The Roles of the Reward System in Sleep and Dreaming

Home , Dopaminergic pathways, Mesolimbic pathway, Reward system

Neuroscience and Biobehavioral Reviews 36 (2012) 1934–1951

Contents lists available at SciVerse ScienceDirect

Neuroscience and Biobehavioral Reviews

journa l homepage: www.elsevier.com/locate/neubiorev

Review

The roles of the reward system in sleep and dreaming

a,b b,c,d,∗

Lampros Perogamvros , Sophie Schwartz

Division of Neuropsychiatry, Department of Psychiatry, University Hospitals of Geneva, Geneva, Switzerland

Department of Neuroscience, University of Geneva, Geneva, Switzerland

Swiss Center for Affective Sciences, University of Geneva, Geneva, Switzerland

Geneva Neuroscience Center, University of Geneva, Geneva, Switzerland

a r t i c l e i n f o a b s t r a c t

Article history: The mesolimbic dopaminergic system (ML-DA) allows adapted interactions with the environment and is

Received 11 October 2011

therefore of critical signiﬁcance for the individual’s survival. The ML-DA system is implicated in reward

Received in revised form 23 May 2012

and emotional functions, and it is perturbed in schizophrenia, addiction, and depression. The ML-DA

Accepted 25 May 2012

reward system is not only recruited during wakeful behaviors, it is also active during sleep. Here, we

introduce the Reward Activation Model (RAM) for sleep and dreaming, according to which activation of

Keywords:

the ML-DA reward system during sleep contributes to memory processes, to the regulation of rapid-eye

Sleep

movement (REM) sleep, and to the generation and motivational content of dreams. In particular, the

Dreaming

Emotion engagement of ML-DA and associated limbic structures prioritizes information with high emotional or

Memory motivational relevance for (re)processing during sleep and dreaming. The RAM provides testable predic-

Learning tions and has clinical implications for our understanding of the pathogenesis of major depression and

Dopamine addiction.

Reward system

Ventral tegmental area Hippocampus Amygdala

Contents

1. Introduction ...... 1935

1.1. The mesolimbic dopaminergic (ML-DA) system...... 1935

1.2. Reward processing ...... 1936

1.2.1. General information about reward processing ...... 1936

1.2.2. Brain circuits of reward processing ...... 1936

2. Introducing the Reward Activation Model (RAM) for sleep and dreaming ...... 1937

2.1. Activation of the ML-DA reward system during sleep ...... 1937

2.1.1. VTA bursting activity is increased during REM sleep ...... 1937

2.1.2. Increased activity of the NAcc, PFC, amygdala and ACC during REM sleep ...... 1938

2.1.3. Activation of HC and VS reward-related neurons during SWS ...... 1939

2.1.4. Activation of other reward-related structures and mechanisms during sleep ...... 1939

2.2. Sleep deprivation and reward system ...... 1939

Abbreviations: ACC, anterior cingulate cortex; AIM model, activation, input/output, modulation model; dlPFC, dorsolateral prefrontal cortex; GABA, gamma-aminobutyric

acid; HC, hippocampus; l-DOPA, precursor to the neurotransmitters known as catecholamines, including dopamine. As a drug it is used to increase dopamine concentrations

in the central nervous system for the clinical treatment of Parkinson’s disease, for example.; LH, lateral hypothalamus; LTP, long-term potentiation; ML-DA, mesolimbic

dopaminergic system; mPFC, medial prefrontal cortex; MRI, magnetic resonance imaging; NAcc, nucleus accumbens; N1, N2, N3, stages N1, N2, and N3 of NREM sleep; NREM

sleep, non-rapid-eye movement sleep; OFC, orbitofrontal cortex; PET, positron emission tomography; PFC, prefrontal cortex; PPT, pedunculopontine tegmental nucleus; PTO

junction, parieto-temporo-occipital junction; RAM, Reward Activation Model; RBD, REM sleep behavior disorder; REM sleep, rapid-eye movement sleep; REMSD, REM sleep

deprivation; SD, sleep deprivation; SLD, sublaterodorsal nucleus; SN, substantia nigra; SNc, substantia nigra pars compacta; SWS, slow-wave sleep; TST, threat simulation

theory; vmPFC, ventromedial prefrontal cortex; VP, ventral pallidum; VS, ventral striatum; VTA, ventral tegmental area.

∗

Corresponding author at: Department of Neuroscience, Faculty of Medicine, University of Geneva, rue Michel-Servet 1, 1211 Geneva 4, Switzerland.

Tel.: +41 22 3795376; fax: +41 22 3795402.

E-mail address: [email protected] (S. Schwartz).

L. Perogamvros, S. Schwartz / Neuroscience and Biobehavioral Reviews 36 (2012) 1934–1951 1935

3. Reward activation and memory processing during sleep ...... 1939

3.1. Memory processing leading to reward activation during sleep ...... 1940

3.2. Reward activation leading to memory formation during sleep ...... 1940

4. Reward activation and REM sleep generation ...... 1940

5. Reward activation and dreaming ...... 1941

5.1. The neural circuits of dreaming ...... 1941

5.2. ML-DA reward system activation and dream generation ...... 1942

5.3. ML-DA reward system activation and dream content ...... 1942

5.4. Links of the RAM to other dream theories ...... 1943

5.4.1. Freud’s psychoanalytic theory of dreams and RAM...... 1943

5.4.2. Activation-input-modulation (AIM) model and RAM...... 1943

5.4.3. Threat Simulation Theory (TST) and RAM...... 1943

6. Clinical context...... 1944

6.1. Psychosis and dreaming ...... 1944

6.2. Sleep and emotion regulation ...... 1944

6.2.1. Insomnia and sleep loss as precursors of depression via alteration of brain reward networks ...... 1944

6.2.2. Evidence from sleep deprivation studies ...... 1945

6.3. Sleep and compulsive behaviors ...... 1945

7. Limitations and testability of the model...... 1945

8. Conclusions ...... 1946

Acknowledgements...... 1946

References ...... 1946

1. Introduction sleep; (b) inﬂuences the regulation of REM sleep; and (c) con-

tributes to the generation and the motivational content of dreams.

‘We have no dreams at all or interesting ones. We should learn to Importantly, these distinct functional roles of ML-DA activation

be awake the same way — not at all or in an interesting manner.’ during sleep involve partially dissociated reward-related mecha-

(Friedrich Nietzsche, ‘The Gay Science’, Third Book, aphorism nisms. The RAM also suggests that the reward function of dreaming

232, 1882) offers humans an evolutionary advantage by optimizing waking

behavior, in particular adapted emotional responses. Our main

The mesolimbic dopaminergic (ML-DA) system originates from

aim in developing the RAM is to propose a theoretical framework

the ventral tegmental area (VTA) of the midbrain and projects to

concerning the roles of the ML-DA system in sleep and reward pro-

various diencephalic structures like the nucleus accumbens (NAcc),

cesses, that integrates recent data from neurophysiology studies in

as well as to the prefrontal cortex (PFC) (Alcaro et al., 2007). The ML-

animals with behavioral and brain imaging studies in humans. By

DA circuit promotes adapted, goal-directed behaviors by mediating

addressing and formalizing the interaction of sleep with reward

different aspects of reward processing (Haber and Knutson, 2010;

and emotional processes, an additional objective of the RAM is

Schultz, 1998). The ML-DA system is also critical for the develop-

to account for some neuropsychiatric symptoms in patients with

ment of instinctual and appetitive drives, a function of the brain

dopaminergic abnormalities (e.g. schizophrenia, depression, addic-

that permits mammals, including humans, to seek for rewards and

tion). This model thus offers to sleep science a missing link between

develop search strategies in order to obtain them (Panksepp, 1998).

sleep neurophysiology, cognition, and dream content.

