Basal ganglia control of sleep-wake behavior and cortical activation

Abstract

The basal ganglia (BG) are involved in numerous neurobiological processes that operate on the basis of wakefulness, including motor function, learning, emotion and addictive behaviors. We hypothesized that the BG might play an important role in the regulation of wakefulness. To test this prediction, we made cell body-specific lesions in the striatum and globus pallidus (GP) using ibotenic acid. We found that rats with striatal (caudoputamen) lesions exhibited a 14.95% reduction in wakefulness and robust fragmentation of sleep-wake behavior, i.e. an increased number of state transitions and loss of ultra-long wake bouts (> 120 min). These lesions also resulted in a reduction in the diurnal variation of sleep-wakefulness. On the other hand, lesions of the accumbens core resulted in a 26.72% increase in wakefulness and a reduction in non-rapid eye movement (NREM) sleep bout duration. In addition, rats with accumbens core lesions exhibited excessive digging and scratching. GP lesions also produced a robust increase in wakefulness (45.52%), and frequent sleep-wake transitions and a concomitant decrease in NREM sleep bout duration. Lesions of the subthalamic nucleus or the substantia nigra reticular nucleus produced only minor changes in the amount of sleep-wakefulness and did not alter sleep architecture. Finally, power spectral analysis revealed that lesions of the striatum, accumbens and GP slowed down the cortical electroencephalogram. Collectively, our results suggest that the BG, via a cortico-striato-pallidal loop, are important neural circuitry regulating sleep-wake behaviors and cortical activation.

Fig. 1

Histology of striatal lesions. Thionin-stained (A–D) and GAD67-immunostained (E–H) coronal sections (rostrocaudal = top-down) from a typical case show the extents of the lesions. The black lines mark the lesion regions. Note that lesions in this case spare the right side of the caudal striatum. High-power Nissl-staining images show intact (I) and lesion (J, from the region marked by * in B) neuronal fields in the striatum. Corresponding high-power images of GAD67 immunostaining show intact (K) and lesion (L, from the region marked by * in F) neuronal fields in the striatum. aca, anterior commissure, anterior part; GP, globus pallidus; SCN, suprachiasmatic nucleus; SON, supraoptic nucleus.

Fig. 2

The effects of striatal lesions on sleep and wakefulness. (A) Light: dark = 12: 12 h time course of the hourly amounts of wake, rapid eye movement (REM) and non-rapid eye movement (NREM) sleep of control (n = 6) and striatum-lesioned (n = 6) rats. Each circle represents the hourly mean ± SEM of wakefulness, REM and NREM sleep. (B) Total time spent in wake, REM and NREM sleep during the light and dark periods and over the 24-h day. (C) Results of sleep–wake transitions (N, W and R represent the stage for NREM, wakefulness and REM sleep, respectively). (D) Results of bout numbers (upper panel) and mean durations (lower panel) during light and dark periods. *P < 0.05, **P < 0.01, two-tailed unpaired t-test.

Fig. 3

Examples of compressed 24-h electroencephalogram (EEG)/electromyogram (EMG) recordings and corresponding hypnograms of control, striatal, nucleus accumbens core (NAc) and globus pallidus (GP) lesions. As compared with controls, the striatal and GP lesions resulted in frequent sleep–wake transitions and the appearance of pronounced ultradian oscillation of wakefulness and sleep. In addition, striatal lesions eliminated ultra-long wake bouts (*), which were commonly observed in the control animals. Although the NAc lesions induced more frequent sleep–wake transitions, they did not affect the diurnal pattern and ultra-long wake bouts were preserved. Similar to NAc lesions, GP lesions did not eliminate ultra-long wake bouts. NREM, non-rapid eye movement; REM, rapid eye movement.

Fig. 4

Histology of nucleus accumbens core (NAc) lesions. GAD67 immunostaining in a control (A, B) and a lesion case (C, D).

Fig. 5

The effects of nucleus accumbens core (NAc) lesions on sleep and wakefulness. (A) Light: dark = 12: 12 h time course of the hourly amounts of wake, rapid eye movement (REM) and non-rapid eye movement (NREM) sleep of control (n = 6) and NAc (n = 4) lesioned rats. Each circle represents the hourly mean ± SEM of wakefulness, REM and NREM sleep. (B) Total time spent in wake, REM and NREM sleep during the light and dark periods and over the 24-h day. (C) Results of sleep–wake transitions (N, W and R represent the stage for NREM, wakefulness and REM sleep, respectively). (D) Results of bout numbers (upper panel) and mean durations (lower panel) during light and dark periods. *P < 0.05, **P < 0.01, two-tailed unpaired t-test.

Fig. 6

Histology of ibotenic acid lesions in the globus pallidus (GP), substantia nigra pars reticulata (SNr) and subthalamic nucleus (STN). The coronal sections (A–D) from rostral to caudal levels show lesion areas in the GP in a rat. (E, G and I) Intact normal morphology of the GP, SNr and STN from control rats. (F, H and J) The morphology of lesions in the GP, SNr and STN, respectively. The insert pictures of (e, g, i) and (f, h, j) are high-magnified images from the rectangular areas marked by ‘e’, ‘g’, ‘i’ and ‘f’, ‘h’, ‘j’, respectively).

Fig. 7

Quantitative changes of sleep–wake times of ibotenic acid lesions in globus pallidus (GP), substantia nigra pars reticulate (SNr) and subthalamic nucleus (STN). (A–C) Diurnal patterns of hourly wake, rapid eye movement (REM) and non-rapid eye movement (NREM) sleep amounts of control (n = 6) and GP (n = 6), SNr (n = 5) and STN (n = 6) lesion groups, *P < 0.05, **P < 0.01, two-tailed unpaired t-test. (D) Total amounts of wake, REM and NREM sleep in light period, dark period and light + dark period in each group. *P < 0.05, **P < 0.01, one-way ANOVA followed by Dunnett’s post hoc test.

Fig. 8

Sleep–wake transition (A), bout number and mean duration (B) of wake, rapid eye movement (REM) and non-rapid eye movement (NREM) sleep in dark and light periods of control and globus pallidus (GP) lesions. *P < 0.05, **P < 0.01, two-tailed unpaired t-test.

Fig. 9

EEG power spectra during wake, rapid eye movement (REM) and non-rapid eye movement (NREM) sleep over 24 h. The power spectrum was normalized to total power (0.5–24.5 Hz). Lesions in the striatum, nucleus accumbens core (NAc) and globus pallidus (GP) all produced a generalized slowing of the EEG, with less theta and more delta density during wake, REM and NREM sleep. In other words, all of the lesions produced a slowing of the cortical EEG.

Fig. 10

Neural circuitry underlying the BG control of sleep–wake behavior. The striatum receiving cortical inputs projects to the GP, which then projects to the cerebral cortex directly or by the thalamus (mainly the mediodorsal thalamic nucleus). We hypothesize that the cortico-striato-pallidal loop regulates sleep–wake behavior and cortical activation. GP, globus pallidus; OC, optic chiasm.