Striatal adenosine A(2A) receptor neurons control active-period sleep via parvalbumin neurons in external globus pallidus

Dysfunction of the striatum is frequently associated with sleep disturbances. However, its role in sleep-wake regulation has been paid little attention even though the striatum densely expresses adenosine A(2A) receptors (A(2A)Rs), which are essential for adenosine-induced sleep. Here we showed that chemogenetic activation of A(2A)R neurons in specific subregions of the striatum induced a remarkable increase in non-rapid eye movement (NREM) sleep. Anatomical mapping and immunoelectron microscopy revealed that striatal A(2A)R neurons innervated the external globus pallidus (GPe) in a topographically organized manner and preferentially formed inhibitory synapses with GPe parvalbumin (PV) neurons. Moreover, lesions of GPe PV neurons abolished the sleep-promoting effect of striatal A(2A)R neurons. In addition, chemogenetic inhibition of striatal A(2A)R neurons led to a significant decrease of NREM sleep at active period, but not inactive period of mice. These findings reveal a prominent contribution of striatal A(2A)R neuron/GPe PV neuron circuit in sleep control.