Available online at www.sciencedirect.

com

ScienceDirect

To sleep or not to sleep: neuronal and ecological

insights
Ada Eban-Rothschild, William J Giardino and Luis de Lecea

Daily, animals need to decide when to stop engaging in an appropriate time of day, while the homeostatic sleep
cognitive processes and behavioral responses to the process is responsible for maintaining a species-specific
environment, and go to sleep. The main processes regulating daily sleep balance. In addition, motivational processes
the daily organization of sleep and wakefulness are circadian such as food and mate seeking, and predator evasion can
rhythms and homeostatic sleep pressure. In addition, powerfully modulate sleep and wake states. Animals can
motivational processes such as food seeking and predator stay awake for extended periods, sleep longer, sleep
evasion can modulate sleep/wake behaviors. Here, we discuss lighter, or sleep with only half of their brain (unihemi-
the principal processes regulating the propensity to stay awake spheric sleep) in response to different internal and
or go to sleep—focusing on neuronal and behavioral aspects. external conditions. Here, we will review the principal
We first introduce the neuronal populations involved in sleep/ processes that regulate the propensity to stay awake or go
wake regulation. Next, we describe the circadian and to sleep, focusing on studies investigating neuronal and
homeostatic drives for sleep. Then, we highlight studies ecological aspects.
demonstrating various effects of motivational processes on
sleep/wake behaviors, and discuss possible neuronal
mechanisms underlying their control.
Neuronal circuitry of sleep/wake state
regulation
Address
In mammals, birds, and reptiles, there are three general
Department of Psychiatry and Behavioral Sciences, Stanford University, states of vigilance: wakefulness, non-rapid eye movement
1201 Welch Road, Stanford, CA 94305, USA (NREM) sleep, and rapid-eye movement (REM) sleep—
that differ in behavior, physiology, and brain electrical
Corresponding authors: Eban-Rothschild, Ada (adae@stanford.edu), de
activity. Over the last century numerous studies have
Lecea, Luis (llecea@stanford.edu)
contributed to the identification of distinct neuronal
populations in the mammalian brain that participate in
Current Opinion in Neurobiology 2017, 44:132–138 the regulation of sleep/wake states. It is currently under-
This review comes from a themed issue on Neurobiology of sleep stood that subcortical neuromodulatory neurons in the
Edited by Yang Dan and Thomas Kilduff
brainstem, midbrain, hypothalamus, and basal forebrain
interact with each other, the thalamus, and the cortex
For a complete overview see the Issue and the Editorial
to drive behavioral, physiological, and electrocortical
Available online 10th May 2017 sleep/wake states. Key components of the wake
http://dx.doi.org/10.1016/j.conb.2017.04.010 regulatory systems are the: (1) monoaminergic neurons
0959-4388/ã 2017 Elsevier Ltd. All rights reserved. (including noradrenergic, dopaminergic, serotonergic,
and histaminergic) of the locus coeruleus (LC), ventral
tegmental area (VTA), dorsal raphe nucleus (DRN), and
tuberomammillary nucleus (TMN); (2) cholinergic neu-
rons of the pedunculopontine and laterodorsal tegmental
nuclei (PPT/LDT), and basal forebrain (BF), and (3)
Introduction hypocretinergic (Hcrt; also known as orexinergic) neurons
Animals, including nematode worms, bees, flies, fish, of the lateral hypothalamus (LH) [3]. A balance between
rodents, humans, and even birds during migration, alter activity in wake-promoting and sleep-promoting neurons
between wake and sleep states, throughout their lives. [4], such as the GABAergic neurons of the ventrolateral
During wakefulness, animals engage in various adaptive preoptic area (VLPO) and brainstem, has been hypothe-
and motivated behaviors, including foraging, courting, sized as a model to understand sleep-to-wake transitions
mating, parenting, and predator evasion. Sleep is a state [5].
of quiescence with reduced responsiveness to external
stimuli, yet it is restorative and recruits essential mecha- Remarkably, the sleep/wake regulatory mechanisms and
nisms for homeostatic balance. How do animals decide neuromodulatory systems involved are highly conserved
whether and when to alternate between sleep and among the animal kingdom [6,7]. For example, in both
wakefulness? The two main processes that regulate the mammals and insects, dopaminergic (mammals: [8,9];
daily organization of sleep and wake periods are circadian insects: [10,11]), noradrenergic (mammals: [12]; insects:
rhythms and homeostatic sleep pressure [1,2]. The [13]), and histaminergic (mammals: [14]; insects: [15])
circadian clock (24 hours long) synchronizes sleep to transmissions promote wakefulness, while GABAergic

