A pontine-medullary loop crucial for REM sleep and its deficit in Parkinson's disease

Abstract

Identifying the properties of the rapid eye movement (REM) sleep circuitry and its relation to diseases has been challenging due to the neuronal heterogeneity of the brainstem. Here, we show in mice that neurons in the pontine sublaterodorsal tegmentum (SubLDT) that express corticotropin-releasing hormone-binding protein (Crhbp⁺ neurons) and project to the medulla promote REM sleep. Within the medullary area receiving projections from Crhbp⁺ neurons, neurons expressing nitric oxide synthase 1 (Nos1⁺ neurons) project to the SubLDT and promote REM sleep, suggesting a positively interacting loop between the pons and the medulla operating as a core REM sleep circuit. Nos1⁺ neurons also project to areas that control wide forebrain activity. Ablating Crhbp⁺ neurons reduces sleep and impairs REM sleep atonia. In Parkinson's disease patients with REM sleep behavior disorders, CRHBP-immunoreactive neurons are largely reduced and contain pathologic α-synuclein, providing insight into the mechanisms underlying the sleep deficits characterizing this disease.

Keywords: Lewy bodies; Parkinson’s disease; RBD; REM sleep; REM sleep behavior disorder; brainstem; chemogenetics; mouse; optogenetics.