Developing focal RNA interference for the identification of neural entry points for sleep-promoting adenosine

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Adenosine promotes sleep through the activation of A_<2A> receptors. A_<2A> receptors are densely expressed on striatopallidal neurons of the basal ganglia, where dopamine D_2 receptors are co-expressed with A_<2A> receptors and involved in motor function, habit formation, and reward/addictive behaviors, all activities that require wakefulness. Abilities to maintain arousal are compromised under low dopamine conditions such as Parkinson's disease, but the extent to which A_<2A> receptors in the basal ganglia contribute to the regulation of sleep and wakefulness is not known. We investigated the role of A_<2A> receptors in the basal ganglia for wakeful consciousness by using powerful tools for site-specific gene manipulations, including conditional A_<2A> receptor knockout mice based on the Cre/lox technology ; focal A_<2A> receptor knockdown in rats through the local infection with adeno-associated virus carrying short-hairpin RNA of A_<2A> receptors ; and modulation of neuronal activity through in-vivo stimulation and inhibition with genetically engineeredreceptor-channel systems, e. g., optical switches, including channelrhodopsin, and designer receptors exclusively activated by a designer drug(DREADD). Our studies have revealed that the arousal effect of caffeine critically depends on A_<2A> receptors on neurons in the shell of the nucleus accumben and that transient activation of these neurons promotes sleep.These observations imply that A_<2A> receptors in the nucleus accumbens are key structural elements for the control of sleep and wakefulness. The ventral striatum has the unique capability to integrate behavioral functions and thus, it is an ideal site where sleep and wakefulness are regulated by processes that require consciousness. We believe that motivation may be considered as an important fundamental principle by which sleep and waking are regulated.