How sleep is homeostatically regulated remains a mystery. In this issue of Neuron, Donlea et al. (2014) provide evidence in Drosophila that a set of sleep-inducing neurons require Crossveinless-c, a specific Rho-GTPase-activating protein (Rho-Gap), to alter their membrane excitability in response to sleep deprivation

Oezcan, GG

Rihel, J

PubMed

Özcan, Güliz Gürel

Rihel, Jason

Elsevier - Publisher Connector 

Neuron
PreviewsA Drosophila Circuit Feels the (Sleep) PressureGu¨liz Gu¨rel O¨zcan1 and Jason Rihel1,*
1Department of Cell and Developmental Biology, University College London, Anatomy Building, Gower Street, London WC1E 6BT, UK
*Correspondence: j.rihel@ucl.ac.uk
http://dx.doi.org/10.1016/j.neuron.2014.02.002
How sleep is homeostatically regulated remains a mystery. In this issue of Neuron, Donlea et al. (2014) pro-
vide evidence in Drosophila that a set of sleep-inducing neurons require Crossveinless-c, a specific Rho-
GTPase-activating protein (Rho-Gap), to alter their membrane excitability in response to sleep deprivation.The influential two-process model of
sleep regulation posits that sleep pres-
sure (i.e., the internal drive to sleep) is
regulated by the interaction of circadian
and homeostatic processes (Borbe´ly,
1982). In this model, the circadian pro-
cess synchronizes sleep drive to the
24 hr day-night cycle, while the homeo-
static process steadily builds sleep pres-
sure in response to wakefulness, then
dissipates this pressure during sleep.
Normally working in concert, the homeo-
static process can be decoupled from
the circadian process by sleep depriva-
tion; as wakefulness is extended beyond
normal physiological amounts, sleep
pressure will also continue to build until
it is homeostatically ‘‘reset’’ by subse-
quent rebound sleep. Although the mech-
anisms for coupling the circadian process
to downstream sleep output remain
murky, work in Drosophila and rodents
over the past 40 years has painted a
detailed picture of both the core molecu-
lar machinery (e.g., interlocking feedback
loops among circadian clock proteins) as
well as the critical pacemaker neurons
(e.g., lateral neurons in Drosophila, the
suprachiasmatic nucleus in mammals).
Meanwhile, the homeostatic regulation
of sleep is still shrouded in mystery.
What aspects of prolonged waking drive
sleep need? What are the molecular
substrates by which this signal is trans-
mitted? Where in the brain do these
signals work to drive changes in sleep
behavior?
Some progress has been made in iden-
tifying critical sleep-wake circuits. In the
mammalian hypothalamus, sleep-active
GABAergic neurons of the ventrolateral
preoptic area (VLPO) form reciprocal
inhibitory connections with a diverse set
of wake-promoting neurons, known as
the ascending arousal system (Saper720 Neuron 81, February 19, 2014 ª2014 Elset al., 2010). These circuits are considered
critical drivers of sleep and wake, as
ablation of the VLPO in rodents leads
to insomnia, while pharmacological or
optogenetic activation of components of
the ascending arousal system promote
waking (Rihel and Schier, 2013). An anal-
ogous sleep-wake circuit has recently
been discovered in Drosophila. When
directly activated by temperature-sensi-
tive Trp channels, a set of neurons that
project to the dorsal fan-shaped body
(FB) induce sleep (Donlea et al., 2011).
These neurons are directly connected
to and inhibited by wake-promoting,
FB-projecting dopaminergic neurons via
the dopamine receptor DopR. Curiously,
both the mammalian VLPO and the
