The Locus Coeruleus-Noradrenergic System in the Healthy and Diseased Brain: A Narrative Review

Abstract

Introduction: The locus coeruleus (LC) is a compact nucleus of noradrenergic neurons in the brainstem. Despite its relatively small size, the LC has widespread axonal connections and serves as the primary source of noradrenaline (NA) throughout the central nervous system. The LC-NA system plays a critical role in regulating cognitive and physiological processes, and its dysfunction has been implicated in various neurological and psychiatric disorders.

Results: This narrative review explores the anatomy, neurochemistry, and function of the LC-NA system in both the healthy and diseased brain. We first provide a detailed overview of LC connectivity, highlighting its afferent and efferent projections and their implications for brain-wide noradrenaline modulation. Next, we discuss the neurochemical properties of noradrenaline, emphasizing its synthesis, release dynamics, and receptor interactions. The core of this review focuses on the functional roles of the LC-NA system, systematically addressing each function first in the healthy brain and then discussing associated disorders. Specifically, we explore the role of LC-NA signaling in attention and arousal, stress, emotion and pain, memory, motion, and neuroprotection, followed by discussions on psychiatric disorders, cognitive dysfunctions, and neurodegenerative diseases that arise from its dysregulation. Lastly, we examine the involvement of the LC in epilepsy, highlighting how alterations in noradrenaline signaling contribute to seizure susceptibility and propagation.

Conclusion: By integrating anatomical, neurochemical, and functional perspectives, this review provides a comprehensive understanding of the LC-NA system's role in brain function and its relevance as a therapeutic target in neurological and psychiatric disorders.

Keywords: epilepsy; locus coeruleus; neurological disorders; neurophysiology; noradrenaline.

FIGURE 1

Schematic representation of noradrenaline (NA) transmission. Tyrosine is converted to L‐DOPA by tyrosine hydroxylase (TH), which is then decarboxylated by DOPA decarboxylase (DDC) to form dopamine (DA). DA is transported into synaptic vesicles via the vesicular monoamine transporter (VMAT), where dopamine β‐hydroxylase (DBH) converts it to NA. Upon stimulation, NA is released into the synaptic cleft and binds postsynaptically to the α₁, α₂ or β adrenergic receptors coupled to different G‐proteins, Gq, Gi, Gs, respectively. This mediates downstream signaling pathways involving phospholipase C (PLC) and adenylyl cyclase (AC). Released NA can also bind to presynaptic autoreceptors to inhibit further release. NA is cleared from the synaptic cleft via reuptake or degraded by catechol‐O‐methyltransferase (COMT) and monoamine oxidase A (MAO‐A).

FIGURE 2

The LC sends widespread projections to numerous brain regions, each associated with specific functions. These include the prefrontal cortex, involved in attention, cognitive processing, and motion; the motor cortex, which regulates voluntary movement; and the sensory cortices, responsible for processing sensory input and mediating arousal. The thalamus also receives input from the LC and contributes to sensory processing and alertness. Projections to the basal forebrain and hypothalamus support sleep–wake regulation and stress responses. The amygdala and hippocampus, which mediate emotional processing and memory formation, are also targets of LC innervation. Additionally, the LC sends projections to the cerebellum, which coordinates movement, and to the spinal cord, where it modulates pain and motor control. The pathways highlighted in the figure demonstrate the LC's widespread influence across brain systems and behavioral functions.