Several lines of evidence suggest the ML-DA reward system is

activated during sleep. Neurophysiological studies in animals have

revealed that regions of the ML-DA circuit such as the NAcc and

the VTA show increased bursting neural activity during rapid-eye 1.1. The mesolimbic dopaminergic (ML-DA) system

movement (REM) sleep (Dahan et al., 2007; Lena et al., 2005), and

a role of dopamine in the generation of REM sleep has been sug- There are two main ascending dopaminergic pathways in the

gested (Dzirasa et al., 2006). It is also striking that brain circuits human brain: the nigrostriatal pathway and the ML-DA (mesolim-

modulating sleep–wake states (e.g. hypocretin/orexin system) may bic or mesocorticolimbic) pathway (Fig. 1; Stahl and Muntner,

inﬂuence reward-related responses and neural plasticity in ML-DA 2008). The nigrostriatal pathway projects from the substantia nigra

regions and amygdala in both animals and humans (Borgland et al., (SN) of the midbrain to the dorsal striatum (caudate and puta-

2008; Harris et al., 2005; Ponz et al., 2010a,b). Moreover, neuronal men). It is mainly implicated in the modulation of cognitive and

activity recorded during the encoding of reward-related mem- behavioral habits, and in procedural aspects of movements; its dys-

ory may be spontaneously reactivated during slow-wave sleep function is associated with Parkinson’s disease (Jankovic, 2008).

(SWS) in the ventral striatum and the hippocampus in rodents The ML-DA pathway originates in the VTA and innervates the lateral

(Lansink et al., 2009). In humans, the replay of elements from wak- hypothalamus (LH), the NAcc and olfactory tubercle of the ventral

ing experience in both sleep (Maquet et al., 2000; Peigneux et al., striatum (VS), the bed nucleus of stria terminalis, lateral septum,

2004; Rudoy et al., 2009) and dreams (Wamsley et al., 2010) was hippocampal complex (HC), amygdala, PFC, and anterior cingu-

found to enhance overnight memory consolidation, and rewarded late cortex (ACC). This system is implicated in motivated behaviors

information may particularly beneﬁt from sleep-related memory (Alcaro et al., 2007), reward processing (Ikemoto, 2007), emotional

consolidation (Fischer and Born, 2009). Finally, elevated dopamine processing (Alcaro et al., 2007), and learning (Adcock et al., 2006).

level in the ML-DA system during sleep has been suggested to play Dysfunctions of the ML-DA system are observed in schizophrenia

an important role in the generation of dreams (Solms, 2000, 2002). (Epstein et al., 1999; Kapur, 2003; Laruelle, 2000; Meltzer and Stahl,

In this article, we present the Reward Activation Model (RAM), 1976; Sarter et al., 2005; Winterer and Weinberger, 2004), addic-

which proposes that activation of the ML-DA reward system dur- tion (Kauer and Malenka, 2007; Koob, 1992; Koob and Volkow,

ing sleep (a) serves learning and memory consolidation functions 2010; Thomas et al., 2008), as well as in depression (Dailly et al.,

by reactivating rewarded or emotionally-relevant memories during 2004; Dunlop and Nemeroff, 2007; Nestler and Carlezon, 2006).

1936 L. Perogamvros, S. Schwartz / Neuroscience and Biobehavioral Reviews 36 (2012) 1934–1951

Box 1: Rewards and punishers Box 2: The SEEKING system

Rewards are considered as stimuli that positively reinforce The SEEKING system has been proposed by Panksepp as

behavior (Schultz, 2006) and that usually (but not always) a “curiosity-interest-expectancy” command system which is

induce a conscious experience of pleasure. Examples of pri- associated with instinctual appetitive craving states (Alcaro

mary rewards are stimuli like food, water, and sexual stimuli. and Panksepp, 2011; Panksepp, 1982, 1998). As a psychobehav-

They reinforce behaviors without having to be learned. They ioral emotional and motivational system of the mammalian

derive their value from innate mechanisms, like the hunger brain, the SEEKING system is related to approach behav-

and thirst states. Secondary (conditioned) rewards gain their iors and to the feeling of anticipation while seeking a reward

reward value from a learned association with primary rewards. (actual external stimuli or internal representation of a reward)

Money, positive feedback, social interactions, and pleasant (Alcaro and Panksepp, 2011). Its core circuits include dense

touch are typical secondary rewards. The organism’s inter- ML-DA projections from the VTA to the LH, mediodorsal tha-

action with a reward may implicate two distinct types of lamus, medioventral pallidum, NAcc shell, olfactory tubercle,

processes, i.e. motivational and hedonic processes (Berridge amygdala, anterior limbic cortex, and prefrontal cortex (Fig. 2).

et al., 2009). The motivational component refers to switch- Although it resembles the ML-DA system, the SEEKING system

ing attention and behavior toward reward-related stimuli or is more extensive, because it includes ascending noradrener-

novel cues. Motivated behavior is mainly associated with gic and cholinergic excitatory inﬂuences, as well as descending

dopaminergic signaling in mesolimbic structures like the VTA, glutamatergic and GABA inﬂuences (Panksepp, 1998). Acti-

hypothalamus, amygdala, NAcc, and PFC. On the other hand, vation of the SEEKING system does not only represent the

the hedonic impact of a reward concerns the pleasurable internal experience of a reward, but also the emotional antici-

reaction of the organism to a sensory cue (e.g. the sensory patory components of an appetitive search strategy (Panksepp,

pleasure of sweet tastes), and implicates opioid, cannabinoid, 1998). Interest, curiosity and anticipation, but not pleasure or

and GABA transmission from the brainstem to the NAcc, ven- consumption, are the feelings related to the activation of the

tral pallidum, insular cortex and orbitofrontal cortex. SEEKING system. This system can be sometimes activated

Punishers are stimuli that induce withdrawal behavior. They independently of voluntary goal-seeking behavior. For exam-

function as negative reinforcers, by increasing a behavior that ple, addictive drugs like cocaine and nicotine directly use and

decreases an aversive outcome. Punishers can induce emo- ‘abuse’ this system, leading to the perpetuation of associated

tional states such as anger or fear. activities, such as the continuous quest for the substance and

Rewards or punishers are not always of an external or percep- the pursuit of the subjective feeling of pleasure induced by its

tual origin; they may also correspond to a cognitive, mental consumption. A maladaptive vicious cycle, known as depen-

representation or a memory reactivation of a reward (Alcaro dence, addiction and tolerance is soon installed.

and Panksepp, 2011).

