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

Modulation of sickness behavior by sleep: the role of neurochemical and neuroinflammatory pathways in mice

Activation of the immune system elicits several behavioral changes that are collectively called sickness behavior and consists in a strategy to overcome infection. Steep deprivation can increase susceptibility to pathogens and to behavioral alterations. Thus, the present study aimed to determine how paradoxical steep deprivation (PSD) affects the behavioral and neurochemical responses to lipopotysaccharide (LPS, potent activator of the immune response). Adult inbred mice were paradoxical steep deprived (72 h), whereas the control group was kept in their home cages. Both groups received either an injection of saline or LPS (5, 10 or 20 mu g/animal ip) before behavioral tasks and tissue collection. During the recovery sleep period, LPS provoked a strong inhibition of steep rebound due to a suppression of paradoxical steep. PSD increased the susceptibility of mice to LPS-induced immobility in the open field, which was capable of affecting the anxiety-like behavior also. These altered behavioral responses to LPS were accompanied by reduction in dopamine turnover within the striatum and increased expression of cyctooxygenase-2 in the cortex. the study provides some insights into how the steep-wake cycle affects the expression of sickness behavior induced by LPS. (C) 2009 Elsevier B.V. and ECNP. All rights reserved.Universidade Federal de São Paulo, Dept Psychobiol, UNIFESP EPM, BR-04024002 São Paulo, BrazilUniv Fed Parana, Dept Pharmacol, BR-80060000 Curitiba, Parana, BrazilUniversidade Federal de São Paulo, Dept Psychobiol, UNIFESP EPM, BR-04024002 São Paulo, BrazilWeb of Scienc

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

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