Current Opinion in Neurobiology 2017, 44:132–138 www.sciencedirect.com

 Neuronal and ethological underpinnings of sleep Eban-Rothschild, Giardino and de Lecea 133

(mammals: [4]; insects: [16,17]) and serotonergic (mam- Sik3 serine-threonine protein kinase involved in the
mals: [18]; insects: [19]) transmissions promote sleep. transduction of the mTOR pathway [38]. Sleepy mutants
This conservation suggests an ancient and common origin show increased NREM sleep amount. Dreamless mutants,
for sleep [6]. that have a mutation in the sodium leak channel NALCN,
show a decrease in REM sleep amount and episode
Circadian regulation of sleep/wake states duration [38]. Although the precise mechanisms by
Animals typically sleep in a specific phase of the day, for which these mutations modulate sleep need are still
example, night in diurnal species. This pattern of unclear, the use of an unbiased forward-genetics approach
sleep/wake organization follows the light-dark cycle, in mammals will likely lead to major insights into the
but also persists in the absence of environmental pathways and mechanisms of sleep regulation.
cues—demonstrating the existence of an internal
regulatory mechanism. This internal rhythm is generated Motivational control of sleep/wake states
by a circadian clock (24 hours long), that regulates Motivational processes can powerfully modulate the pro-
numerous physiological and behavioral processes includ- pensity to stay awake or go to sleep. When motivated,
ing the sleep/wake cycle. The circadian clock can be humans can stay awake and engage in various cognitive
synchronized to the environment by different cues (or and physical activities far beyond their physiological bed
Zeitgebers) [5,20], such as light [21], temperature [22], food time while ignoring the circadian and homeostatic sleep
availability [23], and social interactions [24,25]. Internal drives. In the wild, foraging and mating opportunities and
clocks are advantageous to animals, enabling them to the presence of predators drive motivational responses
predict daily recurring events – even in the absence of and modulate arousal. Animals can stay awake for
environmental cues – and aligning their internal processes extended periods, sleep longer, sleep lighter, or show
to the environment [20,26], as for feeding and metabolism unihemispheric sleep in response to different internal and
[27]. In mammals, overt rhythmicity is coordinated by the external conditions (Figure 1).
central pacemaker located in the suprachiasmatic nucleus
(SCN) of the hypothalamus [28], although various circa- Hunger can drive arousal and locomotor activity and
dian oscillators are present throughout the brain [29,30]. It suppress sleep [39–41,42,43], probably to favor foraging
is hypothesized that the major output region of the SCN behavior. The presence of predators or predator cues can
in regard to sleep/wake regulation is the dorsomedial also modulate sleep/wake states [44], reduce sleep [45] or
nucleus of the hypothalamus, which heavily innervates induce frequent arousals [46–48]. The motivation to mate
sleep- and wake-promoting nuclei via the subparaventri- and reproduce is a strong driving force in animals’ behav-
cular zone [28,31]. Nonetheless, the precise roles of the ior, yet limited studies examined the capacity of this
SCN in sleep/wake state synchronization, sleep structure motivation to drive wakefulness. One notable study not
and sleep quality, as well as the role of additional circa- only demonstrated that the motivation to mate can pow-
dian oscillators in sleep/wake regulation, remain to be erfully affect sleep and wake states, but that this plasticity
elucidated. increases the fitness of animals [49]. Male polygynous
pectoral sandpipers (Calidris melanotos) are able to greatly
Homeostatic regulation of sleep/wake states reduce sleep duration, to as little as 2 hours/day during a
As for other homeostatically regulated processes, such as 3-week period of same-sex competition for access to
hunger and thirst, the need for sleep accumulates as fertile females [49]. Remarkably, the males that slept
wakefulness is extended and only dissipates during sleep. the least had the highest breeding success—measured as
How is this regulation attained? Recent studies in Dro- the number of young sired [49].
sophila provided important insights regarding the mecha-
nisms and circuits that mediate the homeostatic drive, Birds can significantly reduce their daily sleep duration
and raise the intriguing possibility that sleep need is over long migratory [50] and foraging [42] flights. For
sensed by a master control center [32]. In mammals, example, great frigatebirds (Fregata minor) can spend only
the precise identity, location of action, and mechanisms of 0.7 hour/day sleeping while on foraging flight in contrast
the homeostatic regulation of sleep remain unclear. More to 12.8 hours/day while on land [42]. In addition to sleep
than a century ago, researchers discovered that the cere- suppression, birds (and other animals, see below) can
brospinal fluid of sleep deprived animals contained sub- show unihemispheric sleep; during which only one of
stances that promote sleep [33,34]. Among the proposed the hemispheres engages in slow-wave activity, while the
substances and mechanisms involved in promoting sleep other is in the awake state and the eye contralateral to the
are the neuromodulator adenosine, and its receptors A1 awake hemisphere is open [51]. Unihemispheric sleep
and A2A, as well as cytokines such as interleukin-1 and enables the individual to simultaneously engage in two
tumor necrosis factor-a, prostaglandin D2, and Nitric otherwise mutually exclusive tasks; sleep and attention
oxide (NO) [35–37]. A recent forward-genetics screen [51]. Mallard ducks (Anas platyrhynchos) undergo unihemi-
in mice revealed two sleep mutants, Sleepy and spheric sleep while under the risk of predation [52,53],
Dreamless [38]. Sleepy is a gain-of-function mutant of and other birds during long flights [54]. Marine mammals

