Altered sleep regulation in a mouse model of parkinson's disease

Abstract Introduction Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by pathognomonic motor abnormalities that lead to significant disability and morbidity in advanced stages. PD is also associated with sleep abnormalities such as increased fragmentation, insomnia, and excessive daytime sleepiness. Little is known of the underlying mechanisms, in part due to the limited ability of existing mouse models to adequately replicate human PD patient sleep phenotypes. Here we characterize sleep-wake behavior in an innovative genetic mouse model of PD (MCI-Park) targeting a mitochondrial complex I gene (Ndufs2), which experiences progressive dopaminergic neuron loss and displays motor phenotypes resembling those seen in human PD. Methods Undisturbed sleep-wake behavior during 12 hr light: 12 hr dark cycles was evaluated in MCI-Park mice during prodromal stages (6-8 weeks of age) and later parkinsonian stages (14-18 weeks of age) as well as in age-matched wildtype littermate controls. Electroencephalographic (EEG) and electromyographic (EMG) recording electrodes were surgically implanted using sterile technique in male and female MCI-Park and wildtype mice. After one week of recovery and acclimation to recording chambers, EEG and EMG were recorded continuously and sleep phenotypes were analyzed. Results In prodromal stages, MCI-Park mice exhibited similar overall sleep state amounts compared to wildtype mice, however there were significantly more state shifts as well as longer bouts of wakefulness and shorter bouts of non-REM (NREM) sleep. As mice progressed to parkinsonian stages, these fragmentation measures worsened. In addition, parkinsonian MCI-Park mice experienced a significant increase in wakefulness, a significant reduction in NREM sleep amount, and alterations in REM sleep, with pronounced reductions in REM sleep amount and number of REM bouts. Power spectral analysis revealed consistent decreases in theta2 (also known as alpha) power across all sleep-wake states in MCI-Park mice. Conclusion These results indicate that mice harboring a genetic defect causing selective disruption of dopaminergic neurons exhibit progressive sleep abnormalities that resemble sleep disturbances in PD patients. This model thus offers an opportunity to evaluate mechanisms underlying and therapeutic strategies targeting altered sleep in PD patients. Support (if any) This work was supported by the Department of Defense award number W81XWH-21-0582 (F.W.T. and D.J.S.).