Unraveling the multifaceted roles of the aryl hydrocarbon receptor in the central nervous system: neurogenesis, neural function, and disease.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor originally characterized as a mediator of xenobiotic detoxification. Growing evidence now establishes AhR as a central integrator of metabolic, immune, and environmental signals in the central nervous system (CNS). Beyond toxicological responses, AhR regulates neural development, glial programming, neuroendocrine function, synaptic plasticity, and barrier integrity across the lifespan. During embryogenesis, AhR contributes to lineage specification, neurogenesis, and circuit assembly through transcriptional and epigenetic mechanisms. In the adult CNS, AhR preserves cognitive resilience and circuit stability by shaping microglial and astroglial phenotypes, regulating neurotransmission, neurogenesis, myelination, and circadian timing. Dysregulation of AhR signaling by genetic, inflammatory, microbial, and environmental cues disrupts these homeostatic programs and increases vulnerability to CNS dysfunction. Pathologically, AhR exerts context-dependent dual functions, constraining neuroinflammation and supporting tissue repair in some settings while amplifying oxidative stress, barrier disruption, and neuronal loss in others. Finally, ligand-directed programming of AhR signaling emerges as a promising therapeutic framework for CNS disorders. Collectively, this review positions AhR as a ligand-sensitive regulator of CNS homeostasis and disease, while highlighting its broader relevance as a systemic regulator of physiological and pathological processes beyond the nervous system.