www.sciencedirect.com Current Opinion in Neurobiology 2017, 44:132–138

134 Neurobiology of sleep

Figure 1

Sleep
Yes debt No

Circadian
Inactive phase time Active phase

Metabolic
Satiety state Hunger

Immune
Sleep Inflammation function Elevated
Wakefullness
corticosterone

Predation
Species-specific risk Species-specific

Mating
No opportunities Yes

Seasonal and
No migratory status Yes

Current Opinion in Neurobiology

A schematic of the main factors controlling sleep/wake states. Multiple internal and external signals can modulate the propensity of animals to
stay awake or to go to sleep. Distributed networks in the brain integrate these often-conflicting variables to generate a coherent output that results
in consolidated sleep.

show unihemispheric sleep [55] allowing them to keep precursor and are expressed in a glutamatergic neuronal
swimming and breathing, and taking continuous care of population in the LH. Hcrt neurons project to most sleep/
young. Interestingly, other mammals, including rodents wake regulatory nuclei, which express either, or both, of
and humans, can show local slow-wave sleep in cortical the two Hcrt receptors [64]. Transgenic mice in which
areas [56–58], as well as in individual neurons [59] while Hcrt neurons are ablated (Hcrt ataxin3 mice) do not
behaviorally awake. show an increase in wakefulness or locomotion following
fasting [63]. In addition to integrating cues from the
What are the neuronal mechanisms underlying the environment, Hcrt neurons are critical regulators of
arousal response in face of various environmental and brain reward function, in part by modulating VTA dopa-
homeostatic processes? LH Hcrt neurons have been minergic neurons [65,66]. VTA dopaminergic neurons are
suggested to mediate the increase in wakefulness in principal regulators of motivational processes [67], and
response to stressful conditions [60–62], including regulate sleep/wake states and arousal in face of various
reduced food availability [63]. The Hcrts are two neuro- ethologically-relevant salient stimuli [8]. Chemogenetic
peptides, Hcrt-1 and Hcrt-2, produced from a single [68] inhibition of VTA dopaminergic neurons prevent the

Current Opinion in Neurobiology 2017, 44:132–138 www.sciencedirect.com

 Neuronal and ethological underpinnings of sleep Eban-Rothschild, Giardino and de Lecea 135

maintenance of wakefulness even in the presence of a Consolidating sleep/wake states

