Neural Circuitry Regulating REM Sleep and Its Implication in REM Sleep Behavior Disorder

Since the discovery of rapid eye movement sleep (REMs) in 1953, considerable progress has been made in deciphering the neural circuits and mechanisms involved in the generation of this stage and its cardinal signs, including cortical activation and muscle atonia. Research work on animal models has provided important insights on the prognosis, diagnosis, causes, and treatment of REM behavior disorder (RBD), a clinical condition in which muscle atonia is compromised during REMs. In this chapter, we review current knowledge in REMs circuitry and its involvement in the pathophysiology of RBD. Available evidence strongly suggests that glutamatergic neurons in the sublaterodorsal tegmental nucleus (SLD) located in the dorsolateral pons are the principal elements for the generation of REMs. These neurons may cause cortical activation and muscle atonia during REMs respectively through their ascending projections to the parabrachial nucleus and basal forebrain and their descending projections to the ventromedial medulla (VMM) and spinal cord. Activity of SLD neurons, and thereby REMs, is strongly under the influence of inhibitory neurons in the ventrolateral periaqueductal gray and the adjoining lateral pontine tegmentum (vlPAG/LPT). Mutual interaction between the SLD and vlPAG/LPT forms the primary REMs circuit and may determine the occurrence and duration of REMs. Many other brain regions, including medial prefrontal cortex, preoptic area, and lateral hypothalamus, may orchestrate circadian, homeostatic, and allostatic regulation of REMs by acting on this principal circuit. These data indicate that degenerative lesions of the SLD and its descending projections may underlie RBD and that assessing REMs amount and architecture, in addition to motor behavior, may be necessary to track the progression of RBD into alpha-synucleinopathy diseases such as Parkinson’s disease.