Sleep homeostasis

Sleep homeostasisTarja Porkka-Heiskanen

Available online at www.sciencedirect.com

Research on sleep homeostasis aims to answer the question:

how does the brain measure the duration and intensity of

previous wakefulness in order to increase the duration and

intensity of subsequent sleep? The search of regulatory factors

has identified a number of potential molecules that increase

their concentration in waking and decrease it during sleep.

These factors regulate many physiological functions, including

energy metabolism, neural plasticity and immune functions and

one molecule may participate in the regulation of all these

functions. The method to study regulation of sleep homeostasis

is experimental prolongation of waking, which is used also to

address the question of physiological purpose of sleep:

prolonging wakefulness provokes symptoms that tell us what

goes wrong during lack of sleep. The interpretation of the role of

each identified factor in the regulation of sleep/sleep

homeostasis reflects the theoretical background concept of the

research. Presently three main concepts are being actively

studied: the energy (depletion) hypothesis, the neural plasticity

hypothesis and the (immune) defense hypothesis.

Address

University of Helsinki, Institute of Biomedicine, Department of

Physiology, PO Box 63, 00014 University of Helsinki, Finland

Corresponding author: Porkka-Heiskanen, Tarja

([email protected])

Current Opinion in Neurobiology 2013, 23:799–805

This review comes from a themed issue on Circadian rhythm andsleep

Edited by Clifford Saper and Amita Sehgal

For a complete overview see the Issue and the Editorial

Available online 17th March 2013

0959-4388/$ – see front matter, # 2013 Elsevier Ltd. All rights

reserved.

http://dx.doi.org/10.1016/j.conb.2013.02.010

IntroductionSleep homeostasis means that a prolonged period of

wakefulness is followed by a prolonged period of sleep.

Sleep in mammals and birds sleep consists of two main

phases: non-REM (NREM) sleep and REM sleep. These

phases are regulated by separate mechanisms but both are

under homeostatic control, as evidenced by an increase in

both NREM and REM sleep after total sleep deprivation

and in REM sleep only after a specific REM sleep

deprivation. However, the mechanisms of REM sleep

homeostasis are poorly understood, and accordingly,

this presentation will concentrate on NREM sleep

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homeostasis, and use the term ‘sleep homeostasis’ also

when actually speaking of NREM sleep homeostasis.

After a prolonged period of wakefulness, the subsequent

sleep period is enriched with slow wave activity (SWA or

SWS). On the basis of EEG recordings in both humans

and animals, the regulation of sleep homeostasis has been

modeled in the two-process model of sleep regulation by

Borbely [1]. The model describes the increase in sleep

propensity (‘sleep pressure’), starting from the moment of

awakening and continuing till the moment of falling

asleep: the longer the waking period, the more sleep

pressure is accumulated in brain and the longer it takes

to dissipate it in sleep (recovery sleep).

Experimentally sleep homeostasis is addressed by sleep

deprivation: the period of spontaneous waking is pro-

longed, usually by increasing sensory stimulation or motor

activity, and its effects on (sleep) EEG as well as many

physiological parameters are recorded during and after

the prolonged waking period. Restriction of sleep induces

a large amount of physiological changes from gene

expression to metabolism and behavior [2], and it is

not trivial to conclude which of these changes are directly

related to regulation of sleep homeostasis and which are

coincidental, related to, for example, changes of energy

consumption or stress. Criteria for a sleep/homeostatic

factor have been created to overcome this problem [3].

This article will introduce a selection of factors that fulfill

all or most of these criteria (Table 1).

Key questions of sleep homeostasis are: first, is recovery

sleep produced by the same factors that regulate spon-

taneous sleep–wake cycle, or are additional mechanisms

initiated during prolonged wakefulness?; second, what are

the molecular correlates of sleep propensity?; and third,

what anatomical sites participate in the regulation of sleep

homeostasis?

Sleep deprivation is often used also to clarify the purpose

of sleep, and the interpretations of the results reflect the

many theories about this purpose. Interestingly, many of

the relevant molecules (fulfilling the criteria of a sleep

factor) have multiple physiological functions, and thus

not only one but several theories find support from the

same results. The theories of sleep function fall to three

main functional categories: energy metabolism, neural

plasticity, and (cellular) defense (Table 2).

