Progressive Pontine-Medullary Dysfunction Leads to REM Sleep Behavior Disorder Symptoms in a Chronic Model of Parkinson’s Disease

Abstract

Lida Du,1 Linhao Xu,1,2 Tuo Liang,1 Yun-Kwok Wing,3 Ya Ke,1,4 Wing-Ho Yung1,4 1School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, People’s Republic of China; 2Department of Cardiology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 3Department of Psychiatry, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, People’s Republic of China; 4Gerald Choa Neuroscience Centre, The Chinese University of Hong Kong, Hong Kong, People’s Republic of ChinaCorrespondence: Wing-Ho Yung; Ya KeSchool of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, People’s Republic of ChinaTel [phone]; [phone]Fax [phone]Email [email protected]; [email protected]: Clinical observations reveal that rapid eye movement (REM) sleep behavior disorder (RBD) often develops prior to alpha-synucleinopathies including Parkinson’s disease (PD). However, a causal relationship between alpha-synucleinopathy and Parkinsonian neurodegeneration has not been delineated.Methods: Rats were chronically treated with rotenone and EEG and EMG signals were recorded for analysis of sleep behavior, assisted by video recording of body movements. C-fos expression and TUNEL staining were used to assess neuronal activation and apoptosis, respectively. Chemogenetic manipulation of brain stem nuclei was conducted to ameliorate RBD symptoms in rotenone-treated rats.Results: Rats chronically exposed to rotenone exhibited progressive RBD features, from EEG slowing to REM sleep motor behavior and NREM muscle activities. Temporally, these phenomena correlated well with progressive alpha-synuclein aggregation and neuronal apoptosis in the sublaterodorsal tegmental nucleus (SLD) and gigantocellular ventricular reticular nucleus in the brainstem. Chemogenetic activation of glutamatergic neurons in SLD alleviated RBD symptoms in the rotenone model.Conclusion: Taken together, these results are consistent with a progressive degeneration in the REM sleep promoting and atonia circuit in early Parkinsonism that underlies the emergence of RBD symptoms, and demonstrate that the rotenone model is useful for further studies into RBD and its relationship to PD.Keywords: Parkinson’s disease, REM sleep behavior disorder, neurodegeneration, parasomnia, early biomarker

Keywords

• parkinson’s disease
• rem sleep behavior disorder
• neurodegeneration
• parasomnia
• early-biomarker