Abstract
The rostromedial tegmental nucleus (RMTg), also called the GABAergic tail of the ventral tegmental area, projects to the midbrain dopaminergic system, dorsal raphe nucleus, locus coeruleus, and other regions. Whether the RMTg is involved in sleep–wake regulation is unknown. In the present study, pharmacogenetic activation of rat RMTg neurons promoted non-rapid eye movement (NREM) sleep with increased slow-wave activity (SWA). Conversely, rats after neurotoxic lesions of 8 or 16 days showed decreased NREM sleep with reduced SWA at lights on. The reduced SWA persisted at least 25 days after lesions. Similarly, pharmacological and pharmacogenetic inactivation of rat RMTg neurons decreased NREM sleep. Electrophysiological experiments combined with optogenetics showed a direct inhibitory connection between the terminals of RMTg neurons and midbrain dopaminergic neurons. The bidirectional effects of the RMTg on the sleep–wake cycle were mimicked by the modulation of ventral tegmental area (VTA)/substantia nigra compacta (SNc) dopaminergic neuronal activity using a pharmacogenetic approach. Furthermore, during the 2-hour recovery period following 6-hour sleep deprivation, the amount of NREM sleep in both the lesion and control rats was significantly increased compared with baseline levels; however, only the control rats showed a significant increase in SWA compared with baseline levels. Collectively, our findings reveal an essential role of the RMTg in the promotion of NREM sleep and homeostatic regulation.
Highlights
Dopamine (DA) produced by neurons in the midbrain plays a key role in processing reward, aversive, and cognitive signals [1]
The results suggest that the rostromedial tegmental nucleus (RMTg) is involved in the initiation of non-rapid eye movement (NREM) sleep, which is compensated by some brain structures at 25 days after damage to RMTg neurons
The present study shows that the normal neuronal activities of RMTg are necessary for the maintenance of NREM sleep, as demonstrated by the reduction in the numbers of longer bouts of NREM sleep with morphine-RMTg injection, as well as for the initiation of NREM sleep, as shown by the decreased numbers of short-duration bouts of NREM sleep and fewer transitions from wakefulness to NREM sleep with Gi-coupled designer receptor exclusively activated by designer drugs (DREADD) and neurotoxic lesions
Summary
Dopamine (DA) produced by neurons in the midbrain plays a key role in processing reward, aversive, and cognitive signals [1]. Growing evidence suggests that DA-containing neurons are important for arousal maintenance in both humans [6, 7] and animals [8,9,10,11]. It has been found that activation of ventral tegmental area (VTA) γ-amino-butyric acid (GABA) neurons, which indirectly inhibits the firing of VTA DAergic neurons, is sufficient to elicit a place aversion [12, 13]. This suggests that the ability of midbrain DAergic neurons to regulate sleep–wake behavior and sleep problems in DA-associated mental illnesses may be affected by upstream inhibitory neuronal systems
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