potential mate, palatable food and predator scent [8]. Once animals enter wakefulness or sleep, they need to
Future studies examining the necessity of the different maintain the behavioral and physiological state for the
sleep/wake regulatory circuits to arousal if face of various duration necessary to fulfill its physiological purposes. A
motivational processes should deepen our understanding failure to prevent unwanted transitions between wake-
of the link between motivational processes and sleep/ fulness and sleep could result in severe fitness conse-
wake regulation. quences. For example, the survival of animals could be at
risk if a predator defense behavior would be interrupted
Individuals can vary in their capacity to regulate arousal in by unexpected transitions to sleep. In addition, the
response to specific internal and external needs (for restorative and memory consolidation functions of sleep
example, Ref. [49]), possibly due to differences in their are dependent upon proper consolidation of sleep [78–
underlying neuronal machinery. It would be of interest 80]. How do sleep/wake regulatory circuits maintain the
to examine the costs and benefits of this capacity in boundaries between the vigilance states? The Hcrt sys-
various ecologically-relevant conditions. For example, tem is hypothesized to orchestrate the structural organi-
whether individuals with a higher capacity to stay awake zation of sleep/wake states. Hcrt LH neurons are essential
and suppress their sleep to favor motivational processes for the stability of arousal, and malfunction of the Hcrt
(such as mate seeking) will show disadvantages in other network fragments sleep and wake states. The loss of
aspects (such as attentional processes). In addition, it Hcrt-producing neurons or their receptors in rodents,
would be of interest to examine whether reward-related canines, and humans is associated with narcolepsy/cata-
ecologically-relevant demands (such as mate seeking), plexy—a neurological disorder characterized by an inabil-
that reduce or fragment sleep, result in minor negative ity to control the boundaries between sleep/wake states
consequences on animal physiology as compared to [64]. In narcoleptics, periods of wakefulness are inter-
stressful or lab-induced sleep disturbances [54]. Future rupted by unexpected sleep episodes, and REM-like
studies comparing the consequences of sleep/wake episodes co-exist with conscious wakefulness [64]. Trans-
disturbances under different naturalistic environments genic mice lacking Hcrt neurons or Hcrt receptor R2 show
should increase our understanding of the evolution of increased arousal state transitions, but do not vary in the
sleep/wake cycles. total daily duration of sleep and wake states from control
animals. Optogenetic [81] stimulation of Hcrt LH neu-
rons in mice increases the probability for a sleep-to-wake
Motivation to sleep transitions [82], whereas optogenetic, chemogenetic, or
Animals do not just fall asleep, literally speaking, but pharmacological inhibition of Hcrt neurons induces sleep
rather prepare themselves for sleep, and display species- [83–85].
specific behaviors [69–71]. Lizards [72], birds, rodents
[73], great apes [74,75], humans, and even fish [76] among Conclusions
many others, search for a safe and comfortable place to During the last decades, major advances have been made
sleep, may build a nest or a bed, take a species-specific in characterizing the neuronal populations participating in
posture, and engage in other behaviors, such as grooming, sleep/wake regulation. It is now possible to further
before going to sleep. In the wild, the selection of a explore how information from the diverse sleep/wake
sleeping site could have a strong impact on fitness, as regulatory populations is integrated to control overt
the sites may provide protection from predation, shelter arousal, and how diverse external and internal inputs
from thermal challenges, access to food resources, and be modulate the regulatory capacities of these circuits. In
advantageous for territorial defense [44,69]. Remarkably, addition, relatively little is known on the neuronal mech-
the neuronal substrates regulating this sleep-preparatory anism regulating sleep under natural or semi-natural
phase remain poorly understood. Our recent findings conditions. Outstanding questions remain, including
suggest that during this sleep-preparatory phase the how distinct sleep/wake regulatory populations regulate
motivational state of animals is shifted from wake-related arousal in naturalistic environments, how different selec-
goal-directed behaviors to sleep-related but still goal- tive pressures modulate sleep behavior, and what are the
directed behaviors, such as nest-building [8]. Moreover, contributions of sleep to survival and reproduction in the
our data suggest that neurotransmitter systems/brain cir- wild.
cuits involved in wake-related behaviors, such as VTA
dopaminergic neurons [8], need to be suppressed for Conflict of interest statement
animals to prepare for sleep. Although the term motivation Nothing declared.
has traditionally been used to describe the drive to engage
in wake-related behaviors, there seems to be a motivation
to sleep that could recruit distinct neuronal circuits and Acknowledgments
This work was supported by the Edmond and Lily Safra Center of Brain
behavioral repertoires—with the ultimate goal of attain- Science (ELSC) and Katharine McCormick Advanced postdoctoral
ing sleep [8,77]. fellowships (A.E.-R.), the NIH grants: F32-AA022832 (W.J.G.),

www.sciencedirect.com Current Opinion in Neurobiology 2017, 44:132–138

136 Neurobiology of sleep

R01-MH087592, R01-MH102638, and R01-AG04767 (L.d.L.), a Brain and 15. Oh Y, Jang D, Sonn JY, Choe J: Histamine-HisCl1 receptor axis
Behavior Research Foundation (NARSAD) Grant (L.d.L), a Merck Grant regulates wake-promoting signals in Drosophila
(L.d.L) and a Johnson & Johnson Grant. (L.d.L.) and the US Israel melanogaster. PLoS One 2013, 8:e68269.
Binational Science Foundation (L.d.L.).
16. Agosto J, Choi JC, Parisky KM, Stilwell G, Rosbash M, Griffith LC:
Modulation of GABAA receptor desensitization uncouples
References and recommended reading sleep onset and maintenance in Drosophila. Nat. Neurosci.
Papers of particular interest, published within the period of review, 2008, 11:354-359.
have been highlighted as: 17. Parisky KM, Agosto J, Pulver SR, Shang Y, Kuklin E, Hodge JJ,
Kang K, Liu X, Garrity PA, Rosbash M et al.: PDF cells are a
 of special interest GABA-responsive wake-promoting component of the
 of outstanding interest Drosophila sleep circuit. Neuron 2008, 60:672-682.

