4 MARCH 2022 • VOL 375 ISSUE 6584 973GRAPHIC: A. MASTIN/
SCIENCE
SCIENCE science.orgmice showing that DA neurons
within the midbrain ventral
tegmental area (VTA), a brain
region long associated with re-
ward and addiction, had higher
firing rates during REM sleep
and wakefulness than during
non-REM (NREM) sleep and
also increased their activity be-
fore NREM-to-REM transitions
( 5 ). Building on these important
observations, Hasegawa et al.
sought to understand if and how
these “REM-on” dopaminergic
VTA (DAVTA) neurons might con-
tribute to the regulation of REM
sleep. To do so, they used a G pro-
tein–coupled receptor (GPCR)
activation–based (GRAB) sensor
for DA (GRABDA) to assess DA re-
lease at known postsynaptic tar-
gets of DAVTA neurons, including
the BLA, in mice.
The GRABDA tool permits
precise temporal-spatial assess-
ments of DA concentrations
within the brain ( 6 ), even during
complex behaviors. The authors
could thus ascertain extracellu-
lar DA concentrations within the
BLA and other brain regions as
mice cycled through the stages
of wakefulness, NREM sleep,
and REM sleep. From these re-
cordings, they determined that DA was tran-
siently increased in both the BLA and the
nucleus accumbens (NAc) preceding NREM-
to-REM transitions. Subsequent photostimu-
lation of DAVTA terminals in the BLA but not
in the NAc produced a rapid transition to
REM sleep. The authors then acutely and se-
lectively inhibited DA receptor D2 (DRD2)–
expressing BLA neurons in vivo using an op-
togenetic tool ( 7 ), which triggered, albeit with
some delay, an NREM-to-REM transition and
increased total REM sleep time. Together,
these findings reveal a central role for DAVTA
neurons, DA neurotransmission, and inhi-
bition of DRD2-expressing BLA neurons in
the regulation of REM sleep, including the
triggering of REM sleep onset. These results
therefore provide a cellular and circuit sub-
strate for findings from previous studies
showing that the pharmacological manipula-
tion of brain DA (e.g., DA-depleted mice and
the use of DRD2 agonists) can substantially
alter REM sleep ( 8 ).
Can manipulation of DRD2 neurons in the
BLA produce cataplexy in mice? Hasegawaet al. demonstrated that DA release into the
BLA precedes cataplexy in narcoleptic mice
(which are deficient in orexin, a neuropeptide
expressed in cells of the lateral hypothalamus
that regulates wakefulness and appetite).
They also found that the surge of DA in the
BLA—but not in other brain regions tested—
was greater in the narcoleptic mouse model
than in wild-type littermates. The authors
then stimulated DAVTA neurons in nonnarco-
leptic mice, which express normal amounts
of orexin, producing a transient increase in
DA within the BLA and inducing cataplexy.
Given the normal concentrations of orexin in
these mice, this is a striking finding and one
that may require a reconsideration of the pre-
vailing neurobiological models of cataplexy in
the context of narcolepsy because cataplexy is
not known to occur spontaneously in orexin-
competent animals, including humans.
Although the authors’ data firmly support
a role for DAVTA neurons in the control of
REM sleep, how DRD2-expessing BLA neu-
rons are functionally related or connected
with cell groups located in the pontine and
medullary brainstem, which were previously
established to be necessary for the generation
of REM sleep and REM paralysis, remains
uncertain. Notably, BLA DRD2-expressing
neurons do not appear to project beyondthe BLA itself. One possibility is
that disinhibition of non–DRD2-
expressing BLA neurons—which
the authors suggest may occur
after DA-induced inhibition of
DRD2-expressing BLA neurons—
could, in turn, activate inhibitory
g-aminobutyric acid–specific
(GABAergic) neurons of the
central amygdala nucleus (CeA)
that normally serve to inhibit
key pontine cell groups involved
in REM motor control ( 9 – 11 )
(see the figure). It also remains
unclear why the amount of DA
released in the BLA by positive
emotions (e.g., when mice are
fed chocolate) is greatly ampli-
fied in orexin-deficient mice. The
authors propose that this could
be the result of disinhibition of
DAVTA input to the BLA or could
result from plastic changes in
the DA system—e.g., the number
of aminegic neurons is increased
in narcoleptic humans who are
orexin deficient ( 12 , 13 ).
Another remaining mystery is
why drugs that increase extracel-
lular DA (e.g., modafinil) and are
used clinically to enhance wake-
fulness in people with disorders
like idiopathic hypersomnia and
narcolepsy do not have an effect
on cataplexy and REM sleep. Future stud-
ies should also examine the role of BLA DA
signaling in shaping fundamental features of
REM sleep, such as its homeostatic regula-
tion, which is a process that remains incom-
pletely understood. The study of Hasegawa
et al. provides fresh insights into the control
of both REM sleep and cataplexy by DA, and
their findings raise the intriguing possibility
that DRD2 BLA neurons could be a selec-
tive druggable target for treating debilitating
symptoms in a wide range of REM sleep dis-
orders, including cataplexy in narcolepsy and
other disorders, such as Parkinson’s disease,
in which DA signaling is disrupted. jREFERENCES AND NOTES- D. Kennedy, C. Norman, Science 309 , 75 (2005).
- E. Arrigoni, M. C. Chen, P. M. Fuller, J. Physiol. 594 , 5391
(2016). - J. Peever, P. M. Fuller, Curr. Biol. 27 , R1237 (2017).
- E. Hasegawa et al., Science 375 , 994 (2022).
- A. Eban-Rothschild, G. Rothschild, W. J. Giardino, J. R.
Jones, L. de Lecea, Nat. Neurosci. 19 , 1356 (2016). - F. Sun et al., Cell 174 , 481 (2018).
- O. A. Masseck et al., Neuron 81 , 1263 (2014).
- K. Dzirasa et al., J. Neurosci. 26 , 10577 (2006).
- M. B. Snow et al., J. Neurosci. 37 , 4007 (2017).
- C. E. Mahoney, L. J. Agostinelli, J. N. K. Brooks, B. B.
Lowell, T. E. Scammell, J. Neurosci. 37 , 3995 (2017). - E. Hasegawa et al., Proc. Natl. Acad. Sci. U.S.A. 114 ,
E3526 (2017). - P. O. Valko et al., Ann. Neurol. 74 , 794 (2013).
- J. John et al., Ann. Neurol. 74 , 786 (2013).
10.1126/science.abo1987
(^1) Department of Neurology, Beth Israel Deaconess Medical
Center and Harvard Medical School, Boston, MA, USA.
(^2) Department of Neurological Surgery, University of
California, Davis School of Medicine, Davis, CA, USA.
Email: [email protected]; [email protected]
GABA
Pontine
REM-off
neurons
Spinal motor neurons
BLA
CeA
DRD2
Glutamate
GABA
?
?
Anterior Posterior
DAV TA
V TA
Midbrain
Amygdala Pons
Pons
Midbrain
Amygdala
A putative circuit model of REM sleep
Dopamine neurons within the ventral tegmental area (DAV TA neurons) project to
and inhibit locally projecting basolateral amygdala (BLA) neurons that express
DA receptor D2 (DRD2). This disinhibits the BLA efferent pathways, potentially
including projections to the central amygdala nucleus (CeA). In this putative
circuit model, activation of CeA g-aminobutyric acid–specific (GABAergic)
neurons could promote rapid eye movement (REM) sleep and cataplexy through
projections to pontine and medullary cell populations.