or novel (Wittmann et al., 2007), and (b) the cognitive, affective,

or physiological response to these internally-generated rewarding

1.2. Reward processing

or punishing signals while the organism is asleep. This deﬁni-

tion comes close to Panksepp’s concept of the SEEKING disposition

1.2.1. General information about reward processing

(Alcaro and Panksepp, 2011), which corresponds to an instinctual

Reward processing is one of the major functions of the ML-

affective and exploratory drive to seek biologically-important stim-

DA reward system. This system is responsible for appropriate

uli in the external or internal (‘intrapsychic’) environment (see Box

responses to external and internal rewards or punishers, for

2 and Fig. 2).

incentive-based learning, and for the development of goal-directed

and adaptive behaviors (Haber and Knutson, 2010). It is regarded as

a central component in the development and monitoring of moti- 1.2.2. Brain circuits of reward processing

vated behaviors in all mammals (see Box 1). Two main types of The brain areas activated during reward processing vary as a

dopamine signals may be distinguished within this system: pha- function of the type of reward, the behavioral task, and whether a

sic versus tonic neural activity. A phasic dopamine signal (bursting reward (or punisher) is being anticipated or delivered (see Box 1).

activity) is deﬁned as a brief increase (up to 2 s) in dopamine con- Most of the areas involved during reward processing are inner-

centration in terminal mesolimbic regions (subcortical, like the vated by ML-DA projections, originating mainly from the VTA

NAcc, or cortical), resulting from a burst ﬁring of one or more VTA (ML-DA reward system; Fig. 1). The VTA, as well as the NAcc,

neurons (Ikemoto, 2007). Phasic activity is involved in reward pro- constitutes the core of the reward circuit (Hikosaka et al., 2008;

cessing (Heien and Wightman, 2006; Redgrave et al., 1999; Schultz, Wise, 2002). However, some non-mesolimbic structures also con-

2010b), and also relates to the process of switching one’s attention tribute to the processing of rewards, including the orbitofrontal

and behavior toward salient cues in the environment. On the other cortex (OFC), the substantia nigra pars compacta (SNc), the supra-

hand, a tonic signal is deﬁned as a slow change in dopamine concen- mammillary nucleus, the midbrain raphe nuclei, and the dorsal

tration in the aforementioned regions, lasting from tens of seconds striatum (Ikemoto, 2010; Schultz, 2010a). In addition, dopamine

to hours or days, and supporting relatively stable or tonic affective is not the only neurotransmitter related to reward responses. Glu-

states and motivation (Ikemoto, 2007). tamate (Kenny et al., 2009), GABA (Vlachou and Markou, 2010),

The term ‘reward’ can have slightly different uses in neu- serotonin (Higgins and Fletcher, 2003) and acetylcholine (Rada

roscience. On the one hand, reward may primarily refer to et al., 2000; Sarter et al., 2005) can inﬂuence reward processing, by

reinforcement-learning functions of dopamine signals, such as for acting either as modulators of dopamine function or independently

example reward prediction error (Redgrave et al., 1999; Schultz, of dopamine.

1997, 2002, 2010a; Schultz and Dickinson, 2000). On the other Recent neurobiological models of reward processing commonly

hand, reward may relate to motivational and appetitive functions describe a transfer of information from ventral to dorsolateral

of the dopaminergic reward system, such as for example ‘incentive cortico-basal ganglia circuits, which transforms basic reward

salience’ (Berridge, 2007). In this article, reward processing dur- responses and unconditioned responding (mesolimbic pathway)

ing sleep will speciﬁcally concern (a) the spontaneous activation into action planning and associative learning (nigrostriatal path-

of internally-generated rewards or punishers during sleep, such as way) (Haber and Knutson, 2010; Ikemoto, 2007). According to

elements from memory that are relevant (Montague et al., 2006) Ikemoto (2007), mesolimbic projections from the VTA to the NAcc,

L. Perogamvros, S. Schwartz / Neuroscience and Biobehavioral Reviews 36 (2012) 1934–1951 1937

Fig. 1. Main ascending mesolimbic and nigrostriatal dopaminergic pathways. Abbreviations: ACC: anterior cingulate cortex; HC: hippocampal complex; NAcc: nucleus

accumbens; PFC: prefrontal cortex; VTA: ventral tegmental area.

LH, and PFC are activated by incentive stimuli and can lead to posi-

tive affect and approach learning (‘ﬂexible’ responses). On the other

hand, the nigrostriatal projections from the SNc to the dorsal stria-

tum and from there to globus pallidus and ﬁnally to motor regions

in the frontal lobe would be responsible for the initiation of motor

activity and the transient activation of the reward system in well-

learned situations, with predictable outcomes (‘habit’ responses).

2. Introducing the Reward Activation Model (RAM) for

sleep and dreaming

Based on the evidence that the ML-DA system is activated dur-

ing sleep, the RAM proposes that this activation (a) contributes to

memory consolidation mechanisms by prioritizing the processing

of information with high emotional and/or motivational relevance,

(b) participates in the modulation of REM sleep through projections

Fig. 2. The ML-DA component of the SEEKING system. Schematic representation

to REM generating structures (in particular the sublaterodorsal

of the ML-DA projections of the SEEKING system originating in the VTA of the

nucleus of the pons), and (c) contributes to the generation of dreams midbrain. Electrical or chemical stimulation of the regions in red color induces

by means of motivational and affective drives of the SEEKING sys- exploration and approach behaviors, whereas regions in blue color are involved

in the large-scale organization and diffusion of the SEEKING signal (Alcaro and

tem (Box 2). These characteristics of the ML-DA system suggest

Panksepp, 2011). Here, anterior limbic regions include the ventromedial prefrontal

that dreaming may potentially play a role in learning and mem-

cortex, orbitofrontal cortex, anterior cingulate cortex, and the insula. Ascending

ory, including emotion regulation processes. Note however that up

noradrenergic/cholinergic and descending glutamatergic/GABA projections of the

to now there is little empirical evidence in support of this latter SEEKING system are not represented in this ﬁgure. Abbreviations: ACC: anterior

hypothesis. cingulate cortex; NAcc: nucleus accumbens; VTA: ventral tegmental area. (For inter-

pretation of the references to color in this ﬁgure legend, the reader is referred to the

web version of the article.)

2.1. Activation of the ML-DA reward system during sleep

An increasing number of studies indicate that some key struc-

Krebs et al., 2011; Wittmann et al., 2007). VTA bursting activity

tures of the reward processing circuit, and mainly of the ML-DA

in the rat was ﬁrst recorded during sleep by Miller et al. (1983),

reward system, like the VTA and the NAcc are activated during

who showed that VTA neurons ﬁre at the same slow frequency

sleep. In Fig. 3, we propose an integrated summary of the ﬁndings

during SWS, REM sleep and waking, but the ﬁring is more irreg-

that indicate the activation of the ML-DA reward system during

ular during REM sleep. In 2002, Maloney et al. demonstrated that

sleep.

in rats dopaminergic neurons in the VTA are more active dur-

ing REM and wakefulness than during NREM, and are maximally

2.1.1. VTA bursting activity is increased during REM sleep active during REM (Maloney et al., 2002). In 2007, Dahan et al. con-

VTA bursting activity is strongly related to reward processing ﬁrmed that the VTA has an increased bursting activity during REM