Drosophila FB sleep neurons are sensitive
to the anesthetic isoflurane, and, at least
in flies, this sensitivity is increased with
sleep deprivation (Rihel and Schier,
2013). Given the central role that these
neurons play as drivers of sleep/wake
behavior, a natural hypothesis is that
they will ultimately be sensitive, directly
or indirectly, to the signal(s) of homeostat-
ic sleep pressure. In this issue of Neuron,
Donlea et al. (2014) push this hypothesis
to the fore in Drosophila, arriving at an
attractive albeit skeletal model whereby
the electrical excitability of FB sleep
output neurons is modulated in response
to sleep deprivation.
In order to identify and manipulate the
FB neurons, the previous studies relied
on the same set of selective Gal4-driver
lines. To start, Donlea et al. (2014) make
the simple but excellent deduction that
the underlying genes whose enhancers/
promoters are hijacked by the Gal4-
drivers will also be restricted in expres-
sion, critical for the functioning of these
neurons, and, therefore, good candidate
regulators of sleep. The transposon ofevier Inc.one of the FB-restricted lines maps to
an intron of a gene encoding a Rho
GTPase-activating protein (Rho-GAP),
crossveinless-c (cv-c). Flies harboring
various mutations in cv-c sleep less,
but they have normal waking activity and
normal arousal threshold responses to
stimuli (unlike many short-sleeping mu-
tants). They also have normal circadian
locomotor activity. However, when the
flies were sleep deprived for 12 hr, cv-c
mutants failed to show homeostatic
rebound sleep, indicating that cv-c mu-
tants are unable to either sense or convert
increased sleep pressure into recovery
sleep. An alternative explanation for
this result alone is that cv-c mutants are
‘‘superflies’’ that require less sleep. How-
ever, cv-c mutants show impairments in
an olfactory memory task, a result consis-
tent with the cognitive deficits associ-
ated with chronic sleep deprivation. One
caveat to this interpretation is that mem-
ory impairment may be a direct result
of lost Cv-c function instead of a conse-
quence of sleep deprivation. To address
this, forcing the flies to sleep, through
either pharmacological or direct activa-
tion of sleep circuits, should restore
normal memory function if it is indeed
due to chronic short sleep. Regardless,
given that selective rescue of Cv-c in
a few neurons restores sleep and mem-
ory (see below), they are likely to have
defective sleep homeostasis, not a lower
sleep need.
The cv-c mutants are not the first
Drosophila sleep mutant to be identified
with defects in sleep homeostasis. Previ-
ous molecular components implicated
in Drosophila sleep homeostasis include
cyclic-AMP and CREB signaling, ERK
signaling, Shaker potassium channels
and its regulator, Sleepless, dopamine,
octopomine, and serotonin signaling,
Wake-Promoting
Neuron
dorsal
Fan Shaped 
Body
Sleep-Promoting
Neuron
Sleep
Behavior
DopR DA
Dopamine +
Cv-c
DopR
Cv-c
Sleep Pressure
Synaptic?
Metabolic?
Hormonal?
Cell-intrinsic?
etc.
Dopamine +
?
?
Sleep
Behavior 
A Post Recovery Sleep B  Sleep Deprivation 
Figure 1. A Drosophila Sleep Pressure Point in the Fan-Shaped Body?
(A) During low sleep pressure states, sleep-promoting FB neurons remain at their baseline excitability.
(B) After sleep deprivation, sleep pressure signals are transmuted into increased electrical excitability of
FB neurons in a process that requires functional Cv-c. The FB neurons are shown in context with
wake-promoting dopamine neurons, which inhibit FB neurons and reduce sleep.