1. Borbely AA, Achermann P: Sleep homeostasis and models of 18. McGinty DJ, Harper RM: Dorsal raphe neurons: depression of
sleep regulation. J. Biol. Rhythms 1999, 14:557-568. firing during sleep in cats. Brain Res. 1976, 101:569-575.

2. Borbely AA, Daan S, Wirz-Justice A, Deboer T: The two-process 19. Yuan Q, Joiner WJ, Sehgal A: A sleep-promoting role for the
model of sleep regulation: a reappraisal. J. Sleep Res. 2016, Drosophila serotonin receptor 1A. Curr. Biol. 2006, 16:1051-
25:131-143. 1062.
3. Scammell TE, Arrigoni E, Lipton JO: Neural circuitry of 20. Albrecht U: Timing to perfection: the biology of central and
wakefulness and sleep. Neuron 2017, 93:747-765. peripheral circadian clocks. Neuron 2012, 74:246-260.
4. Luppi PH, Peyron C, Fort P: Not a single but multiple 21. Gooley JJ, Lu J, Fischer D, Saper CB: A broad role for
 populations of GABAergic neurons control sleep. Sleep Med. melanopsin in nonvisual photoreception. J. Neurosci. 2003,
Rev. 2016. 23:7093-7106.
A review that summarizes recent advances in our understanding of the
roles of different GABAergic populations across the brain in the regulation 22. Buhr ED, Yoo SH, Takahashi JS: Temperature as a universal
of NREM and REM sleep. resetting cue for mammalian circadian oscillators. Science
2010, 330:379-385.
5. Saper CB, Fuller PM, Pedersen NP, Lu J, Scammell TE: Sleep
state switching. Neuron 2010, 68:1023-1042. 23. Stephan FK: The “other” circadian system: food as a Zeitgeber.
J. Biol. Rhythms 2002, 17:284-292.
6. Allada R, Siegel JM: Unearthing the phylogenetic roots of sleep.
Curr. Biol. 2008, 18:R670-R679. 24. Fuchikawa T, Eban-Rothschild A, Nagari M, Shemesh Y, Bloch G:
7. Nall A, Sehgal A: Monoamines and sleep in Drosophila. Behav. Potent social synchronization can override photic entrainment
 Neurosci. 2014, 128:264-272. of circadian rhythms. Nat. Commun. 2016, 7:11662.
A review that summarizes the various roles of dopamine, serotonin, 25. Bloch G, Herzog ED, Levine JD, Schwartz WJ: Socially
histamine and octopamine in sleep–wake regulation synchronized circadian oscillators. Proc. Biol. Sci. 2013,
in Drosophila. They describe the input and output pathways of these 280:20130035.
monoamine and mechanisms of actions.
8. Eban-Rothschild A, Rothschild G, Giardino WJ, Jones JR, de 26. Sharma VK: Adaptive significance of circadian clocks.
 Lecea L: VTA dopaminergic neurons regulate ethologically Chronobiol. Int. 2003, 20:901-919.
relevant sleep-wake behaviors. Nat. Neurosci. 2016. 27. Asher G, Schibler U: Crosstalk between components of
This study provides the first causal demonstration that VTA dopaminergic circadian and metabolic cycles in mammals. Cell Metab. 2011,
neurons regulate sleep–wake behaviors. Using optogenetic and chemo- 13:125-137.
genetic tools the authors demonstrate that activity in VTA dopaminergic
neurons promotes wakefulness and wake-related behaviors, while their 28. Saper CB: The central circadian timing system. Curr. Opin.
inhibition promotes sleep or sleep-related behaviors. Neurobiol. 2013, 23:747-751.
9. Taylor NE, Van Dort CJ, Kenny JD, Pei J, Guidera JA, Vlasov KY, 29. Guilding C, Piggins HD: Challenging the omnipotence of the
 Lee JT, Boyden ES, Brown EN, Solt K: Optogenetic activation of suprachiasmatic timekeeper: are circadian oscillators present
dopamine neurons in the ventral tegmental area induces throughout the mammalian brain? Eur. J. Neurosci. 2007,
reanimation from general anesthesia. Proc. Natl. Acad. Sci. U. 25:3195-3216.
S. A. 2016.
This study demonsrates that optogenetic activation of VTA dopaminergic 30. Dibner C, Schibler U, Albrecht U: The mammalian circadian
neurons is sufficuent to restore the righting reflex and behavioral arousal timing system: organization and coordination of central and
from isoflurane-induced anesthesia. The capasity of these neurons to peripheral clocks. Annu. Rev. Physiol. 2010, 72:517-549.
restore arousal was mediated by D1 receptors.
31. Deurveilher S, Semba K: Indirect projections from the
10. Andretic R, van Swinderen B, Greenspan RJ: Dopaminergic suprachiasmatic nucleus to major arousal-promoting cell
modulation of arousal in Drosophila. Curr. Biol. 2005, 15:1165- groups in rat: implications for the circadian control of
1175. behavioural state. Neuroscience 2005, 130:165-183.
11. Kume K, Kume S, Park SK, Hirsh J, Jackson FR: Dopamine is a
regulator of arousal in the fruit fly. J. Neurosci. 2005, 25:7377- 32. Donlea JM, Pimentel D, Miesenbock G: Neuronal machinery of
7384.  sleep homeostasis in Drosophila. Neuron 2014, 81:860-872.
The authors have identified sleep-promoting neurons of the dorsal FB as
12. Aston-Jones G, Bloom FE: Activity of norepinephrine- the effector arm of Drosophila’s sleep homeostat. Moreover, they found
containing locus coeruleus neurons in behaving rats that ion channel modulation in these neurons transduces sleep pressure
anticipates fluctuations in the sleep-waking cycle. J. Neurosci. into increased sleep.
1981, 1:876-886.
33. Ishimori K: True cause of sleep: a hypnogenic substance as
13. Crocker A, Sehgal A: Octopamine regulates sleep in drosophila evidenced in the brain of sleep-deprived animals. Tokyo Igakkai
through protein kinase A-dependent mechanisms. J. Neurosci. Zasshi 1909, 23:429-457.
2008, 28:9377-9385.
34. Legendre R, Pieron H: Recherches sur le besoin de sommeil
14. Parmentier R, Ohtsu H, Djebbara-Hannas Z, Valatx JL, consecutif a une veille prolongee. Z Allgem Physiol 1913,
Watanabe T, Lin JS: Anatomical, physiological, and 14:235-262.
pharmacological characteristics of histidine decarboxylase
knock-out mice: evidence for the role of brain histamine in 35. Brown RE, Basheer R, McKenna JT, Strecker RE, McCarley RW:
behavioral and sleep-wake control. J. Neurosci. 2002, Control of sleep and wakefulness. Physiol. Rev. 2012,
22:7695-7711. 92:1087-1187.