(Kiyatkin, 1995; Yun et al., 2004). The VTA ﬁres bursts of spikes sleep in rats (phasic dopamine signals), inducing a large synap-

during reward and punisher anticipation (Carter et al., 2009), as tic dopamine release in the NAcc shell (Dahan et al., 2007). In this

well as in response to stimulus novelty (Bunzeck and Duzel, 2006; study, the percentage of spikes ﬁring in bursts was signiﬁcantly

1938 L. Perogamvros, S. Schwartz / Neuroscience and Biobehavioral Reviews 36 (2012) 1934–1951

Fig. 3. Schematic illustration of the activation of the ML-DA reward system during sleep. (A) During NREM sleep, the HC–VS activation underlies a spontaneous reactivation

(replay) of reward-related neuronal ﬁring patterns in the VS, which involves a transfer of novelty/relevance signal from the HC to the VTA (see main text, Lansink et al., 2008;

Lisman and Grace, 2005; Pennartz et al., 2011). VTA is activated during the transition from a NREM episode to REM sleep, with induction of both tonic (HC–VTA projection) and

phasic (PPT–VTA) increase of dopamine. Other reward-related structures activated during NREM sleep include the amygdala, the ACC and the insula. (B) During REM sleep,

increased bursting activity (phasic response) in the VTA (Dahan et al., 2007) may represent stimulus saliency and could fulﬁll reward-related functions, like processing of

stimulus-reward associations, novelty-seeking and enhancement of learning procedures. During REM sleep, several VTA projections are activated, including the upward arc

of hippocampal–VTA loop (dopaminergic input from the VTA to the HC), the NAcc, the amygdala, the orexin/hypocretin neurons, the ACC, and the PFC. All these regions have

strong anatomical and functional links with the hippocampus and VTA (among others). Activation of the upward arc of the hippocampal–VTA loop contributes to synaptic

plasticity and learning by enhancing long-term potentiation (Lisman and Grace, 2005). Abbreviations: HC: hippocampus; PFC: prefrontal cortex; PPT: penduculopontine

tegmental nuclei; VS/NAcc: ventral striatum/nucleus accumbens; VTA: ventral tegmental area.

higher in REM compared to waking and to NREM. The sustained intra-hippocampal infusion of tetrodotoxin (Legault and Wise,

bursting activity was comparable in duration with VTA bursting 2001). In humans, brain imaging studies also demonstrate that nov-

during motivated behaviors such as feeding, punishment, or sex. elty activates the amygdala, the VTA and the HC (Bunzeck et al.,

Moreover, this VTA activation, which started 10–20 s before the 2012; Guitart-Masip et al., 2010; Krebs et al., 2011). The HC can

onset of REM sleep, was as important in intensity as an activation activate VTA dopamine cells via a pathway involving the activation

induced by the consumption of food. Because high phasic dopamine of NAcc, which in turn inhibits the ventral pallidum (VP) leading

signaling in the midbrain has primarily been linked to reward pro- to the disinhibition of dopamine cells (Floresco et al., 2003). This

cessing (Schultz, 2010b), strong bursting activity of the VTA before pathway (HC → VTA), which corresponds to the downward arc of

and during REM sleep may putatively be related to reward-related the ‘hippocampal–VTA loop’ (Lisman and Grace, 2005), increases

processes, as we discuss below. the population activity of dopaminergic neurons, modulates tonic

The increase of VTA bursting activity at the end of an episode extrasynaptic dopamine levels in the VTA (Floresco et al., 2003),

of SWS (or NREM sleep) is explained by the activation, during and is related to motivational salience (Lisman and Grace, 2005)

SWS sleep, of several structures that project either directly or indi- (Fig. 3A). The upward arc (dopaminergic input from the VTA to

rectly to the VTA (pedunculopontine tegmental nucleus, amygdala, the HC) is related to synaptic plasticity and learning by enhancing

HC, striatum, hypothalamus, basal forebrain). Studies have focused long-term potentiation (LTP) (Adcock et al., 2006) (Fig. 3B). Fur-

mainly on two of these projection sites, i.e. the HC and the peduncu- thermore, the PPT, which sends direct excitatory inputs to the VTA

lopontine tegmental nucleus (PPT) (Holmstrand and Sesack, 2011; (Omelchenko and Sesack, 2006) and plays a key role in the gener-

Lisman and Grace, 2005). However, it is important to note that the ation of REM sleep (Bandyopadhya et al., 2006; Saper et al., 2005),

amygdala (Fudge and Haber, 2001), as well as sleep-related struc- has been shown to be activated speciﬁcally by salient stimuli (Pan

tures, such as the suprachiasmatic nucleus (Luo and Aston-Jones, and Hyland, 2005) and to participate in increased bursting activ-

2009) and orexin/hypocretin neurons in the hypothalamus (Fadel ity and phasic synaptic dopamine levels in the VTA (Floresco et al.,

and Deutch, 2002) also send dense projections to the VTA. As for 2003).

orexin neurons speciﬁcally, their receptors are expressed at the To summarize, several projection circuits may contribute to

surface of VTA dopaminergic neurons (Marcus et al., 2001; Narita increase VTA activation during the transition from a NREM

et al., 2006). In addition, the orexin system is involved both in the episode to REM sleep, among which are the downward arc of

regulation of sleep and in drug-seeking behaviors and associated the hippocampal–VTA loop and the PPT (Fig. 3A). The simultane-

ML-DA activity, as observed in animal studies (Borgland et al., 2006; ous hippocampal–VTA and PPT–VTA activation can induce a 4-fold

Boutrel et al., 2005; Harris et al., 2005) and in neuroimaging stud- increase in the number of dopaminergic neurons ﬁring in bursts

ies performed on orexin-deﬁcient narcoleptic patients (Ponz et al., (Lodge and Grace, 2006). Note that circadian factors (CLOCK gene)

2010a; Schwartz et al., 2008). seem also to be implicated in this activation (Roybal et al., 2007).

Lisman and Grace (2005) proposed that the VTA and hippocam-

pus form a functional loop designed to control the entry of relevant 2.1.2. Increased activity of the NAcc, PFC, amygdala and ACC

information into long-term memory. Below we introduce the main during REM sleep

components of this loop because it constitutes a very useful model Activity in the NAcc is proportional to the magnitude of antic-

on which we will rely for the integration of existing data about the ipated reward (Knutson et al., 2001) and is the greatest when

activation of the reward system during sleep. In this model, the salience (e.g. uncertainty about outcomes) is maximal (Cooper and

activation of the VTA induced by novel salient stimuli and required Knutson, 2008). Exposure to both primary and secondary rewards

for memory consolidation is triggered mainly by the HC and the also increases activity in the PFC, particularly in the ventrome-

PPT. This hypothesis is based on the observation that novelty- dial PFC (vmPFC) (Haber and Knutson, 2010). The ACC is another

induced increase in extracellular dopamine levels can be blocked by important component of reward processing as it is related to

L. Perogamvros, S. Schwartz / Neuroscience and Biobehavioral Reviews 36 (2012) 1934–1951 1939

predicting reward, to assigning a positive or negative value to future in these patients provide further support for the activation of

outcomes (Takenouchi et al., 1999), and to reward-based decision- reward-seeking mechanisms during sleep. Moreover, the orexin

making (Bush et al., 2002). In 2005, Gottesmann’s group showed neurons, which play an important role both in sleep–wake regu-

that there was an increase in extracellular levels of dopamine in lation (Saper et al., 2005) and in motivated behaviors (Harris et al.,

the NAcc during REM sleep, not signiﬁcantly different from waking, 2005; Thompson and Borgland, 2011) have occasional burst dis-

but signiﬁcantly higher than NREM sleep (Lena et al., 2005). Dur- charges during REM sleep (Mileykovskiy et al., 2005; Takahashi

ing REM sleep, increased activity is also observed in the PFC (Lena et al., 2008), with levels comparable to those of quiet waking

et al., 2005), in the human vmPFC, amygdala, and ACC (Maquet (Kiyashchenko et al., 2002). This phasic activation, which might

et al., 1996, 2000). Dense ML-DA projections from the activated be related to orexin projections to and from the VTA (Nakamura

VTA (Dahan et al., 2007) to these sites could, at least in part, explain et al., 2000), could express motivational and/or emotional process-

these activations. ing during REM sleep.

