Substantia nigra pars reticulata-mediated sleep and motor activity regulation

Abstract

Study objectives: The substantia nigra pars reticulata (SNR) is a major output nucleus of the basal ganglia. Animal studies have shown that lesions of the SNR cause hyposomnia and motor hyperactivity, indicating that the SNR may play a role in the control of sleep and motor activity.

Methods: Eight 8- to 10-week-old adult male Sprague-Dawley rats were used. After 3 days of baseline polysomnographic recording, dialysates were collected from the lateral SNR across natural sleep-wake states. Muscimol and bicuculline were microinfused into the lateral SNR.

Results: We found that GABA release in the lateral SNR is negatively correlated with slow wave sleep (SWS; R = -0.266, p < 0.01, n = 240) and positively correlated with waking (R = 0.265, p < 0.01, n = 240) in rats. Microinfusion of muscimol into the lateral SNR decreased sleep time and sleep quality, as well as eliciting motor hyperactivity in wake and increased periodic leg movement in SWS, while bicuculline infused into the lateral SNR increased sleep and decreased motor activity in SWS in rats. Muscimol infusion skewed the distribution of inter-movement intervals, with most between 10 and 20 s, while a flat distribution of intervals between 10 and 90 s was seen in baseline conditions.

Conclusions: Activation of the lateral SNR is important for inducing sleep and inhibiting motor activity prior to and during sleep, and thus to the maintenance of sleep. Abnormal function of the lateral SNR may cause hyposomnia and motor hyperactivity in quiet wake and in sleep.

Keywords: bicuculline; infusion; microdialysis; muscimol; restless legs syndrome.

Figure 1.

(A) Photomicrograph showing the dialysate collection and drug infusion sites in the SNR. (B) Normalized GABA level (yellow line) in the lateral SNR vs percent of wake (blue area) and SWS (orange area), respectively, in 24 consecutive dialysate collections. REM sleep did not occur during the period of dialysate collection. (C) EEG power spectral analysis showing changes in EEG frequency before (baseline) and after muscimol infusion. The yellow and white arrows, shown in A represent the tracts of guide cannulae and the tip of probe, respectively. PAG, periaqueductal gray; R, red nucleus; SN, substantia nigra; 3, oculomotor nucleus. *p < 0.05; **p < 0.01; ***p < 0.001, ANOVA, n: SWS: 575, REM sleep: 47.

Figure 2.

Effect of muscimol (Mus) and bicuculline (Bic) infused into the SNR on sleep–wake states and motor activity. Muscimol microinfused into the lateral SNR increased wake time and decreased SWS and REM sleep time. In contrast, bicuculline microinfused into the lateral SNR decreased wake time and increased SWS and REM sleep time. Infusion of muscimol into the lateral SNR also increased PLM in SWS (PLMS) and induced PLM in quiet wake (PLMW). In contrast, bicuculline infused into the lateral SNR suppressed PLMS. Isolated leg movements in SWS (ILMS) were not altered by either muscimol or bicuculline infused into the lateral SNR. The y-axis for wake, SWS, and REM is minutes. The y-axis for motor activity is the index of PLMS, PLMW, and ILMS. CSF, artificial cerebrospinal fluid; inf, infusion; post-1/2 h and post-3/4 h, post-infusion 1 and 2 h and post-infusion 3 and 4 h. The red and black stars represent significant differences between drug infusion and baseline and CSF infusion, respectively. *p < 0.05; **p < 0.01; ***p < 0.001, post hoc analysis, n = 8.

Figure 3.

Example of muscimol infusion into the lateral SNR inducing PLM in SWS (A) and PLM in wake that extended into SWS (E). (B) The inter-leg movement interval of eight rats during muscimol infusion into the lateral SNR and during the 4 h post-infusion period. (C) Bilateral leg movements of PLM in SWS during artificial CSF infused into the lateral SNR. (D) Mixed ipsilateral and bilateral leg movements in SWS were observed after muscimol infused into the left lateral SNR, however, contralateral right leg movements alone did not meet the criteria for PLM. LegL and LegR, left and right leg, respectively.

Figure 4.

Hypothetical neural circuitry generating hyposomnia and PLM in sleep. The role of the SNR in the control of sleep and sensory–motor activity may be mediated by its thalamic projection. See text for details. Red, green, and pink lines represent glutamatergic, GABAergic, and dopaminergic projections. SNC, substantia nigra pars compacta.