Beyond the role in motor function, entopeduncular nucleus, a critical neural hub in psychiatric disorders and sleep regulation

BACKGROUND: The entopeduncular nucleus (EP) is a major output nucleus of the basal ganglia and plays a critical role in integrating motor, emotional, and behavioral processes. Although traditionally linked to motor control, accumulating evidence indicates that the EP is deeply involved in psychiatric disorders, sleep regulation, addiction, and mood-related behaviors. As the rodent homolog of the human internal Globus pallidus (GP) the EP represents a key translational structure bridging preclinical and clinical neuroscience. METHODS: This narrative review was conducted following established narrative review methodology. Relevant literature was identified through a structured search of major biomedical databases. Peer-reviewed experimental and clinical studies investigating EP anatomy, connectivity, neurotransmitter systems, and functional roles were included. The review synthesizes findings from mouse and rat models employing optogenetic and chemogenetic manipulation, electrophysiological recording, neuroanatomical tracing, molecular approaches, and behavioral assays, alongside human neuroimaging, lesion, and deep brain stimulation studies. RESULTS: Evidence from rodent models demonstrates that the EP functions as a convergence hub integrating GABAergic, glutamatergic, dopaminergic, serotonergic, and endocannabinoid signaling. EP projections to the lateral habenula regulate aversive processing, addiction-related behaviors, and mood states. Cell-type-specific mouse studies identify entopeduncular circuits implicated in anxiety regulation. Dysregulation of EP circuits is implicated in depression, anxiety, and Parkinsonian motor dysfunction. Clinical and preclinical neuromodulation studies further support the therapeutic relevance of targeting EP circuits. CONCLUSION: The EP is a multifunctional neural hub extending beyond motor control. Integrating evidence from rodent and human studies highlights its importance in psychiatric and sleep disorders and supports its potential as a translational therapeutic target.