Neuron
Previewscircadian clock components, cyclinA
and its regulators, and the ubiquitin ligase
Cullin-3 and its adaptor, Insomniac
(Bushey and Cirelli, 2011; Rogulja and
Young, 2012; Pfeiffenberger and Allada,
2012). In addition to the specificity of the
cv-c behavioral phenotype (e.g., they are
not hyper- or hypoactive, unlike many of
the dopamine and insomniac mutants),
what distinguishes the cv-c mutant from
most of these others is the high degree
of neuronal specificity. Replacing or
depleting Cv-c function selectively in the
sleep-inducing FB neurons is sufficient
to respectively rescue or exacerbate
the sleep homeostatic defect of cv-c mu-
tants. Furthermore, altering Cv-c function
in adult FB neurons demonstrates the
sleep defect is not of developmental
origin. Taken together, these data point
directly to the FB neurons—and func-
tioning Cv-c within these neurons—as
critical for proper sleep homeostasis.
To explore this idea further, Donlea
et al. (2014) performed direct electrophys-
iological recordings of both wild-type andcv-c mutant FB neurons before, during,
and after sleep deprivation. First, they
found a critical role for Cv-c in maintain-
ing electrical excitability of FB neurons
under current-clamp recordings—most
wild-type FB neurons were excited by de-
polarizing current, while most cv-cmutant
neurons remained electrically silent with
reduced input resistances (Rm) and mem-
brane time constants (tm). Cv-c is not
required in all neuron types, as olfactory
projection neurons remain electrically
normal in cv-c mutants. Most intriguingly,
they observed that wild-type FB neurons
increased their electrical excitability in
sleep-deprived flies and returned to base-
line excitability following recovery sleep.
This sleep deprivation-dependent modu-
lation required functional Cv-c, as cv-c
mutant FB neurons failed to alter electrical
excitability to prolonged wakefulness.
Only the scaffolding of a full sleep ho-
meostasis model is brought into view by
these results: some unknown direct or
indirect signal for sleep pressure is trans-
mitted into changes in electrical excit-Neuron 81,ability of the major sleep output neurons,
and this change depends, in an unknown
way, on Cv-c (Figure 1). However, the
potential implications of the model are
substantial. In its strongest and perhaps
most elegant form, the FB sleep output
neurons themselves would act as a
kind of sleep pressure antenna, directly
receiving homeostatic cues and convert-
ing them into changes in electrical excit-
ability, be these changes due to syn-
aptic remodeling, metabolic cues, toxic
breakdown products, hormonal signals
of wakefulness, or even cell-intrinsic
processes. Furthermore, how Cv-c might
read sleep pressure signals and facilitate
or convert this into electrical properties
is unclear, although one potential clue
may lie in Cv-c’s previously described
role in synaptic homeostasis at the neuro-
muscular junction (Pilgram et al., 2011).
Nevertheless, the model has the potential
to unify myriad observations inDrosophila
sleep studies. For example, Cv-c may
regulate trafficking or channel properties
of the sleep-relevant Shaker postassium
channel or Sleepless within FB neurons,
adding cellular specificity to these mutant
phenotypes. Or perhaps Cv-c modulates
cAMP/PKA signaling, which has been
implicated in fly sleep homeostasis as
well as dopamine inhibition of FB neu-
rons. The model may also hint at possible
mechanisms to explain other unusual