2.1.3. Activation of HC and VS reward-related neurons during

2.2. Sleep deprivation and reward system

SWS

In 2004, Pennartz’s team demonstrated that a spontaneous reac-

The role of sleep in reward processing can be proved indirectly

tivation (replay) of neuronal ﬁring patterns may occur in the VS

by studies of sleep deprivation (SD). Steiner and Ellman (1972)

during SWS after a reward searching behavior of the rat (Pennartz

demonstrated that REM sleep deprivation (REMSD) caused rats to

et al., 2004). In 2008, the same group conﬁrmed the activation of VS

seek more of a previously trained rewarding stimulation. Moreover,

reward-related neurons (sensitive to either the presence or absence

after allowing rats to self-stimulate, the typical ‘rebound’ increase

of reward) during SWS after a reward searching behavior (Lansink

in REM sleep following REMSD was decreased. Similarly, acute

et al., 2008). This spontaneous reactivation during SWS was as

sleep deprivation in rats increased goal-directed behaviors toward

strong as during quiet wakefulness and could not be detected dur-

cocaine (Puhl et al., 2009). In humans, SD increases the risk of sub-

ing REM sleep. It appears to be induced by and temporally aligned

stance abuse (Shibley et al., 2008; Wong et al., 2009) and appetitive

to hippocampal ripples (100–300 Hz oscillations) and could con-

behavior (Benedict et al., 2012). This increase in impulsivity and

tribute to linking a memory trace to a motivational value during

reward seeking post-SD may reﬂect a compensatory mechanism to

sleep (Lansink et al., 2009; Pennartz et al., 2011; Singer and Frank,

adjust for the downregulation of D2 and D3 receptors in the ven-

2009), as well as to the transfer of a novelty signal from the HC to the

tral striatum immediately after SD (Volkow et al., 2012). Decreased

VTA (Lisman and Grace, 2005). This mechanism may thus use the

D2/D3 receptor availability (Volkow et al., 2012) and attenuated

downward arc of the hippocampal–VTA loop (Fig. 3A). In humans,

representations of parametric value in the SN/VTA, bilateral insula,

HC and VS activation during NREM sleep has been demonstrated

vmPFC and parietal cortex (Menz et al., 2012), may also account

by neuroimaging studies (e.g. Peigneux et al., 2004; Nofzinger et al.,

for the impairment in performance, reward learning and decision

2002), although it remains uncertain if activation in both HC and

making after SD. In line with this interpretation, Hanlon et al. (2005)

VS is temporally coordinated.

demonstrated that REMSD reduces the rate of responding to the

It should be noted that, in rats, SWS is synonymous to human

acquisition and maintenance of an operant task for food reward in

NREM sleep (Franken et al., 1998), and is not restricted to human

rats, which might be due to a suppression of dopamine activity in

SWS (stage N3). In humans, the hippocampal ripples are tempo-

the NAcc during REMSD (Hanlon et al., 2010). In addition, total SD

rally coupled with the sleep spindles (Clemens et al., 2007, 2011),

can disrupt the reconsolidation of morphine reward memory (Shi

which are most pronounced in stage N2 but also occur in SWS (De

et al., 2011). In humans, studies have reported that insufﬁcient sleep

Gennaro and Ferrara, 2003). Thus, the aforementioned activations

is associated with changes in reward-related decision making: peo-

of HC and VS in rats may primarily but not uniquely concern stage

ple take greater risks (Harrison and Horne, 2000; McKenna et al.,

N2 in humans. For example, a recent study showed that sleepwalk-

2007), are less concerned with negative consequences of risky deci-

ing patients may re-enact during NREM sleep a motor task in which

sions (Chee and Chuah, 2008; Venkatraman et al., 2007, 2011), and

they were trained before sleep, thus providing direct evidence for

overestimate positive emotional experiences (Gujar et al., 2011).

the off-line replay of newly acquired information during SWS in

In 2009, Holm et al. showed that in both reward anticipation and

humans (Oudiette et al., 2011).

outcome phases of a card-game, adolescents with fewer minutes

asleep and later sleep onset time exhibited less caudate activa-

2.1.4. Activation of other reward-related structures and

tion (Holm et al., 2009), a structure implicated in linking reward

mechanisms during sleep

to behavior and learning (Haber and Knutson, 2010). Collectively,

Apart from the regions already mentioned above, some other

these recent data suggest that less sleep may impact on neural

reward-related regions are also found to be activated during NREM

systems of reward in ways that exacerbate behavioral problems

and REM sleep. In humans, the posterior insula, ACC (Schabus et al.,

(e.g. increased risk-taking). Thus, sleep deprivation may have major

2007), and the amygdala (Nofzinger et al., 2002) were found to be

health implications in adolescents and adults, by altering reward

activated during NREM sleep. During REM sleep, the amygdala and

and emotional processing.

the HC are also activated (Braun et al., 1997; Maquet et al., 1996,

2000; Nofzinger et al., 1997). Activation in the HC is consistent

with animal (Popa et al., 2010; Winson, 1972) and human (Cantero 3. Reward activation and memory processing during sleep

et al., 2003) data showing that the HC exhibits a theta rhythm dur-

ing REM sleep. The theta rhythm is common when animals are The data reviewed above suggest that many components of

exploring their environment by snifﬁng, an exploratory behavior the ML-DA reward system are activated during sleep. What could

which is present during REM sleep (Panksepp, 1998; Seelke and be the functional meaning of activating a system devoted to the

Blumberg, 2004). Similar exploratory and instinctual behaviors in processing of rewards while the organism sleeps and is thus

humans are observed in parasomnias: locomotion in sleepwalk- typically deprived of interactions with its environment? Based

ing, aggression in REM sleep behavior disorder, sexual behaviors on recent accumulating evidence showing that memory replay

in confusional arousals, and feeding, chewing or swallowing in the and consolidation processes are present during all sleep stages

sleep-related eating disorder (Schenck et al., 2007; Vetrugno et al., (Diekelmann and Born, 2010; Maquet, 2001; Stickgold, 2005), we

2006; Winkelman, 2006). Hence, the speciﬁc behaviors observed suggest that activation of the ML-DA system during sleep may

1940 L. Perogamvros, S. Schwartz / Neuroscience and Biobehavioral Reviews 36 (2012) 1934–1951

relate to the reprocessing of memories with a high emotional of a reward can boost ofﬂine learning mechanisms during sleep

or motivational relevance (e.g. related to current or future chal- (Fischer and Born, 2009).

lenges). A functional link between memory and reward processes

is substantiated by strong mutual interactions between the hip-

pocampus and the VTA: while memory processing may lead to 4. Reward activation and REM sleep generation

reward activation (‘memory → reward’ direction), following the

downward arc of the HC–VTA loop (Fig. 3A), VTA activity can in turn The role of dopamine in the sleep/wake cycle has been stud-

lead to the reactivation of memories and learning enhancement ied in rodents since more than 30 years (e.g. Monti et al., 1988).