Current Opinion in Neurobiology 2017, 44:132–138 www.sciencedirect.com

 Neuronal and ethological underpinnings of sleep Eban-Rothschild, Giardino and de Lecea 137

36. Mang GM, Franken P: Genetic dissection of sleep homeostasis. 56. Huber R, Ghilardi MF, Massimini M, Tononi G: Local sleep and
Curr. Top. Behav. Neurosci. 2015, 25:25-63. learning. Nature 2004, 430:78-81.
37. Benington JH, Heller HC: Restoration of brain energy 57. Krueger JM, Rector DM, Roy S, Van Dongen HP, Belenky G,
metabolism as the function of sleep. Prog. Neurobiol. 1995, Panksepp J: Sleep as a fundamental property of neuronal
45:347-360. assemblies. Nat. Rev. Neurosci. 2008, 9:910-919.

38. Funato H, Miyoshi C, Fujiyama T, Kanda T, Sato M, Wang Z, Ma J, 58. Nir Y, Staba RJ, Andrillon T, Vyazovskiy VV, Cirelli C, Fried I,
 Nakane S, Tomita J, Ikkyu A et al.: Forward-genetics analysis of Tononi G: Regional slow waves and spindles in human sleep.
sleep in randomly mutagenized mice. Nature 2016, 539:378- Neuron 2011, 70:153-169.
383.
59. Vyazovskiy VV, Olcese U, Hanlon EC, Nir Y, Cirelli C, Tononi G:
The authors used forward genetics in randomly mutagenized mice to
Local sleep in awake rats. Nature 2011, 472:443-447.
identify two novel molecular determinants of sleep, one that exhibit
increased NREM sleep (Sleepy) while the other exhibited decreased 60. Winsky-Sommerer R, Boutrel B, de Lecea L: Stress and arousal:
REM sleep (Dreamless). the corticotrophin-releasing factor/hypocretin circuitry. Mol.
Neurobiol. 2005, 32:285-294.
39. Borbely AA: Sleep in the rat during food deprivation and
subsequent restitution of food. Brain Res. 1977, 124:457-471. 61. Mahler SV, Moorman DE, Smith RJ, James MH, Aston-Jones G:
Motivational activation: a unifying hypothesis of orexin/
40. Danguir J, Nicolaidis S: Dependence of sleep on nutrients’ hypocretin function. Nat. Neurosci. 2014, 17:1298-1303.
availability. Physiol. Behav. 1979, 22:735-740.
62. Bonnavion P, Jackson AC, Carter ME, de Lecea L: Antagonistic
41. Dewasmes G, Duchamp C, Minaire Y: Sleep changes in fasting interplay between hypocretin and leptin in the lateral
rats. Physiol. Behav. 1989, 46:179-184. hypothalamus regulates stress responses. Nat. Commun.
2015, 6:6266.
42. Rattenborg NC, Voirin B, Cruz SM, Tisdale R, Dell’Omo G, Lipp HP,
 Wikelski M, Vyssotski AL: Evidence that birds sleep in mid- 63. Yamanaka A, Beuckmann CT, Willie JT, Hara J, Tsujino N,
flight. Nat. Commun. 2016, 7:12468. Mieda M, Tominaga M, Yagami K, Sugiyama F, Goto K et al.:
This is the first demonstration that birds can sleep during long flights. Hypothalamic orexin neurons regulate arousal according to
Great frigatebirds can sleep with either one hemisphere at a time or both energy balance in mice. Neuron 2003, 38:701-713.
