Abstract
Our previous studies in the rat model of Parkinson’s disease (PD) cholinopathy demonstrated the sleep-related alterations in electroencephalographic (EEG) oscillations at the cortical and hippocampal levels, cortical drives, and sleep spindles (SSs) as the earliest functional biomarkers preceding hypokinesia. Our aim in this study was to follow the impact of a unilateral substantia nigra pars compacta (SNpc) lesion in rat on the cortical and hippocampal sleep architectures and their EEG microstructures, as well as the cortico-hippocampal synchronizations of EEG oscillations, and the SS and high voltage sleep spindle (HVS) dynamics during NREM and REM sleep. We performed unilateral SNpc lesions using two different concentrations/volumes of 6-hydroxydopamine (6-OHDA; 12 μg/1 μl or 12 μg/2 μl). Whereas the unilateral dopaminergic neuronal loss >50% throughout the overall SNpc rostro-caudal dimension prolonged the Wake state, with no change in the NREM or REM duration, there was a long-lasting theta amplitude augmentation across all sleep states in the motor cortex (MCx), but also in the CA1 hippocampus (Hipp) during both Wake and REM sleep. We demonstrate that SS are the hallmarks of NREM sleep, but that they also occur during REM sleep in the MCx and Hipp of the control rats. Whereas SS are always longer in REM vs. NREM sleep in both structures, they are consistently slower in the Hipp. The dopaminergic neuronal loss increased the density of SS in both structures and shortened them in the MCx during NREM sleep, without changing the intrinsic frequency. Conversely, HVS are the hallmarks of REM sleep in the control rats, slower in the Hipp vs. MCx, and the dopaminergic neuronal loss increased their density in the MCx, but shortened them more consistently in the Hipp during REM sleep. In addition, there was an altered synchronization of the EEG oscillations between the MCx and Hipp in different sleep states, particularly the theta and sigma coherences during REM sleep. We provide novel evidence for the importance of the SNpc dopaminergic innervation in sleep regulation, theta rhythm generation, and SS/HVS dynamics control. We suggest the importance of the underlying REM sleep regulatory substrate to HVS generation and duration and to the cortico-hippocampal synchronizations of EEG oscillations in hemiparkinsonian rats.
Highlights
Parkinson’s disease (PD) is a multisystem neurodegenerative syndrome with a significant heterogeneity of motor and non-motor features, whose prevalence increases with age (Müller et al, 2013; Blesa and Przedborski, 2014)
Since we always quantified the dopaminergic neuronal loss of the lesioned substantia nigra pars compacta (SNpc) vs. its corresponding contralateral control SNpc of each stereotaxic range, those were expressed as percentage differences with respect to the mean contralateral control absolute numbers for each stereotaxic range, taken as 100%; we have to note here that we did not find a statistical difference (z ≥ −1.89; p ≥ 0.07) between the control absolute number of dopaminergic cells at any level of the SNpc rostro-caudal dimension between the two experimental groups (12 μg/1 μl of 6-hydroxy dopamine hydrobromide salt (6-OHDA) and 12 μg/2 μl of 6-OHDA)
Our results showed that the unilateral lesion of SNpc in both experimental groups of rats, consistently increased Wake duration, during their normal inactive circadian phase, between 14 and 42 days following the SNpc lesion (X2 ≥ 6.02; p ≤ 0.05; z ≥ −2.84; p ≤ 0.05; Table 1) in the motor cortex (MCx), and likewise in the Hipp
Summary
Parkinson’s disease (PD) is a multisystem neurodegenerative syndrome with a significant heterogeneity of motor and non-motor features, whose prevalence increases with age (Müller et al, 2013; Blesa and Przedborski, 2014). Beside the well-known reductions in dopaminergic pathways, there is evidence for alterations in the pedunculopontine tegmental nucleus (PPT) cholinergic pathways in PD, which are associated with impaired cognition, frequent falling, gait problems and sleep disorders (Bohnen and Albin, 2011; Bohnen et al, 2012; Müller et al, 2013; Petrovic et al, 2013a,b, 2014; Ciric et al, 2016, 2017, 2018). There is evidence that PD is preceded by REM sleep behavioral disorders (RBD) prior to the dopaminergic neuropathology, and that these REM sleep alterations are associated with the neuronal loss of the REM sleep regulatory neuronal population, such as the sublaterodorsal nucleus (Garcia-Lorenzo et al, 2013; Boucetta et al, 2016)
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