Sleep propensity

The core of the sleep homeostasis is sleep propensity, or

sleep pressure that arises from waking. While SWA is the


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800 Circadian rhythm and sleep

Table 1

Humoral substances that have been shown to regulate sleep homeostasis

Substance Molecule type Known functions Produced Species studied for

sleep

Mechanism in

sleep SWA

increase

Site of action in sleep

regulation

ADE Energy carrier,

co-neurotransmitter

Signals for energy

depletion Inhibits

neuronal activity

through A1 receptors

and activates it

through A2a

receptors

In all cells Cat, rat, mouse,

Djungarian hamster,

human, Drosophila,

Zebra fish

Inhibition of

wake-promoting

cells, activation of

sleep-promoting

cells

Basal forebrain,

VLPOA,

subarachnoidal

space, cortex (?)

NO Gaseous

neuromodulator

Vasodilatation,

energy metabolism,

through iNOS also

immune function

Glia, BF cholinergic

neurons

Rat, mice, rabbit Release of

adenosine

Basal forebrain,

cortex?

BDNF Neural growth

factor

Synapse formation Neurons Rat, rabbit,

Drosophila

Synaptic function,

other???

Cortex

TNFa Cytokine Immune function,

synapse formation

Glia (astorocytes) Rat, rabbit, mice,

human

Increase in

adenosine, Direct

synaptic function?

Cortex, monoamine

neurons

IL-1 Cytokine Immune function Glia Rat, rabbit, mice,

human

PGD2 Prostaglandin Vasodilatation,

bronchoconstriction

Microglia,

leptomeninges?

Rat, mice, rabbit Increase in

adenosine

Leptomeninges

below basal forebrain

GHRH Peptide hormone Growth hormone

secretion

Hypothalamus Rat, mice, rabbit,

human

GABA, direct

effect on synaptic

function?

Hypothalamus

Table 2

Connection of sleep factors to physiological functions

Function ADE NO BDNF TNFa IL-1b PGD2 GHRH

Neural plasticity ++ + +++ +++ + ? ?

Energy metabolism +++ +++ ++ � � + (?) +

Cellular defense + +++ + +++ +++ +++ �

+++ = strong connection, ++ = connection established, + = some indication of connection.

best marker of sleep homeostasis during sleep [1], the

increase in sleep propensity can be measured as increase

in theta activity during waking, both in humans and

animals [4�,5,6]. But what are the molecular correlates

of sleep pressure? Or, in other words, what is the phys-

iological variable or entity that is regulated for maintain-

ing stability? On the basis of an assumption that the

information of the duration of wakefulness is mediated

by humoral substances, the earliest attempts to identify

such molecules were made in the beginning of the 19th

century. These experiments also established sleep depri-

vation as the key method to study sleep homeostasis.

What (in the brain) is homeostaticallyregulated by sleep?There is a general agreement that neuronal activity

during waking is the driving force of sleep homeostasis:


there is direct experimental evidence from both humans

[7] and animals [8��,9] showing that those areas of brain

that are actively used during waking will produce more

SWA during the subsequent sleep period. The intensity

of the waking period, described as high-frequency theta

activity, is an important denominator of the recovery

sleep, to the extent that if a prolonged period of waking

lacks high frequency theta, it will not induce sleep

recovery [4�,9].

However, there is not a consensus of what aspects of this

activity/what molecules are responsible for the generation

of the sleep homeostasis. Is the excessive neuronal

activity consuming too much energy, or other molecular

resources, and initiates a defense response, which

decreases neuronal activity and produces SWA? Or is

the neuronal activity per se able to produce molecules


Sleep homeostasis Porkka-Heiskanen 801

Figure 1

NF-kBactivation

PGD2Cytokinerelease

Adenosine

BDNF Neuralplasticity

TNF alpha

iNOS NOG

LIA

Receptor synthesis

ATP release

Increasedenergyconsumption

Increasedneuralactivity

Energydepletion

Inhibition ofneural activity

Current Opinion in Neurobiology

Players in the regulation of sleep homeostasis. Increased neural activity consumes energy and may promote release of ATP to extracellular space,