hemispheres simultaneously while on long flights. In addition, the authors
demonstrate that the birds dramatically reduce their daily sleep duration 64. de Lecea L: Optogenetic control of hypocretin (orexin) neurons
during these periods. and arousal circuits. Curr. Top. Behav. Neurosci. 2015, 25:367-
378.
43. Jacobs BL, McGinty DJ: Effects of food deprivation on sleep
and wakefulness in the rat. Exp. Neurol. 1971, 30:212-222. 65. Borgland SL, Chang SJ, Bowers MS, Thompson JL, Vittoz N,
Floresco SB, Chou J, Chen BT, Bonci A: Orexin A/hypocretin-1
44. Lima SL, Rattenborg NC, Lesku JA, Amlaner CJ: Sleeping under selectively promotes motivation for positive reinforcers. J.
the risk of predation. Anim. Behav. 2005, 70:723-736. Neurosci. 2009, 29:11215-11225.

45. Lesku JA, Bark RJ, Martinez-Gonzalez D, Rattenborg NC, 66. Boutrel B, Kenny PJ, Specio SE, Martin-Fardon R, Markou A,
Amlaner CJ, Lima SL: Predator-induced plasticity in sleep Koob GF, de Lecea L: Role for hypocretin in mediating stress-
architecture in wild-caught Norway rats (Rattus norvegicus). induced reinstatement of cocaine-seeking behavior. Proc.
Behav. Brain Res. 2008, 189:298-305. Natl. Acad. Sci. U. S. A. 2005, 102:19168-19173.

46. Lendrem DW: Sleeping and vigilance in birds, II. An 67. Salamone JD, Pardo M, Yohn SE, Lopez-Cruz L, SanMiguel N,
experimental study of the Barbary dove (Streptopelia risoria). Correa M: Mesolimbic dopamine and the regulation of
Anim. Behav. 1984, 32:243-248. motivated behavior. Curr. Top. Behav. Neurosci. 2016, 27:231-
257.
47. Gauthier-Clerc M, Tamisier A, Cezilly F: Sleep-vigilance trade-off 68. Sternson SM, Roth BL: Chemogenetic tools to interrogate brain
in Green-winged Teals (Anas crecca crecca). Can. J. Zool. 1998, functions. Annu. Rev. Neurosci. 2014, 37:387-407.
76:2214-2218.
69. Meddis R: On the function of sleep. Anim. Behav. 1975, 23:676-
48. Dominguez J: Sleeping and vigilance in Black-tailed Godwit. J. 691.
Ethol. 2003, 21:57-60.
70. Hediger H: Comparative observations on sleep. Proc. R. Soc.
49. Lesku JA, Rattenborg NC, Valcu M, Vyssotski AL, Kuhn S, Med. 1969, 62:153-156.
Kuemmeth F, Heidrich W, Kempenaers B: Adaptive sleep loss in
polygynous pectoral sandpipers. Science 2012, 337:1654-1658. 71. Parmeggiani PL: Behavioral phenomenology of sleep (somatic
and vegetative). Experientia 1980, 36:6-11.
50. Rattenborg NC, Mandt BH, Obermeyer WH, Winsauer PJ,
Huber R, Wikelski M, Benca RM: Migratory sleeplessness in the 72. Singhal S, Johnson MA, Ladner JT: The behavioral ecology of
white-crowned sparrow (Zonotrichia leucophrys gambelii). sleep: natural sleeping site choice in three Anolis lizard
PLoS Biol. 2004, 2:E212. species. Behaviour 2007, 144:1033-1052.

