Arousal-related neural circuits in consciousness disorders: Updated model integrating ascending reticular activating system and mesocircuit

ABSTRACT: Consciousness emerges from the dynamic coupling of arousal and conscious content. Although the ascending reticular activating system predominantly regulates arousal, mesocircuit activity supports the integration of conscious content. Disorders of consciousness arise primarily from structural damage or functional disruption of these two core neural systems. Recent advances in neuroscience have enabled high-resolution mechanistic investigations of disorders of consciousness at the cellular and circuit levels. This review synthesizes advances from the past 5 years to delineate how distinct neuronal subpopulations within the ascending reticular activating system precisely regulate conscious states. Key neuronal regulators include cholinergic and glutamatergic neurons in the pedunculopontine tegmental nucleus, noradrenergic neurons in the locus coeruleus, orexinergic neurons in the lateral hypothalamus, and basal forebrain astrocytes. The nucleus accumbens has emerged as a previously underrecognized hub that coordinates arousal and conscious processing. The ascending reticular activating system and mesocircuit achieve dynamic coupling through specialized thalamic subnuclei, notably the paraventricular thalamic nucleus, central lateral, and medial dorsal nuclei, as well as through experience-dependent cortical reorganization, thereby orchestrating transitions between conscious states. These circuit-level insights have informed the development of a multi-level, multi-modal intervention framework for disorders of consciousness. Future priorities include transitioning from acute anesthesia models to clinically relevant chronic disorders of consciousness models, identifying robust cross-species circuit biomarkers, and translating basic circuit findings into patient-oriented clinical research. The development of closed-loop adaptive neurostimulation may further refine our mechanistic understanding of disorders of consciousness and lay the groundwork for clinical translation.