both resulting in increase in extracellular adenosine concentration. Increase in cytokine release may be induced directly by neural activity or as

response to developing energy depletion. Cytokines are able to activate a number of signaling cascades, including iNOS and NF-kB, and induce

adenosine increase, which decrease neural activity. TNFa may directly modulate neural plasticity. The figure presents the key players and their

relationships in one configuration. While the players stay the same, there is discussion of the order of the events, and the relative importance of the

different players.

that regulate neural activity to produce more SWA, or is

SWA produced by neural plasticity-induced changes in

activity of neuronal networks? (Figure 1).

Energy metabolism: adenosine and nitric oxide (NO)

The basic idea is that neuronal activity during waking

consumes energy while sleep allows energy restoration

[10�]. As the overall neuronal firing increases during

prolonged wakefulness in the cortex [11] and in the basal

forebrain [12] it can be anticipated that even more energy

is consumed, which in the long run could lead to energy

depletion. The molecule to connect energy balance to

sleep regulation is adenosine [10�,13,14��], which acts also

as an inhibitory neuromodulator. The adenosine theory

states that during waking, due to neuronal activity-

induced energy depletion, adenosine concentration in

the basal forebrain increases decreasing neuronal activity

of wake-active neurons to induce sleep [14��].

Several experimental studies give support to this theory.

Experimentally induced, local energy depletion by pre-

venting ATP synthesis increases extracellular adenosine

concentration and subsequent sleep [15]. During pro-

longed wakefulness, the concentration of extracellular

adenosine increases in the basal forebrain (BF), and to


a lesser extent in the cortex, but in no other brain areas.

During recovery sleep the concentrations decrease [14��].If the effect of adenosine in the BF is blocked by blocking

the A1 receptors, recovery sleep is not induced [16],

implicating that the increase in sleep is dependent on

BF adenosine concentration. Adenosine has a direct and

immediate effect on neuronal activity presynaptically and

postsynaptically [17,18], and through changes in A1 re-

ceptor synthesis [19] it can further modulate the activity

of the neuronal networks over longer time periods.

Another molecule increasing its concentration in the BF

during prolonged wakefulness is nitric oxide (NO). This

increase is induced by inducible nitric oxide synthase

(iNOS) and it precedes the increase in adenosine levels,

possibly contributing to this increase [20]. Manipulations

that prevent the increase in either NO or adenosine levels

abolish also recovery sleep [21]. Activation of iNOS

implies activation of a danger signal, possibly induced

by energy depletion in the BF cholinergic cells [22��].Prompted by the fact that adenosine levels increase only

in a very selective area of the brain [23��], and that specific

lesion of the BF cholinergic cells abolishes increases in

both adenosine and NO levels, as well as in recovery sleep

[21], we have proposed that the excessive activation of the



cholinergic cells during prolonged waking triggers the

cascades leading to increase in BF extracellular adenosine

and decrease in cortical activity through A1 adenosine

receptors. In this scenario, prolonged activity of the

cholinergic cells would trigger a warning signal and acti-

vate the defense responses, including cytokines [24],

iNOS [25] and activation of the NF-kB [26] contributing

to the adenosine increase. The main findings of these invivo experiments have recently been confirmed using invitro slice preparates from sleep deprived rodents [27��].

While adenosine has generally been accepted as one of

the important regulatory molecules of sleep homeostasis,

its origin in the extracellular space has remained

unsolved. Energy depletion would first increase intra-

cellular adenosine, which then would be reflected as

increase in extracellular adenosine. The iNOS-induced

increase in NO in prolonged waking would contribute to

this increase. Another possibility is that the ATP, co-

released in neuronal activity, is metabolized to adenosine

in the extracellular space [24], and yet another possibility

is that adenosine originates from glia [28�].