51. Rattenborg NC, Amlaner CJ, Lima SL: Behavioral, 73. Latham N, Mason G: From house mouse to mouse house: the
neurophysiological and evolutionary perspectives on behavioural biology of free-living Mus musculus and its
unihemispheric sleep. Neurosci. Biobehav. Rev. 2000, 24:817- implications in the laboratory. Appl. Anim. Behav. Sci. 2004,
842. 86:261-289.

52. Rattenborg NC, Lima SL, Amlaner CJ: Facultative control of 74. Anderson JR: Sleep, sleeping sites, and sleep-related
avian unihemispheric sleep under the risk of predation. Behav. activities: awakening to their significance. Am. J. Primatol.
Brain Res. 1999, 105:163-172. 1998, 46:63-75.
75. Stewart FA: Brief communication: why sleep in a nest?
53. Rattenborg NC, Lima SL, Amlaner CJ: Half-awake to the risk of
Empirical testing of the function of simple shelters made by
predation. Nature 1999, 397:397-398.
wild chimpanzees. Am. J. Phys. Anthropol. 2011, 146:313-318.
54. Rattenborg NC: Sleeping on the wing. Interface Focus 2017, 7. 76. Winn HE: Formation of a mucous envelope at night by parrot
 review that summarizes work on plasticity in sleep in birds. The authors
A fishes. Zool. N. Y. 1955, 40:145-148.
discuss the implications of recent findings demonstrating adaptive sleep
loss and unihemishperic sleep. 77. Moruzzi G: Sleep and instinctive behavior. Arch. Ital. Biol. 1969,
107:175-216.
55. Lyamin OI, Manger PR, Ridgway SH, Mukhametov LM, Siegel JM:
Cetacean sleep: an unusual form of mammalian sleep. 78. Roth T: Insomnia: definition, prevalence, etiology, and
Neurosci. Biobehav. Rev. 2008, 32:1451-1484. consequences. J. Clin. Sleep Med. 2007, 3:S7-S10.

www.sciencedirect.com Current Opinion in Neurobiology 2017, 44:132–138

138 Neurobiology of sleep

79. Mignot E, Taheri S, Nishino S: Sleeping with the hypothalamus: 83. Sasaki K, Suzuki M, Mieda M, Tsujino N, Roth B, Sakurai T:
emerging therapeutic targets for sleep disorders. Nat. Pharmacogenetic modulation of orexin neurons alters sleep/
Neurosci. 2002, 5(Suppl):1071-1075. wakefulness states in mice. PLoS One 2011, 6:e20360.
80. Rolls A, Colas D, Adamantidis A, Carter M, Lanre-Amos T, 84. Tsunematsu T, Kilduff TS, Boyden ES, Takahashi S, Tominaga M,
Heller HC, de Lecea L: Optogenetic disruption of sleep Yamanaka A: Acute optogenetic silencing of orexin/hypocretin
continuity impairs memory consolidation. Proc. Natl. Acad. Sci. neurons induces slow-wave sleep in mice. J. Neurosci. 2011,
U. S. A. 2011, 108:13305-13310. 31:10529-10539.
81. Tye KM, Deisseroth K: Optogenetic investigation of neural 85. Alam MN, Kumar S, Suntsova N, Bashir T, Szymusiak R,
circuits underlying brain disease in animal models. Nat. Rev. McGinty D: GABAergic regulation of the perifornical-lateral
Neurosci. 2012, 13:251-266. hypothalamic neurons during non-rapid eye movement sleep
in rats. Neuroscience 2010, 167:920-928.
82. Adamantidis AR, Zhang F, Aravanis AM, Deisseroth K, de Lecea L:
Neural substrates of awakening probed with optogenetic
control of hypocretin neurons. Nature 2007, 450:420-424.

Current Opinion in Neurobiology 2017, 44:132–138 www.sciencedirect.com