The Role of the Substantia Nigra Pars Compacta in Regulating Sleep Patterns in Rats

Background. As of late, dopaminergic neurotransmission has been recognized to be involved in the generation of sleep disturbances. Increasing evidence shows that sleep disturbances in Parkinson's disease (PD) patients are mostly related to the disease itself, rather than being a secondary phenomenon. Evidence contained in the literature lends support to the hypothesis that the dopaminergic nigrostriatal pathway is closely involved in the regulation of sleep patterns. Methodology/Principal Findings. To test this hypothesis we examined the electrophysiological activity along the sleep-wake cycle of rats submitted to a surgically induced lesion of the SNpc by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We demonstrated that a 50% lesion of the substantia nigra pars compacta (SNpc) suffices to produce disruptions of several parameters in the sleep-wake pattern of rats. A robust and constant decrease in the latency to the onset of slow wave sleep (SWS) was detected throughout the five days of recording in both light [F((22.16)) = 72.46, p<0.0001] and dark [F((22.16)) = 75.0, p<0.0001] periods. Also found was a pronounced increase in the percentage of sleep efficiency during the first four days of recording [F((21.15)) = 21.48, p<0.0001], in comparison to the sham group. Additionally, the reduction in the SNpc dopaminergic neurons provoked an ablation in the percentage of rapid eye movement sleep (REM) during three days of the sleep-wake recording period with a strong correlation (r = 0.91; p<0.0001) between the number of dopaminergic neurons lost and the percentage decrease of REM sleep on the first day of recording. On day 4, the percentage of REM sleep during the light and dark periods was increased, [F((22.16)) = 2.46, p<0.0007], a phenomenon consistent with REM rebound. Conclusions/Significance. We propose that dopaminergic neurons present in the SNpc possess a fundamental function in the regulation of sleep processes, particularly in promoting REM sleep.AFIPCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Universidade Federal de São Paulo, Dept Psicobiol, São Paulo, BrazilUniv Fed Parana, Dept Farmacol, BR-80060000 Curitiba, Parana, BrazilUniversidade Federal de São Paulo, Dept Psicobiol, São Paulo, BrazilFAPESP: 98/14.303-3Web of Scienc

Neuroinflammation in the pathophysiology of Parkinson’s disease and therapeutic evidence of anti-inflammatory drugs

Parkinson’s disease (PD) is the second most common neurodegenerative disease affecting approximately 1.6% of the population over 60 years old. The cardinal motor symptoms are the result of progressive degeneration of substantia nigra pars compacta dopaminergic neurons which are involved in the fine motor control. Currently, there is no cure for this pathology and the cause of the neurodegeneration remains unknown. Several studies suggest the involvement of neuroinflammation in the pathophysiology of PD as well as a protective effect of anti-inflammatory drugs both in animal models and epidemiological studies, although there are controversial reports. In this review, we address evidences of involvement of inflammatory process and possible therapeutic usefulness of anti-inflammatory drugs in PD

The roles of the nucleus accumbens core, dorsomedial striatum, and dorsolateral striatum in learning : performance and extinction of Pavlovian fear conditioned responses and instrumental avoidance responses

This study examined the effects of bilateral excitotoxic lesions of the nucleus accumbens core (NAc-co), dorsomedial striatum (DMS) or dorsolateral striatum (DLS) of rats on the learning and extinction of Pavlovian and instrumental components of conditioned avoidance responses (CARs). None of the lesions caused sensorimotor deficits that could affect locomotion. Lesions of the NAc-co, but not DMS or DLS, decreased unconditioned and conditioned freezing. The NAc-co and DLS lesioned rats learned the 2-way active avoidance task more slowly. These results suggest: (i) CARs depend on both Pavlovian and instrumental learning; (ii) learning the Pavlovian component of CARs depends on the NAc-co; learning the instrumental component of CARs depends on the DLS, NAc and DMS; (iii) although the NAc-co is also needed for learning the instrumental component, it is not clear whether it plays a role in learning the instrumental component per se or if it simply allows learning of the Pavlovian component which is a pre-condition for learning the instrumental component; (iv) we did not find evidence that the DMS and DLS play the same roles in habit and goal-directed aspects of the instrumental component of CARs as observed in appetitive motivated instrumental responding

Slight increase in the percentage of SWS after SNpc lesion.

<p>The percentage of SWS was increased on the second and fourth days, only in the dark periods, indicating sleepiness effect in the activity period of the rodent. The values are expressed as mean±S.E.M. *p<0.05 compared to those of baseline, ^#p<0.05 compared to the respective sham group. ANOVA followed by the Tukey test.</p

Dual effects upon the latencies to SWS and REM sleep after selective SNpc lesion.

<p>(a) Latency to SWS showed to be decreased at all time-points after MPTP exposure, in both light and dark periods. (b) Latency to REM sleep was increased in the light and dark periods after MPTP only on the first day of recording. The values are expressed as mean±S.E.M. *p<0.05, ***p<0.0001 compared to baseline, ANOVA followed by the Tukey test.</p

Dopaminergic neurons present in the SNpc are reduced by half after MPTP intranigral microinjection.

<p>A representative immunohistochemistry labeling of TH-ir neurons is shown in animals at the end of 5-day sleep-wake cycle recordings; (a) sham group (the inset square shows the specific region depicted in the panel below), (b) MPTP group (the inset square shows the specific region depicted in the panel below), (c) sham group in higher magnification (d) MPTP group in higher magnification, (e) bilateral quantification of the loss of TH-ir neurons in the SNpc, (f) the loss of TH-ir neurons in the SNpc correlated closely with the decrease of REM sleep on the first day of recording, subsequent to MPTP microinjection. The values are expressed as mean±S.E.M. **p<0.01, ANOVA followed by the Newman–Keuls test.</p

Schematic representation of the experimental design.

<p>After the intranigral microinjections of saline or MPTP, the rats were distributed for sleep-wake cycle recording (n = 8/group), midbrain TH immunohistochemical examination (n = 5) and nigral TH protein expression study (n = 5). Histological and western blotting experiments used animals that had their brains collected along the 5 days of recording (n = 5/day/group) at the same hour they were lesioned, according to the time-points schedule.</p