Neural plasticity: the synaptic homeostasis theory

The synaptic homeostasis theory emphasizes the import-

ance of maintaining postsynaptic excitability at a stabile

level by regulating synaptic strength [29�]. In relation to

sleep, the hypothesis states that during waking, more

synapses are formed and during sleep (particularly non-

REM sleep) they are downscaled [30��]. In favor of this

hypothesis are, among others, findings of increased min-

iature excitatory currents in waking as compared to sleep

[31], increase in number and size of synapses in Drosophilabrain in waking [32��] and circadian/homeostatic synaptic

modifications in zebra fish hypocretin neurons [33]. How-

ever, a recent experiment showed that NREM rather up-

scaled than downscaled brain responsiveness [34��],which possibly could be explained by yet another finding

suggesting that downscaling takes place during REM

sleep, rather than NREM [35��].

Molecules that participate in synaptic potentiation, such

as BDNF-1 [36��], increase their expression in waking. In

addition, BDNF administration into the brain increases

sleep while suppression has an opposite effect [36��].Administration of BDNF into the cortex during waking

increases SWA in subsequent sleeping period and inhi-

biting its receptors decreases it, supporting the idea that

synaptic strength increases during waking [36��]. How-

ever, prolonging wakefulness, as in sleep deprivation,

decreases the brain concentration of BDNF in many

brain areas [37].

A computer model shows that decrease in synaptic

strength directly modulates neuronal networks decreas-

ing SWA activity [38]. Thus molecules that participate in

strengthening of synapses (e.g. BDNF) may, use-depen-


dently, alter synaptic weights of neuronal networks and

thus regulate neural activity.

Cellular defense: the immune system, cytokines and

other factors

Numerous studies have shown that components of the

immune system, including the most widely studied cyto-

kines TNFa and IL-1b, regulate also sleep (for review,

see [39��,40]), and that prolonged waking, both in humans

and in other species, results in activation of the immune

responses, including increased cytokine expression and

metabolism [41], increase in CRP [42��], induction of

iNOS expression [22��] and changes in numbers of white

blood cells [43].

Why is the immune system activated during (prolonged)

wakefulness? One explanation is that the (prolonged)

wakefulness introduces a threat, possibly in the form of

restriction of the energy supplies, which initiates immune

defense. The interesting question is, whether these

mechanisms are limited to induction of recovery sleep,

or whether they have a role also in the regulation of

spontaneous sleep–wake cycle. The activation of iNOS

only in prolonged waking suggests the former. On the

other hand, inactivation of cytokines during spontaneous

sleep decreases sleep [44,45] suggesting a role also in the

regulation of spontaneous sleep.

One possibility is that the participation of the molecules

of the immune system in sleep regulation is actually

unrelated to immune function. This possibility is raised

by studies implicating that glial TNFa participates in the

regulation of synaptic scaling [46,47,48,49��], which

would offer a route to directly regulate neuronal excit-

ability and electric activity in neuronal networks.

Prostaglandin D2 also fulfills the criteria of a sleep-indu-

cing substance (for review, see [50]), including increase in

prolonged waking. The site of action of this substance is

in the subarachnoidal space, below hypothalamus and the

basal forebrain. Cyclooxygenase is the key enzyme in

PGD2 synthesis, and it is induced by cytokines,

suggesting that PGD2 in sleep restriction may mediate

its effects through cytokines [51], and as PGD2 increases

adenosine [52], increase sleep through this mechanism.

Localization of sleep homeostasisIs sleep local or global? Several experiments show that

SWA production reflects previous, local neuronal activity.

However, the behavioral state of sleep is global: we are

either awake or sleeping, ‘flip-flopping’ between the

states [53��], and a lot is known about the neuronal groups

that regulate global state of sleep (for review, see [54��]).

The same question relates also to sleep homeostasis: is

sleep homeostasis regulated at all brain areas or does it

have specific regulatory centers? Local sleep need and



local SWA response [40] appear to suggest that equal

regulatory mechanisms would exist in all brain areas.

Sleep homeostasis has frontal dominance: the largest

SWA activity is found in the frontal areas in the brain,

not only in humans but also in animals [5,55], in

accordance with the higher neural activity, reflected

as higher blood flow in the frontal areas in waking [56].