(‘reward → memory’ direction) through activation of the upward Small doses of a D2 preferring dopamine agonist (apomorphine,

arc of the HC–VTA loop (Fig. 3B) (Adcock et al., 2006; Fischer bromocriptine, quinpirole or pergolide) decrease wakefulness and

and Born, 2009; Lisman and Grace, 2005; Shohamy and Adcock, increase the duration of SWS and REM sleep (Dzirasa et al., 2006;

2010). Monti et al., 1988, 1989). It has been proposed that these soporiﬁc

effects are related to an activation of the D2 autoreceptors in

3.1. Memory processing leading to reward activation during sleep the VTA (Bagetta et al., 1988), which induces an inhibition in the

mesolimbic pathway (Szabadi, 2006). On the other hand, moder-

One of the main hypotheses of the RAM is that reward processing ate doses of the D3 agonist pramipexole were found to increase

and memory consolidation interact during sleep. During SWS, this SWS and REM sleep via D3 receptors (Lagos et al., 1998), which

interaction involves the downward arc of the HC–VTA loop (Fig. 3A). are not autoreceptors (inhibitory). Similar results have been found

During this sleep stage, activation of the HC and VS enables the in humans. A small dose of the D2 preferring agonist pergolide

formation of a memory trace comprising both contextual and moti- (Staedt et al., 1997) or the dopamine reuptake inhibitor, bupro-

vational components (Lansink et al., 2009) and could be associated pion (Nofzinger et al., 1995; Ott et al., 2004) induced an increase

with tonic dopamine release in the VTA (Floresco et al., 2003). The of REM sleep duration and density. A moderate dose of pramipex-

coordinated reactivation of both HC and VS during SWS provides a ole produced a reduction of sleep latency, an increase of total sleep

possible mechanism for the consolidation of memory-reward asso- time (Micallef et al., 2009), and of time in REM sleep (Jama et al.,

ciations (Lansink et al., 2009). In particular, the activation of VS 2009). Together, these data show that administration of D2 or D3

reward-related neurons during SWS in rats seems important for agonists can facilitate sleep (including REM sleep), but the exact

selecting memories with a high storage priority (Lansink et al., underlying mechanisms are not yet well understood. Actually, in

2008) and may lead to the optimization of adapted behavior during 2006, Dzirasa et al. demonstrated that a hyperdopaminergic state

wakefulness. Consistent with this hypothesis, declarative memory is necessary for the generation of REM sleep. It seems that both D2

and skill consolidation observed during sleep seem to be guided by autoreceptors and D3 postsynaptic receptors are implicated in this

emotional relevance and/or motivational biases (Cohen et al., 2005; mechanism.

Fischer and Born, 2009; Pennartz et al., 2004; Sterpenich et al., Can reward processing also inﬂuence the regulation of REM

2007, 2009; Wilhelm et al., 2011). Reciprocally, active memory pro- sleep? Low doses of cocaine, a drug that stimulates the ML-DA

cessing could also explain the reward-related sustained bursting reward system, can increase REM sleep in rats (Knapp et al.,

activity of the VTA (Dahan et al., 2007) and NAcc (Lena et al., 2005) 2007). Moreover, in decerebrate cats the introduction of a tube

during REM sleep. The RAM supports that phasic VTA dopamine sig- for gastric feeding (Villablanca, 1966), or other cutaneous, propri-

naling during REM sleep favors an off-line replay of recent memory oceptive and sensory stimuli like repetitive sounds (Jouvet and

traces during this sleep stage (Louie and Wilson, 2001; Peigneux Delorme, 1965; Villablanca, 2004), can induce REM sleep. This

et al., 2003; Walker and van der Helm, 2009). These memories phenomenon may bear some analogy to cataplexy in narcoleptic

could serve both as salient and novel stimuli for the PPT and VTA, patients. Indeed, episodes of REM-like atonia (cataplexy) during

because recent relevant memories (e.g. emotional events, current wakefulness can be triggered by emotional experiences, includ-

concerns) are activated in the absence of associated contextual ing the anticipation of reward (Anic-Labat et al., 1999; Ponz et al.,

cues from wakefulness, and of cognitive control from dorsolateral 2010a; Schwartz et al., 2008; Sturzenegger and Bassetti, 2004), and

PFC (dlPFC) during REM sleep (Fosse et al., 2003; Maquet et al., cataplexy is also triggered by feeding, in narcoleptic dogs and orexin

1996; Schwartz, 2003; Schwartz and Maquet, 2002). Moreover, knockout mice (Clark et al., 2009; Mitler et al., 1974; Reid et al.,

during REM dreaming, dream elements (including bizarre features 1994).

in dreams; Revonsuo and Salmivalli, 1995) could also act as stimuli Based on these ﬁndings, we suggest that the activation of

that potentially drive VTA and NAcc bursting activity. emotionally-relevant information such as reward can potentially

inﬂuence the generation of REM sleep. More speciﬁcally, increased

3.2. Reward activation leading to memory formation during sleep dopaminergic activity in the VTA could modulate activity in brain

regions that are critical for the generation of REM sleep, in partic-

The activation of the VTA (predominantly during REM sleep) ular the sublaterodorsal nucleus (SLD) of the pons, which is a key

may contribute to long-term potentiation (LTP) and memory for- structure for generating REM sleep (Boissard et al., 2002; Clement

mation in the HC (Adcock et al., 2006; Lisman and Grace, 2005). This et al., 2011; Fort et al., 2009). Indeed, VTA provides efferent pro-

mechanism, which is considered necessary for associative learning jections to the SLD, thus potentially gating the onset of REM sleep

(Adcock et al., 2006), is served mainly by the upward arc of the (Boissard et al., 2003). The RAM supports that, at the end of an NREM

hippocampal–VTA loop, namely dopaminergic projections from the episode, the downward arc of the hippocampal–VTA loop, which

VTA to the HC (Fig. 3B). LTP in the HC is dependent on dopamine: involves active memory processing (‘memory → reward’ direction;

it is blocked by D1 antagonists (Bach et al., 1999) and enhanced Fig. 3A), leads to an activation of the VTA, which in turns projects

by D1 agonists (Li et al., 2003; Swanson-Park et al., 1999). Besides, to SLD and gates the onset of REM sleep. In addition, the LH-to-VTA

dopamine transmission can regulate gene expression and lead to orexin pathway could also be implicated. Indeed, occasional burst

permanent synaptic changes (Nestler, 2004; Wolf et al., 2003). A discharges of orexin neurons during REM sleep (Takahashi et al.,

recent behavioral study in humans showed that sleep can induce 2008), with their projections to VTA dopaminergic neurons (Fadel

a signiﬁcantly stronger improvement of a motor ﬁnger sequence and Deutch, 2002), may contribute to reward-driven dopamin-

associated with an anticipated monetary reward (‘sequence to-be- ergic induction or maintenance of REM sleep (a hypothesis that

rewarded after sleep’), thus supporting that the mere expectation would require and may inspire future experimental investigations).

