Sleep circuits welcome the cortex

In mammals, the electroencephalogram (EEG) serves as a rough measure of cortical activity that distinguishes waking and sleep states, including rapid eye movement (REM) sleep and non-REM (NREM) sleep. Although cortical EEG signals are routinely used to score sleep, the cortex itself has not traditionally been considered critical for sleep regulation. Prevailing models suggest that neural networks in subcortical regions, like the hypothalamus and brainstem, regulate both REM and NREM sleep [1, 2]. However, a series of recent papers challenge this traditional view by providing compelling evidence that the cortex actively takes part in controlling NREM and REM sleep. The most recent of these studies, published by Groenhout et al. [3] in the current issue of SLEEP, performed pharmacological inactivation experiments in rats, demonstrating an important role of the medial prefrontal cortex (mPFC) in regulating REM sleep.

The first study to revisit the cortex’s role in sleep regulation was Krone et al. [4]. The authors found that silencing excitatory layer 5 neurons across the cortex in mice resulted in an increase in wakefulness and dampened the increase in slow-wave activity observed after sleep deprivation, thereby expanding the map of sleep control circuits into the cortex. During REM sleep, select cortical areas are robustly activated [5]. Two studies performing wide-field imaging across the entire dorsal cortex revealed an early and strong activation of the retrosplenial cortex (RSP) during REM sleep [6, 7], consistent with a prior electrophysiological study [8]. Optogenetic activation of the RSP enhanced the chance of NREM-to-REM sleep transitions [7], while its inhibition during REM sleep delayed the onset of rapid eye movements [6].

Among cortical areas, the mPFC stands out because of its dense connectivity with subcortical areas, many of which are involved in sleep–wake regulation [9, 10]. Two simultaneously published studies highlighted the prominent role of prefrontal projections to the hypothalamus for sleep regulation: Tossell et al. [11] showed that optogenetically stimulating somatostatin-expressing GABAergic projections from the mPFC to the lateral preoptic hypothalamus induced sleep-preparatory behaviors such as nesting, while projections to the lateral hypothalamus (LH) facilitated NREM sleep with enhanced delta power. Hong et al. [12] found that stimulating excitatory mPFC neurons promotes REM sleep via their projections to the LH and increases the density of phasic events, reflected in accelerated EEG theta oscillations and an increased REM density during REM sleep. Consistent with these optogenetic effects, calcium imaging showed that large subpopulations of the LH-projecting neurons are strongly activated during REM sleep and phasic events [12].

By pharmacologically inactivating the mPFC in rats, the study by Groenhout et al. complements these findings. Tetrodotoxin (TTX) microinjections into the prelimbic region of the mPFC resulted in a persistent reduction in REM sleep, even lasting till the end of the 24-h recordings. The TTX injections further caused a delayed increase in NREM sleep and a corresponding decrease in wakefulness, beginning approximately 9 h after the start of the recording. Together these findings show that also in rats, the mPFC plays a prominent role in sleep regulation and that suppression of its activity has a particularly strong and long-lasting impact on REM sleep.

These recent studies, including Groenhaut et al., portray the mPFC as a key circuit hub within cortex responsible for multiple aspects of sleep–wake regulation in both mice and rats. Recent work has provided further intriguing evidence that potentiating synapses at excitatory neurons in the dorsomedial PFC promotes NREM sleep and slow-wave activity, supporting a direct role in sleep homeostasis [13]. Besides NREM and REM sleep regulation, there is also evidence for a role of the mPFC in wake control: Activation of the prelimbic cortex using carbachol in rats increased wakefulness [14], and optogenetic activation of excitatory projections from the mPFC to the dorsomedial hypothalamus rapidly awakened mice [15]. Thus, different subdivisions of the PFC, cell types, projection neurons, and even subcompartments within cortical neurons control multiple aspects of both NREM and REM sleep, sleep-preparatory behaviors, and sleep homeostasis [3, 11–13, 16]. The major task for future research will be to identify better markers for these different prefrontal subpopulations and to resolve how interactions ranging from the synaptic to the network-level regulate the induction of different sleep states and their homeostatic needs. Regardless of the outcomes, the cortex—and especially the PFC—has earned a fixed spot on the sleep control circuit map.

Disclosure Statements

Financial disclosure: none. Non-financial disclosure: none.

Funding

This work was supported by the National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI), R01HL149133, to FW and the National Science Foundation Graduate Research Fellowship Program to EP.