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CD(IF=38) Zhili Huang/Weimin Qu/Fengfei Ding, Fudan University, reveal the underlying neural mechanisms of REM sleep termination and sleep continuation

 Last Update: 2022-10-31
 Source: Internet
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Physiological rapid eye movement (REM) sleep termination is essential for initiating non-rapid eye movement (NREM) sleep or wakefulness, while inhibition of excessive REM sleep is promising
in the treatment of narcolepsy.
However, the neural mechanisms that control REM sleep termination and keeping sleep going remain unclear
.

On October 25, 2022, Huang Zhili, Qu Weimin and Ding Fengfei of Fudan University jointly published a joint communication entitled "A cluster of mesopontine GABAergic neurons suppresses REM sleep and curbs cataplexy" online in Cell Discovery (IF=38).
The study revealed a key brainstem region
in the control of GABAergic neurons in controlling physiological rapid eye movement sleep and cataplexy (cataplexy, an outof-phase sleep disorder in which muscle tone suddenly disappears throughout the body during an onset, and suddenly moves from wakefulness to heterogeneous sleep).
。 Using fiber photometry and optical quadrupole recording technology, this study characterized the relative inactivity of REM and two different discharge modes of
dDpMe's dorsal GABAergic neurons in the deep midbrain nucleus (dDpMe) under spontaneous sleep-wake cycles.
Next, the study used optogenetics, RNA interference techniques, and cell type-specific lesions to investigate the role of
dDpMe GABAergic neuronal circuits in brain state regulation.

Physiologically, dDpMe GABAergic neurons inhibit REM sleep through the dorsal inferior nucleus and lateral hypothalamus and promote non-REM sleep
.
In-depth studies of neural circuits have shown that dorsal inferior nucleostamatergic neurons are essential
for dDpMe GABAergic neurons to terminate REM sleep.
In addition, in rodent models, dDpMe GABAergic neurons can effectively inhibit cataplexy
.
In conclusion, the results suggest that dDpMe GABA neurons control REM sleep termination and REM/NREM switchover, which is a new potential target for the treatment of narcolepsy
.

In addition, on October 21, 2022, Chen Xiaowei and Qin Han of the Army Medical University published a joint communication entitled "REM sleep-active hypothalamic neurons may contribute to hippocampal social-memory" online on Neuron (IF=19).
Consolidation" research paper suggests that REM sleep-active hypothalamic neurons may contribute to social memory consolidation
in the hippocampus.
The study used circuit-specific optical and single-cell electrophysiology to record mice to explore the role of sleep in social memory consolidation and its underlying circuit mechanisms
.
The study found that SuM neurons projected to CA2 were highly active during REM sleep, but not during
non-REM sleep or restful wakefulness.
REM sleep-selective photogene silencing in these neurons impairs social memory
.
In contrast, silencing SuM neurons of REM sleep activity projected into the dentate gyrus had no effect
on social memory.
Thus, the study provides causal evidence that hypothalamic neurons projecting REM sleep activity to CA2 are particularly needed for social memory consolidation (click to read).

Periodic rhythms and continuity are essential
for sleep physiology.
For continuous sleep in healthy people, rapid eye movement (REM) sleep occurs multiple times after non-rapid eye movement (NREM) sleep during a typical night's sleep, while decreased REM sleep, deinhibition of REM sleep, and insomnia are often accompanied by non-consolidation sleep
.
In 1953, Kleitman and Atherlinsky first described REM sleep as "active sleep" that occurs periodically in human infants, as opposed
to periods of resting sleep known as non-REM sleep.
REM sleep is a rapid eye movement produced by an outburst of oculomotor muscles and is also characterized by cortical electroencephalogram (EEG) out-of-synchronization, high-amplitude theta waves, and muscle relaxation
.
REM sleep is associated with
brain development and memory.
Disorders of REM sleep can lead to many sleep disorders, including narcolepsy
.
Although several brain regions that promote REM sleep, such as the dorsal nucleus (SLD), ventral medulla, and lateral hypothalamus (LH), have been described, the core mechanisms that control REM sleep termination and REM/non-REM alternation have received less attention
.
Previous studies have shown that monoaminegic neurons in the brainstem stop firing specifically during REM sleep, including serotonergic neurons from the midsuture nucleus and noradrenergic neurons
from the coelenteral site (LC).
Since the 70s of the 20th century, non-monoamine-inhibiting neurons in the gray matter/deep diencephalic nucleus (vlPAG/DpMe) around the ventrolateral aqueduct have been reported as a key part of
REM sleep suppression.
However, the important mechanisms of REM sleep arrest remain controversial, and the neural mechanisms of REM sleep required to maintain continuous REM sleep or REM-like pathological sleep remain largely uncertain
.
dDpMe^{GABA neurons} are essential for REM sleep suppression and the transition from REM to non-REM sleep (Figure from Cell Discovery) In 1975, Petitjean et al.
reported that electrical disruption of the dorsal norepinephrine tract (including vlPAG/DpMe) of the midbrain led to an increase in
REM sleep.
In mice, chemical damage to the ventrolateral zone of vlPAG and the dorsal zone of the deep midbrain nucleus (dDpMe) consistently increased REM sleep
.
Boissard et al.
found that vlPAG/DpMe GABAergic neurons project SLD
, a key center for REM sleep.
In addition, dDpMe GABAergic (dDpMe^GABA) neurons were found to be activated
during REM sleep deprivation.
A recent study reported that a cluster of Atoh1-expressing neurons from the hindbrain inhibited REM sleep
via dDpMe.
In humans, pontine damage containing dDpMe causes cataplexy and visual hallucinations
due to excessive REM sleep.
However, direct evidence of dDpMe^GABA neurons as an essential element of REM sleep regulation and REM-related disorders remains insufficient
.
How real-time manipulation of dDpMe^GABA neurons affects REM, non-REM, and wakefulness transitions has not been reported
.
In this study, the spontaneous activity
of dDpMe^GABA neurons corresponding to REM sleep was investigated by fiber photometry and in vivo multichannel recording.
In addition, the authors used optogenetics and RNA interference to reveal the critical role
of dDpMe^GABA neurons in REM sleep termination and sleep continuity.
Finally, the study applied optogenetic manipulation to a rodent model of virus-based orexin neuronal injury to investigate the therapeutic effects
of dDpMe^GABA neurons on cataplexy.
These findings may provide further insights into the pathophysiology of narcolepsy and reveal potential therapeutic pathways
for sleep disorders.

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