observations. For example, starvation
or methamphetamine sleep deprives
flies without apparent rebound (Andretic
et al., 2005; Bushey and Cirelli, 2011),
perhaps because they prolong wakeful-
ness yet short-circuit Cv-c-dependent
electrical changes in FB neurons and
block sleep homeostatic responses.
Finally, the question of whether the
model may be directly relevant to mam-
mals should be addressed. Does the anal-
ogy of the Drosophila sleep circuitry to
the mammalian flip-flop circuit extend
even to this nascent homeostasis model?
One popular mammalian view envisions
homeostatic sleep processes working on
local cortical circuits (Krueger et al.,
2008), in part because local slow waves
respond homeostatically to use-depen-
dent changes in neuronal activity. This
view also reflects another distinction be-
tween mammalian and fly sleep rebound;
namely, in mammals, sleep pressure
more consistently tracks with the depthFebruary 19, 2014 ª2014 Elsevier Inc. 721
Neuron
Previewsof recovery than the amount of rebound
sleep (Bushey andCirelli, 2011). However,
sleep depth changes in flies have been
measured and could also be regulated
by the proposed homeostatic model
(van Alphen et al., 2013). Furthermore,
local mammalian sleep homeostats do
not preclude the existence of additional,
central mechanisms to relate sleep pres-
sure to whole animal sleep. Indeed, a
recent study found that the VLPO neurons
increase their firing rate in response to
sleep deprivation in a way that is sensitive
to adenosine antagonism, one of the ma-
jor metabolites suspected to signal sleep
pressure in mammals (Alam et al., 2014).
To conclude, Donlea et al. (2014) have
identified Cv-c as a molecular player in
sleep homeostasis and more importantly
have localized the effects to specific
sleep-promoting cells in the Drosophila
brain. Many questions remain, including722 Neuron 81, February 19, 2014 ª2014 Elswhether the FB response to sleep depri-
vation also applies to the normal sleep-
wake cycle, how sleep pressure is sensed
by the FB cell, and how electrical excit-
ability is restored following recovery
sleep. While short on answers, the pro-
posed model should now frame focused
questions in Drosophila sleep research
and should inspire the wider sleep com-
munity to investigate similar homeostatic
models in a vertebrate context.
REFERENCES
Alam, M.A., Kumar, S., McGinty, D., Alam, M.N.,
and Szymusiak, R. (2014). J. Neurophysiol. 111,
287–299.
Andretic, R., van Swinderen, B., and Greenspan,
R.J. (2005). Curr. Biol. 15, 1165–1175.
Borbe´ly, A.A. (1982). Hum. Neurobiol. 1, 195–204.
Bushey, D., and Cirelli, C. (2011). Int. Rev. Neuro-
biol. 99, 213–244.evier Inc.Donlea, J.M., Thimgan, M.S., Suzuki, Y., Gott-
schalk, L., and Shaw, P.J. (2011). Science 332,
1571–1576.
Donlea, J.M., Pimentel, D., and Miesenbo¨ck, G.
(2014). Neuron 81, this issue, 860–872.
Krueger, J.M., Rector, D.M., Roy, S., Van Dongen,
H.P.A., Belenky, G., and Panksepp, J. (2008). Nat.
Rev. Neurosci. 9, 910–919.
Pfeiffenberger, C., and Allada, R. (2012). PLoS
Genet. 8, e1003003.
Pilgram, G.S.K., Potikanond, S., van der Plas,
M.C., Fradkin, L.G., and Noordermeer, J.N.
(2011). J. Neurosci. 31, 492–500.
Rihel, J., and Schier, A.F. (2013). Curr. Opin. Neu-
robiol. 23, 831–840.
Rogulja, D., and Young, M.W. (2012). Science 335,
1617–1621.
Saper, C.B., Fuller, P.M., Pedersen, N.P., Lu, J.,
and Scammell, T.E. (2010). Neuron 68, 1023–1042.
van Alphen, B., Yap, M.H.W., Kirszenblat, L.,
Kottler, B., and van Swinderen, B. (2013).
J. Neurosci. 33, 6917–6927.


