Control of REM sleep by ventral medulla GABAergic neurons

Abstract

Rapid eye movement (REM) sleep is a distinct brain state characterized by activated electroencephalogram (EEG) and complete skeletal muscle paralysis, and it is associated with vivid dreams1-3. Transection studies by Jouvet first demonstrated that the brainstem is both necessary and sufficient for REM sleep generation2, and the neural circuits in the pons have since been studied extensively4-8. The medulla also contains neurons that are active during REM sleep9-13, but whether they play a causal role in REM sleep generation remains unclear. Here we show that a GABAergic pathway originating from the ventral medulla (vM) powerfully promotes REM sleep. Optogenetic activation of vM GABAergic neurons rapidly and reliably initiated REM sleep episodes and prolonged their durations, whereas inactivating these neurons had the opposite effects. Optrode recordings from channelrhodopsin 2 (ChR2)-tagged vM GABAergic neurons showed that they were most active during REM sleep (REM-max), and during wakefulness they were preferentially active during eating and grooming. Furthermore, dual retrograde tracing showed that the rostral projections to the pons and midbrain and caudal projections to the spinal cord originate from separate vM neuron populations. Activating the rostral GABAergic projections was sufficient for both the induction and maintenance of REM sleep, which are likely mediated in part by inhibition of REM-suppressing GABAergic neurons in the ventrolateral periaqueductal gray (vlPAG). These results identify a key component of the pontomedullary network controlling REM sleep. The capability to induce REM sleep on command may offer a powerful tool for investigating its functions.

Gamma band directional interactions between basal forebrain and visual cortex during wake and sleep states

“…We suggest that REM BF gamma is mediated mainly by ''P-max" as well as ''WP-max" GABAergic neurons, given that these are fast-spiking neurons that are most active during REM sleep. Consistent with our findings, the ''P-max" GABAergic BF population does not in fact project to cortex, but instead targets the hypothalamus (Gritti et al, 1994) and brainstem structures (Semba et al, 1989) including the medulla that has recently been linked to REM sleep initiation (Weber et al, 2015).…”

Melanin-concentrating hormone neurons specifically promote rapid eye movement sleep in mice

“…The SLD and PC are held in check by inhibitory inputs from the ventrolateral periaqueductal gray matter (vlPAG) and adjacent lateral pontine tegmentum (LPT, also called the deep mesencephalic nucleus) (Lu et al, 2006, Vetrivelan et al, 2011, Luppi et al, 2012). Both the REM-On (SLD/PC/LDT/PPT) and the REM-Off (vlPAG/LPT) structures receive intense MCH input (Torterolo et al, 2009, Clement et al, 2012, Torterolo et al, 2013), as does the ventrolateral medullary (vM) area (Bittencourt et al, 1992) where Weber and colleagues have recently identified GABAergic neurons that generate REM sleep by inhibiting the vlPAG/LPT (Weber et al, 2015). Thus, MCH neurons are likely to regulate REM sleep by inhibiting the vlPAG/LPT and activating the SLD/PC/LDT/PPT/vM, although the physiology of these connections remains to be investigated.…”

Circadian Rhythms, Sleep, and Disorders of Aging

“…Hypocretinergic neurons send dense excitatory projections to multiple nuclei including the LC [34], a noradrenergic nucleus that also promotes arousal [35]. Both VLPO and hypocretinergic neurons send projections to the brainstem, where REM sleep in particular is regulated [36,37]. In the ‘flip-flop’ model of sleep and wakefulness, the sleep-active VLPO and the wake-active monoaminergic nuclei (including the LC) mutually inhibit each other, creating rapid transition between sleep and wake states; the wake-active hypocretin neurons reinforce the arousal system and stabilize the switch [38].…”