detail the intricate connectivity of its afferent and efferent circuits, explaining how specific inputs and outputs modulate LC activity and govern diverse behaviors under physiological and disease conditions. Together, we aim to highlight the central role of the LC in brain function and disease through an evolutionary and circuit-based lens.