A Drosophila Circuit Feels the (Sleep) Pressure 

UCL Discovery

NeuronPreviewsA Drosophila Circuit Feels the (Sleep) PressureGu¨liz Gu¨rel O¨zcan1 and Jason Rihel1,*1Department of Cell and Developmental Biology, University College London, Anatomy Building, Gower Street, London WC1E 6BT, UK*Correspondence: j.rihel@ucl.ac.ukhttp://dx.doi.org/10.1016/j.neuron.2014.02.002How sleep is homeostatically regulated remains a mystery. In this issue of Neuron, Donlea et al. (2014) pro-vide evidence in Drosophila that a set of sleep-inducing neurons require Crossveinless-c, a specific Rho-GTPase-activating protein (Rho-Gap), to alter their membrane excitability in response to sleep deprivation.The influential two-process model ofsleep regulation posits that sleep pres-sure (i.e., the internal drive to sleep) isregulated by the interaction of circadianand homeostatic processes (Borbe´ly,1982). In this model, the circadian pro-cess synchronizes sleep drive to the24 hr day-night cycle, while the homeo-static process steadily builds sleep pres-sure in response to wakefulness, thendissipates this pressure during sleep.Normally working in concert, the homeo-static process can be decoupled fromthe circadian process by sleep depriva-tion; as wakefulness is extended beyondnormal physiological amounts, sleeppressure will also continue to build untilit is homeostatically ‘‘reset’’ by subse-quent rebound sleep. Although the mech-anisms for coupling the circadian processto downstream sleep output remainmurky, work in Drosophila and rodentsover the past 40 years has painted adetailed picture of both the core molecu-lar machinery (e.g., interlocking feedbackloops among circadian clock proteins) aswell as the critical pacemaker neurons(e.g., lateral neurons in Drosophila, thesuprachiasmatic nucleus in mammals).Meanwhile, the homeostatic regulationof sleep is still shrouded in mystery.What aspects of prolonged waking drivesleep need? What are the molecularsubstrates by which this signal is trans-mitted? Where in the brain do thesesignals work to drive changes in sleepbehavior?Some progress has been made in iden-tifying critical sleep-wake circuits. In themammalian hypothalamus, sleep-activeGABAergic neurons of the ventrolateralpreoptic area (VLPO) form reciprocalinhibitory connections with a diverse setof wake-promoting neurons, known asthe ascending arousal system (Saper720 Neuron 81, February 19, 2014 ª2014 Elset al., 2010). These circuits are consideredcritical drivers of sleep and wake, asablation of the VLPO in rodents leadsto insomnia, while pharmacological oroptogenetic activation of components ofthe ascending arousal system promotewaking (Rihel and Schier, 2013). An anal-ogous sleep-wake circuit has recentlybeen discovered in Drosophila. Whendirectly activated by temperature-sensi-tive Trp channels, a set of neurons thatproject to the dorsal fan-shaped body(FB) induce sleep (Donlea et al., 2011).These neurons are directly connectedto and inhibited by wake-promoting,FB-projecting dopaminergic neurons viathe dopamine receptor DopR. Curiously,both the mammalian VLPO and theDrosophila FB sleep neurons are sensitiveto the anesthetic isoflurane, and, at leastin flies, this sensitivity is increased withsleep deprivation (Rihel and Schier,2013). Given the central role that theseneurons play as drivers of sleep/wakebehavior, a natural hypothesis is thatthey will ultimately be sensitive, directlyor indirectly, to the signal(s) of homeostat-ic sleep pressure. In this issue of Neuron,Donlea et al. (2014) push this hypothesisto the fore in Drosophila, arriving at anattractive albeit skeletal model wherebythe electrical excitability of FB sleepoutput neurons is modulated in responseto sleep deprivation.In order to identify and manipulate theFB neurons, the previous studies reliedon the same set of selective Gal4-driverlines. To start, Donlea et al. (2014) makethe simple but excellent deduction thatthe underlying genes whose enhancers/promoters are hijacked by the Gal4-drivers will also be restricted in expres-sion, critical for the functioning of theseneurons, and, therefore, good candidateregulators of sleep. The transposon ofevier Inc.one of the FB-restricted lines maps toan intron of a gene encoding a RhoGTPase-activating protein (Rho-GAP),crossveinless-c (cv-c). Flies harboringvarious mutations in cv-c sleep less,but they have normal waking activity andnormal arousal threshold responses tostimuli (unlike many short-sleeping mu-tants). They also have normal circadianlocomotor activity. However, when