Mysteries of pedunculopontine nucleus physiology: Towards a deeper understanding of arousal and neuropsychiatric disorders☆

This issue of Sleep Science contains two excellent review articles by Garcia-Rill and his colleagues examining the role of reticular activating system, especially the pedunculopontine (PPT) nucleus, in the pathophysiology of insomnia, schizophrenia, and other neuropsychiatric disorders [1,2]. The PPT nucleus is one of the major aggregations of cholinergic neurons in the mammalian brainstem capable of synthesizing acetylcholine, but also other neurotransmitters and peptides [3]. In addition, PPT cholinergic cells also synthesize a gaseous neuromodulator, nitric oxide. Interestingly, cells in the PPT are involved in regulation of both wakefulness and REM sleep [3,4]. About 10 years ago, the Garcia-Rill lab reported for the first time the presence of electrical coupling through gap junctions of some cells in each of three major elements of the arousal system, including the PPT [5]. This discovery helped explain how gap junction blockers like halothane and propofol can put us to sleep so rapidly. A year later, his lab resolved a 20-year mystery, the mechanism of action of the stimulant modafinil used in the treatment of narcolepsy. Modafinil was found to increase electrical coupling and coherence of cell activity in the same centers found to manifest electrical coupling, increasing arousal [6]. All of these breakthroughs