L. Perogamvros, S. Schwartz / Neuroscience and Biobehavioral Reviews 36 (2012) 1934–1951 1941

in brain connectivity across all sleep stages (e.g. Massimini et al.,

2005, 2010).

The speciﬁc pattern of regions activated during REM sleep in

humans is consistent with some main features of dreaming expe-

rience, as we brieﬂy review below (Hobson et al., 1998; Schwartz,

2004; Schwartz and Maquet, 2002) (Fig. 5).

A ﬁrst set of activated regions consists of the PPT, thalamus, basal

forebrain, as well as of limbic and paralimbic structures, including

bilateral amygdala, hippocampal formation, mPFC and ACC (Braun

et al., 1997; Maquet et al., 1996; Nofzinger et al., 1997). Activation of

the amygdala may reﬂect intense emotions, in particular fear and

anxiety, often experienced in dreams (Smith et al., 2004). Amyg-

dala, mPFC and ACC activity could also subserve emotion regulation

Fig. 4. Activation of ML-DA reward system during NREM sleep and the generation

processes (e.g. extinction of fear; Fu et al., 2007; Pace-Schott et al.,

of REM sleep. According to the RAM, tonic dopamine response induced by the down-

2009). Consistent with the RAM, activation of limbic and paralim-

ward arc of the hippocampal–VTA loop may contribute to the generation of an REM

sleep episode. The downward arc of the hippocampal–VTA loop, which involves bic regions suggests that REM sleep could favor the reactivation

active memory processing, leads to an activation of the VTA at the end of an NREM and processing of relevant, novel and emotionally salient memo-

episode. VTA would then provide an excitatory projection to the SLD, which is con-

ries (Sterpenich et al., 2007, 2009; Wagner et al., 2001; Walker and

sidered as the REM sleep generator (red dashed arrow). A hyperdopaminergic state

van der Helm, 2009). This pattern of activation would also allow

related to reward processing could thus potentially contribute to the generation of

the incorporation of recent memories in dreams, which is com-

REM sleep. Projections from orexin neurons or from the amygdala to VTA could also

be implicated. Abbreviations: HC: hippocampus; REM: rapid eye movement sleep; monly observed in dream studies (Schredl and Hofmann, 2003;

SLD: sublaterodorsal nucleus VS: ventral striatum; VTA: ventral tegmental area. (For Schwartz, 2010). When compared to wakefulness, several regions

interpretation of the references to color in this ﬁgure legend, the reader is referred

implicated in executive and attentional functions during wake-

to the web version of the article.)

fulness are signiﬁcantly deactivated during REM sleep, including

the dlPFC, OFC, posterior cingulate gyrus, precuneus, and the infe-

rior parietal cortex (Braun et al., 1997; Maquet et al., 1996, 2000,

Finally, it was also suggested that projections from the amygdala

2005; Nofzinger et al., 1997). Deactivations in these regions may

to SLD may be implicated in emotion-related induction of REM-like

cause disorientation, illogical thinking and impaired working mem-

features, such as muscle atonia (cataplexy) in narcolepsy (Luppi

ory in dreaming (Hobson et al., 1998; Schwartz, 2004; Schwartz

et al., 2011).

and Maquet, 2002). Finally, other activated regions comprise asso-

The VTA was until recently thought to be a dopaminergic struc-

ciative sensory regions and the parieto-temporo-occipital (PTO)

ture predominantly involved in promoting wakefulness (Bagetta

junction which could contribute to the generation of sensory and

et al., 1988; Rye, 2004; Szabadi, 2006). However, there is some

d spatial imagery in dreams (Braun et al., 1997, 1998), and activa-

recent indication that N-methyl- -aspartate (NMDA)-induced VTA

tion in motor circuits (including the cerebellum and basal ganglia,

lesions in cats produce an increase in wakefulness (rather than an

Braun et al., 1997; Maquet et al., 2000) is consistent with dreamed

increase in sleep) (Vetrivelan et al., 2010). Further evidence for the

motor actions.

role of the VTA in REM sleep comes from the canine model of cat-

Changes in dreaming can also be observed after focal brain

aplexy: administration of D2/D3 agonists in the VTA of narcoleptic

lesions. In 1997, Solms established the ﬁrst nosology of dream dis-

dogs induced sleep attacks and aggravated cataplexy, whose under-

orders based on the study of 361 neurological and neurosurgical

lying mechanism implicates the activation of REM-on SLD neurons

patients (Solms, 1997). Approximately one third of these patients

(Luppi et al., 2011; Reid et al., 1996).

reported a global cessation of dreaming subsequent to the brain

Fig. 4 shows how activation of the VTA at the end of a NREM

damage, which predominantly involved a lesion in the PTO junction

episode (stage N2 in humans) may result in an enhancement of

(see also Bischof and Bassetti, 2004; Cathala et al., 1983; Murri et al.,

REM sleep.

1984). Global cessation of dreaming after a lesion in the PTO region

is consistent with the idea that this region may subserve cognitive

5. Reward activation and dreaming functions that are necessary for dreaming such as visual imagery

and spatial cognition. Cessation of dreaming was also observed in

5.1. The neural circuits of dreaming a few patients with lesions in the white matter surrounding the

frontal horns of the lateral ventricles, in about the same region

Dreaming is a state of consciousness in which internally- that was targeted in prefrontal leucotomy (Bradley et al., 1958).

generated sensory, motor, emotional and cognitive experiences Lesions in this region, which provoke dream cessation but maintain

develop into actions and imaginary plots (Desseilles et al., 2011). REM sleep (Solms, 2000), disrupt the ML-DA connections from the

Our knowledge about the neural bases of dreaming derives pri- VTA to the shell of the NAcc, amygdala, HC, ACC and frontal cortex

marily from the study of REM sleep, because this sleep stage has (insular and medial OFC, medial frontal cortex, vmPFC). This cir-

initially been linked to dreaming activity (Dement and Kleitman, cuit corresponds to the mesolimbic circuits of the SEEKING system

1957). Moreover, dream reports are on average more vivid and as described by Panksepp (Alcaro and Panksepp, 2011; Panksepp,

bizarre, with more complex narratives, i.e. are more ‘dream-like’, 1982; Panksepp, 1998) (see Box 2). Solms proposed that a REM

after awakenings from REM than from NREM sleep (Fosse et al., state is not in itself mandatory for dreaming; instead dreaming

2001; Strauch and Meier, 1996). Early neuroimaging studies have would require the activation of the SEEKING system (Solms, 2000).

revealed that the distribution of brain activity during REM sleep Several other observations converge to further support the role of

is not homogeneous but is characterized by speciﬁc activation and this system in dreaming. Prefrontal leukotomy targeting the vmPFC

deactivation patterns (e.g. Braun et al., 1997; Maquet et al., 1996; in patients with schizophrenia caused anhedonia and cessation of