theflies were sleep deprived for 12 hr, cv-cmutants failed to show homeostaticrebound sleep, indicating that cv-c mu-tants are unable to either sense or convertincreased sleep pressure into recoverysleep. An alternative explanation forthis result alone is that cv-c mutants are‘‘superflies’’ that require less sleep. How-ever, cv-c mutants show impairments inan olfactory memory task, a result consis-tent with the cognitive deficits associ-ated with chronic sleep deprivation. Onecaveat to this interpretation is that mem-ory impairment may be a direct resultof lost Cv-c function instead of a conse-quence of sleep deprivation. To addressthis, forcing the flies to sleep, througheither pharmacological or direct activa-tion of sleep circuits, should restorenormal memory function if it is indeeddue to chronic short sleep. Regardless,given that selective rescue of Cv-c ina few neurons restores sleep and mem-ory (see below), they are likely to havedefective sleep homeostasis, not a lowersleep need.The cv-c mutants are not the firstDrosophila sleep mutant to be identifiedwith defects in sleep homeostasis. Previ-ous molecular components implicatedin Drosophila sleep homeostasis includecyclic-AMP and CREB signaling, ERKsignaling, Shaker potassium channelsand its regulator, Sleepless, dopamine,octopomine, and serotonin signaling,Wake-PromotingNeurondorsalFan Shaped BodySleep-PromotingNeuronSleepBehaviorDopR DADopamine +Cv-cDopRCv-cSleep PressureSynaptic?Metabolic?Hormonal?Cell-intrinsic?etc.Dopamine +??SleepBehavior A Post Recovery Sleep B  Sleep Deprivation Figure 1. A Drosophila Sleep Pressure Point in the Fan-Shaped Body?(A) During low sleep pressure states, sleep-promoting FB neurons remain at their baseline excitability.(B) After sleep deprivation, sleep pressure signals are transmuted into increased electrical excitability ofFB neurons in a process that requires functional Cv-c. The FB neurons are shown in context withwake-promoting dopamine neurons, which inhibit FB neurons and reduce sleep.NeuronPreviewscircadian clock components, cyclinAand its regulators, and the ubiquitin ligaseCullin-3 and its adaptor, Insomniac(Bushey and Cirelli, 2011; Rogulja andYoung, 2012; Pfeiffenberger and Allada,2012). In addition to the specificity of thecv-c behavioral phenotype (e.g., they arenot hyper- or hypoactive, unlike many ofthe dopamine and insomniac mutants),what distinguishes the cv-c mutant frommost of these others is the high degreeof neuronal specificity. Replacing ordepleting Cv-c function selectively in thesleep-inducing FB neurons is sufficientto respectively rescue or exacerbatethe sleep homeostatic defect of cv-c mu-tants. Furthermore, altering Cv-c functionin adult FB neurons demonstrates thesleep defect is not of developmentalorigin. Taken together, these data pointdirectly to the FB neurons—and func-tioning Cv-c within these neurons—ascritical for proper sleep homeostasis.To explore this idea further, Donleaet al. (2014) performed direct electrophys-iological recordings of both wild-type andcv-c mutant FB neurons before, during,and after sleep deprivation. First, theyfound a critical role for Cv-c in maintain-ing electrical excitability of FB neuronsunder current-clamp recordings—mostwild-type FB neurons were excited by de-polarizing current, while most cv-cmutantneurons remained electrically silent withreduced input resistances (Rm) and mem-brane time constants (tm). Cv-c is notrequired in all neuron types, as olfactoryprojection neurons remain electricallynormal in cv-c mutants. Most intriguingly,they observed that wild-type FB neuronsincreased their electrical excitability insleep-deprived flies and returned to base-line excitability following recovery sleep.This sleep deprivation-dependent modu-lation required functional Cv-c, as cv-cmutant FB neurons failed to alter electricalexcitability to prolonged wakefulness.Only the scaffolding of a full sleep ho-meostasis model is brought into view bythese results: some unknown direct orindirect signal for sleep pressure is trans-mitted into changes in electrical excit-Neuron 81,ability of the major sleep output neurons,and this change depends, in an unknownway, on Cv-c (Figure 1). However, thepotential implications of the model aresubstantial. In its strongest and perhapsmost elegant form, the FB sleep outputneurons themselves would act as akind of sleep pressure antenna, directlyreceiving homeostatic cues and convert-ing them into changes in electrical excit-ability, be these changes due to syn-aptic