Sleep disorder and altered locomotor activity as biomarkers of the Parkinson’s disease cholinopathy in rat

Abstract

In order to find out the possible earliest biomarkers of Parkinson's disease (PD) cholinopathy, we followed the impact of bilateral pedunculopontine tegmental nucleus (PPT) lesion in rat on: the cortical and hippocampal sleep/wake states architectures, all sleep states related EEG microstructures, sleep spindles, the basal and stimulated locomotor activity. Sleep and basal locomotor activity in adult Wistar rats were followed during their inactive circadian phase, and throughout the same aging period. The bilateral PPT lesions were done by 0.1M ibotenic acid (IBO) during the surgical procedure for implantation of the electroencephalographic (EEG) and electromyographic (EMG) electrodes for chronic sleep recording. The cholinergic neuronal loss was identified by NADPH - diaphorase histochemistry. After all sleep and behavioral recording sessions, the locomotor activity was stimulated by d-amphetamine (d-AMPH) and the neuronal activity of striatum was followed by c-Fos immunolabeling. Impaired cholinergic innervation from the PPT was expressed earlier as sleep disorder then as movement disorder, and it was the earliest and long-lasting at hippocampal and thalamo-cortical level, and followed by a delayed "hypokinesia". This severe impact of a tonically impaired PPT cholinergic innervation was evidenced as the cholinergic interneuronal loss of the caudate putamen and as a suppressed c-Fos expression after stimulation by d-AMPH. In order how they occurred, the hippocampal non rapid eye movement (NREM) sleep disorder, altered high voltage sleep spindle (HVS) dynamics during rapid eye movement (REM) sleep in the hippocampus and motor cortex, and "hypokinesia" may serve as the biomarkers of PD cholinopathy onset and progression.

Sleep spindle dynamics during NREM and REM sleep following distinct general anaesthesia in control rats and in a rat model of Parkinson’s disease cholinopathy

“…On the other hand, the increased density of prolonged HVS in the motor cortex versus increased density of slower and shorter HVS in the hippocampus, during their simultaneous REM sleep, in the rat model of PD cholinopathy, reflects serious rearrangements within the thalamo‐cortical regulatory network, as a result of the tonically and sustainably decreased inhibition of RT neurons and the excitation of TC neurons (Ciric et al, ). In addition, a recent study has suggested that pentobarbital anaesthesia is highly beneficial for post‐anaesthesia REM sleep in the physiological condition as well as during PD cholinergic neuropathology in rats (Lazic et al, ).…”

“…The first step for automatic SS and HVS detection during the 1 hr of NREM or REM sleep for each rat and experimental group was to filter the EEG signals using the 11–17 Hz band pass filter for SS, or the 4.1–10 Hz band pass filter for HVS. Then, we applied the continuous wavelet transform with the mother wavelet “cmorl‐2’’ MATLAB R2011a function, providing a complex Morlet wavelet with a determined central frequency f 0 = 2 (Adamczyk, Genzel, Dresler, Steiger, & Friess, ; Ciric et al, ). In addition, all the SS had a minimal duration of 0.5 s, whereas all the HVS had a minimal duration of 1 s. However, because we automatically detected many false positive or negative SS or HVS, we had to visually correct all the automatically detected SS or HVS for their final extraction from each NREM/REM sleep episode of each rat and each experimental group.…”

“…All control means 48 hr after both types of anaesthesia (Ctrl K 48 hr and Ctrl P 48 hr) and after the PPT lesion (PPT before) were compared with the control means before any anaesthesia (Ctrl before), whereas the means, 48 hr after both types of anaesthesia in the PPT-lesioned rats (PPT K 48 hr and PPT P 48 hr) were compared with the control means 48 hr after anaesthesia (Ctrl K 48 hr and Ctrl P 48 hr). (Ciric et al, 2018). In addition, a recent study has suggested that pentobarbital anaesthesia is highly beneficial for post-anaesthesia REM sleep in the physiological condition as well as during PD cholinergic neuropathology in rats acetylcholine release in the hippocampus and the frontal cortex, with no effect in the striatum, pentobarbital decreases acetylcholine release in all brain structures (Sato et al, 1996).…”

“…We applied Fourier analysis to those signals acquired throughout the 6-hr period (2160 10-s Fourier epochs), and each 10-s epoch was differentiated, on the basis of EEG and EMG, as a wake, an NREM or an REM sleep state. The differentiation of all the wake/NREM/REM sleep epochs was improved by using the logarithmic values of the quantities on both the EEG and EMG axes, and was finally achieved using the two cluster K means algorithm (Ciric et al, , 2018Ciric, Lazic, Petrovic, Kalauzi, & Saponjic, 2016;Lazic et al, 2015Lazic et al, , 2017.…”

“…In addition, HVS are associated with memory impairment and the progression of brain dysfunction in rats (Radek, Curzon, & Decker, ; Sales‐Carbonell et al, ), and distinctly altered HVS dynamics in the motor cortex versus the hippocampus during REM sleep preceded decreased locomotor activity in the rat model of PD cholinopathy (Ciric et al, ).…”