Secretion of cytokines and BDNF can be connected to

increased neuronal activity, and would take place on

the site of neuronal activity. Studies on neural plasticity

have concentrated on the cortex. Since the formation of

synapses is not restricted to cortex, similar mechanisms

would be expected to exist also in subcortical areas.

Their role in the overall regulation of synaptic strength

and their contribution to formation of SWA remain to

be explored.

Energy consumption in all areas with increased neuronal

activity will increase. However, during prolonged wake-

fulness, energy depletion, as measured by increased

extracellular adenosine concentration, in rodents

increases only in very selective areas: the basal forebrain

and later and to a lesser degree in the cortex [23��].Importantly, it does not increase in areas which are

known to be active during waking: the dorsal raphe

nucleus and LDT/PPT, no increases are seen in the

hypothalamus (POA) or in the thalamus either [23��].Moreover, the increase in extracellular adenosine during

sleep deprivation was abolished after specific lesion of

the BF cholinergic cells [57��], indicating that either

adenosine originated from these cells, or the cells

mediated the signal that increased adenosine during

SD. On the basis of these data, the basal forebrain in

mammals appears to be a central site for regulation of

sleep homeostasis.

ConclusionsUnderstanding sleep homeostasis is intimately linked to

the question of physiological purpose of sleep. Interpret-

ation of experimental data reflects the theories on this

purpose. Another important question, often overlapping

with the ‘purpose of the sleep-question’, is whether sleep/

sleep homeostasis is local or global. Using rules to dis-

tinguish genuinely sleep regulation-related molecules,

researchers have identified a number of factors that

regulate sleep homeostasis. Interestingly, many of these

molecules have several physiological roles, and thus can be

used to support different theories. The presently known

key molecules in the regulation of sleep homeostasis are

adenosine, TNFa and BDNF. No doubt many other

molecules can and will be identified with future research.

AcknowledgementsThis work was supported by the Academy of Finland, FinskaLakaresallskapet and EuRhyDia Consortium Funding (HEALTH-F2-2011-278397). I thank Dr Erkki Kronholm for critical review of the finalmanuscript.


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39.��

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42.��

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One of the first publications to show that sleep loss will also in humansinduce inflammatory reactions and that these reactions may have serioushealth consequences.

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49.��

Park KM, Bowers WJ: Tumor necrosis factor-alpha mediatedsignaling in neuronal homeostasis and dysfunction. Cell Signal2010, 22:977-983.

The cytokine TNFa signals not only immunological information but isintimately involved in synaptic plasticity. This opens new avenues forinterpretation of its role in sleep regulation.

50. Urade Y, Hayaishi O: Prostaglandin D2 and sleep/wakeregulation. Sleep Med Rev 2011, 15:411-418.

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involvement in the regulation of non-rapid eye movementsleep. Proc Natl Acad Sci U S A 2001, 98:11674-11679.

53.��

Saper CB, Fuller PM, Pedersen NP, Lu J, Scammell TE: Sleepstate switching. Neuron 2010, 68:1023-1042.

A recent review about general mechanisms to regulate sleep. The reci-procal inhibition of sleep–active and waking-active neurons is the basis ofthe ‘flip-flop’ model that explains falling asleep and waking from sleep.

54.��

Brown RE, Basheer R, McKenna JT, Strecker RE, McCarley RW:Control of sleep and wakefulness. Physiol Rev 2012, 92:1087-1187.

A comprehensive and up-dated review on general sleep mechanisms.The global regulators of sleep, as well as adenosine and other sleepfactors are explained in detail with extensive list of references.

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Kalinchuk AV, McCarley RW, Stenberg D, Porkka-Heiskanen T,Basheer R: The role of cholinergic basal forebrain neurons inadenosine-mediated homeostatic control of sleep: lessonsfrom 192 IgG-saporin lesions. Neuroscience 2008, 157:238-253.

This work shows that specific lesion of the basal forebrain cholinergiccells using IgG-saporin will abolish all markers of prolonged wakefulness:increases in basal forebrain adenosine and NO concentrations as well asrecovery sleep.


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Sleep homeostasis