Chronic stress-induced LC-NE dysfunction: cellular and axonal mechanisms underlying impaired neuromodulation

Abstract

The locus coeruleus-noradrenergic (LC-NE) system is a central neuromodulatory network involved in regulation of arousal, attention, and adaptive behavioral function. Chronic stress has been associated with altered LC activity, including shifts in tonic-phasic regulation, yet the direction, magnitude, and persistence of these alterations appear to depend on stress paradigm, duration, and context, and the biological mechanisms underlying the emergence and persistence of this dysregulated state remain incompletely understood. Here, we examine how prolonged stress exposure may contribute to LC-NE dysfunction through interacting cellular and axonal mechanisms. Prolonged corticotropin-releasing factor (CRF)-mediated activation is proposed to impose a chronic tonic load on LC neurons, increasing metabolic demand, calcium burden, and mitochondrial oxidative stress. Because LC neurons combine autonomous pacemaking activity with exceptionally extensive axonal arborization, prolonged stress exposure is likely to promote cumulative cellular strain, impaired intracellular transport, and reduced efficiency of distal norepinephrine signaling. Within this model, chronic stress is conceptualized as producing a loss of dynamic regulatory capacity—a reduced ability of the LC-NE system to shift flexibly between tonic and phasic modes of signaling—rather than simply a quantitative increase or decrease in norepinephrine levels, even in the absence of overt neuronal loss. Disruption of tonic-phasic signaling balance, reduced phasic responsiveness, impaired autoregulatory function, and diminished neuromodulatory flexibility could collectively contribute to persistent alterations in network regulation and cognitive function. This perspective reframes stress-related dysfunction as a progressive, cumulative process rather than a transient alteration in stress signaling alone. By linking chronic stress exposure to LC-NE dysfunction through integrated cellular and axonal mechanisms, this work provides a mechanistic basis for understanding persistent stress-related alterations in brain function and highlights restoration of adaptive LC-NE regulation as a potential therapeutic principle. The proposed framework integrates systems-level stress physiology with cellular and axonal neurobiology into a unified model of stress-induced LC-NE dysfunction.

The authors' abstract, as published at the source. Frontiers in Neuroscience, 2026 · DOI ↗