remodeling, metabolic cues, toxicbreakdown products, hormonal signalsof wakefulness, or even cell-intrinsicprocesses. Furthermore, how Cv-c mightread sleep pressure signals and facilitateor convert this into electrical propertiesis unclear, although one potential cluemay lie in Cv-c’s previously describedrole in synaptic homeostasis at the neuro-muscular junction (Pilgram et al., 2011).Nevertheless, the model has the potentialto unify myriad observations inDrosophilasleep studies. For example, Cv-c mayregulate trafficking or channel propertiesof the sleep-relevant Shaker postassiumchannel or Sleepless within FB neurons,adding cellular specificity to these mutantphenotypes. Or perhaps Cv-c modulatescAMP/PKA signaling, which has beenimplicated in fly sleep homeostasis aswell as dopamine inhibition of FB neu-rons. The model may also hint at possiblemechanisms to explain other unusualobservations. For example, starvationor methamphetamine sleep deprivesflies without apparent rebound (Andreticet al., 2005; Bushey and Cirelli, 2011),perhaps because they prolong wakeful-ness yet short-circuit Cv-c-dependentelectrical changes in FB neurons andblock sleep homeostatic responses.Finally, the question of whether themodel may be directly relevant to mam-mals should be addressed. Does the anal-ogy of the Drosophila sleep circuitry tothe mammalian flip-flop circuit extendeven to this nascent homeostasis model?One popular mammalian view envisionshomeostatic sleep processes working onlocal cortical circuits (Krueger et al.,2008), in part because local slow wavesrespond homeostatically to use-depen-dent changes in neuronal activity. Thisview also reflects another distinction be-tween mammalian and fly sleep rebound;namely, in mammals, sleep pressuremore consistently tracks with the depthFebruary 19, 2014 ª2014 Elsevier Inc. 721NeuronPreviewsof recovery than the amount of reboundsleep (Bushey andCirelli, 2011). However,sleep depth changes in flies have beenmeasured and could also be regulatedby the proposed homeostatic model(van Alphen et al., 2013). Furthermore,local mammalian sleep homeostats donot preclude the existence of additional,central mechanisms to relate sleep pres-sure to whole animal sleep. Indeed, arecent study found that the VLPO neuronsincrease their firing rate in response tosleep deprivation in a way that is sensitiveto adenosine antagonism, one of the ma-jor metabolites suspected to signal sleeppressure in mammals (Alam et al., 2014).To conclude, Donlea et al. (2014) haveidentified Cv-c as a molecular player insleep homeostasis and more importantlyhave localized the effects to specificsleep-promoting cells in the Drosophilabrain. Many questions remain, including722 Neuron 81, February 19, 2014 ª2014 Elswhether the FB response to sleep depri-vation also applies to the normal sleep-wake cycle, how sleep pressure is sensedby the FB cell, and how electrical excit-ability is restored following recoverysleep. While short on answers, the pro-posed model should now frame focusedquestions in Drosophila sleep researchand should inspire the wider sleep com-munity to investigate similar homeostaticmodels in a vertebrate context.REFERENCESAlam, M.A., Kumar, S., McGinty, D., Alam, M.N.,and Szymusiak, R. (2014). J. Neurophysiol. 111,287–299.Andretic, R., van Swinderen, B., and Greenspan,R.J. (2005). Curr. Biol. 15, 1165–1175.Borbe´ly, A.A. (1982). Hum. Neurobiol. 1, 195–204.Bushey, D., and Cirelli, C. (2011). Int. Rev. Neuro-biol. 99, 213–244.evier Inc.Donlea, J.M., Thimgan, M.S., Suzuki, Y., Gott-schalk, L., and Shaw, P.J. (2011). Science 332,1571–1576.Donlea, J.M., Pimentel, D., and Miesenbo¨ck, G.(2014). Neuron 81, this issue, 860–872.Krueger, J.M., Rector, D.M., Roy, S., Van Dongen,H.P.A., Belenky, G., and Panksepp, J. (2008). Nat.Rev. Neurosci. 9, 910–919.Pfeiffenberger, C., and Allada, R. (2012). PLoSGenet. 8, e1003003.Pilgram, G.S.K., Potikanond, S., van der Plas,M.C., Fradkin, L.G., and Noordermeer, J.N.(2011). J. Neurosci. 31, 492–500.Rihel, J., and Schier, A.F. (2013). Curr. Opin. Neu-robiol. 23, 831–840.Rogulja, D., and Young, M.W. (2012). Science 335,1617–1621.Saper, C.B., Fuller, P.M., Pedersen, N.P., Lu, J.,and Scammell, T.E. (2010). Neuron 68, 1023–1042.van Alphen, B., Yap, M.H.W., Kirszenblat, L.,Kottler, B., and van Swinderen, B. (2013).J. Neurosci. 33, 6917–6927.

A Drosophila Circuit Feels the (Sleep) Pressure

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A Drosophila Circuit Feels the (Sleep) Pressure

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