Arousal Regulation by the External Globus Pallidus: A New Node for the Mesocircuit Hypothesis

In the decade since its debut, the Mesocircuit Hypothesis (MH) has provided researchers a scaffolding for interpreting their findings by associating subcortical-cortical dysfunction with the loss and recovery of consciousness following severe brain injury. Here, we leverage new findings from human and rodent lesions, as well as chemo/optogenetic, tractography, and stimulation studies to propose the external segment of the globus pallidus (GPe) as an additional node in the MH, in hopes of increasing its explanatory power. Specifically, we discuss the anatomical and molecular mechanisms involving the GPe in sleep-wake control and propose a plausible mechanistic model explaining how the GPe can modulate cortical activity through its direct connections with the prefrontal cortex and thalamic reticular nucleus to initiate and maintain sleep. The inclusion of the GPe in the arousal circuitry has implications for understanding a range of phenomena, such as the effects of the adenosine (A2A) and dopamine (D2) receptors on sleep-wake cycles, the paradoxical effects of zolpidem in disorders of consciousness, and sleep disturbances in conditions such as Parkinson’s Disease.