Nofzinger et al., 1997). More recent studies using imaging meth- dreams (Jus et al., 1973). Hyperactivation of the SEEKING system by

ods with increasingly higher temporal and spatial resolution (e.g. the administration of dopaminergic agents like l-DOPA (Nausieda

functional MRI, high-density EEG) have started to describe more et al., 1982; Sharf et al., 1978), amphetamines (Thompson and

transient changes in brain activity (e.g. Dang-Vu et al., 2008) and Pierce, 1999), bupropion (Balon, 1996), and dopamine agonists

1942 L. Perogamvros, S. Schwartz / Neuroscience and Biobehavioral Reviews 36 (2012) 1934–1951

Fig. 5. Functional neuroanatomy of human REM sleep. Brain regions more activated during REM sleep are shown in red and less activated in blue. This ﬁgure combines

the results from studies using PET imaging (Braun et al., 1997, 1998; Maquet et al., 1996, 2000; Nofzinger et al., 1997). Abbreviations: ACC: anterior cingulate cortex; dlPFC:

dorsolateral prefrontal cortex; HC: hippocampus; mPFC: medial prefrontal cortex; OFC: orbitofrontal cortex; PPT: penduculopontine tegmental nuclei; REM: rapid eye

movement sleep. (For interpretation of the references to color in this ﬁgure legend, the reader is referred to the web version of the article.)

(Pinter et al., 1999; Thompson and Pierce, 1999) can induce vivid and motivational value for the individual are privileged to be

dream-like experiences. By contrast, hypoactivity of this system reactivated during sleep, and may thus amplify the activation of

for example after administration of D2 antagonists is associated the ML-DA system and of the SEEKING system.

with a reduction in vivid dreaming (Gaillard and Moneme, 1977),

although this ﬁnding would need replication. Finally, as we pre-

5.3. ML-DA reward system activation and dream content

viously mentioned, reward-related components of the SEEKING

system are active during REM sleep, including the VTA, VS, amyg-

Lesion studies in cats in which REM sleep atonia was prevented

dala, HC, ACC, and vmPFC.

revealed that these animals exhibit a speciﬁc range of behaviors

However, it should be noted that effects of dopamine on dream-

during REM sleep, such as exploration, fear, anger, and groom-

ing may involve interactions with other neuromodulatory systems,

ing behaviors (‘oneiric behaviors’, Jouvet and Delorme, 1965).

like basal forebrain cholinergic cells that activate cortical and lim-

Interestingly, these behaviors could be driven by emotional and

bic structures (Perry and Piggott, 2000). Lesions resulting from

motivational components of the SEEKING system (Panksepp, 1998).

leucotomy may alter not only dopaminergic, but also choliner-

Similarly, patients with RBD may act out their dreams, often in

gic and noradrenergic efferent and afferent connections (Doricchi

the form of aggressive-violent movements mimicking attacks or

and Violani, 2000). Finally, dreaming enhancement, as induced

defense behaviors, with non-violent behaviors being compara-

by dopaminergic agents, can also be observed in patients receiv-

tively less frequent (e.g. Oudiette et al., 2009). Dream reports also

ing a noradrenergic beta-receptor blocker (Thompson and Pierce,

appear to be biased toward content with emotional and motiva-

1999) or cholinesterase inhibitors (Zadra, 1996). Consequently, the

tional value (e.g. socializing, ﬁghting, or sexual activity) and less

interaction of dopaminergic functions with other neuromodula-

oriented toward life content with no such particular value. For

tory systems must be taken into consideration when studying the

example, daily routine activities such as typing, washing dishes, or

neurobiology of dreaming.

buying food at the supermarket, are not frequent in dream reports

(Schredl, 2010).

5.2. ML-DA reward system activation and dream generation Sustained activation of the ML-DA reward system (in particular

the VTA) during REM sleep may favor the activation of stimu-

What force would activate the ML-DA reward system dur- lus representations or behaviors of high motivational relevance,

ing sleep and thus induce dreaming? The RAM proposes that which would induce instinctual exploration as well as approach

dreaming may result from the activation of the reward and emo- and avoidance behaviors. For example, pleasant and positive con-

tional components of the SEEKING system by ‘off-line’ memory tent of a dream (e.g. winning a game or having sex) would constitute

→

and cognitive processes during sleep (‘memory reward’ direc- a rewarding (approach-prone) stimulus, whereas threat-related

tion). This is in agreement with Wamsley and Stickgold (2010) content (e.g. being chased or attacked) would be an aversive

who recently proposed that dreaming may reﬂect sleep-dependent (avoidance-prone) stimulus. NAcc and VTA may be activated inde-

memory processing during sleep, as well as with models stating pendently of the emotional valence of the dream content, because

that dreams are inﬂuenced by waking emotional concerns of the both structures are found to be activated during both reward and

sleeper (Cartwright et al., 2006; Mancia, 2004; Nielsen and Levin, punisher anticipation (Carter et al., 2009; Delgado et al., 2008).

2007; Schredl, 2010). Substantial mesolimbic reward-system acti- Motivational and emotional content may be more prominent in

vation during REM sleep would thus explain why this stage may be REM than in NREM dreaming (Smith et al., 2004). This is consistent

considered as a ‘dream facilitator’. On the other hand, activation of with the ﬁnding that several limbic and ML-DA regions are selec-

contextual and emotional memories by reward-related structures tively activated during REM, with amygdala activity and burst ﬁring

during NREM sleep (amygdala, ACC, hippocampus, ventral stria- in the VTA being signiﬁcantly higher in REM compared to NREM.

tum) could also explain NREM dreaming. We do not know yet what For Smith and collaborators ‘the primary role of the limbic system

the conditions are for a memory trace to facilitate the production during sleep may be to activate the motivational characteristics of

of a dream. We hypothesize that memories with high emotional the sleep experience’ (Smith et al., 2004, p. 502).

L. Perogamvros, S. Schwartz / Neuroscience and Biobehavioral Reviews 36 (2012) 1934–1951 1943

5.4. Links of the RAM to other dream theories behaviors or drives (such as feeding, mating, ﬁghting, ﬂeeing, etc.)

or to memory elements (such as current concerns), as well as to

Dreams may fulﬁll important psychological or cognitive func- novel cues (e.g. novel combinations of elements from memory).

tions. Many theories have been proposed in relation to such Thus, while the RAM supports that the off-line replay of a mem-

functions of dreaming. Below, we show how the RAM may relate ory is responsible for the generation of a dream (see Section 5.2), it

and differ from some of these theories, in particular Freud’s theory also claims that the content and function of this very dream does

of dreams, Hobson’s AIM theory, and Revonsuo’s threat simulation not only relate to episodic memories, as suggested by classic psy-

theory. Note that by confronting the RAM with these theories, our choanalytical theories but also, and importantly, to probable and/or

aim is to better characterize some main features of the RAM but novel experiences. This mechanism would potentially contribute to

not to provide an exhaustive review of theories about dreaming. adaptive behavior by improving future performance and emotion

While activation of ML-DA circuits during dreaming might be regulation processes.

consistent with some of the most important propositions of these

theories, the RAM places the dopaminergic-driven motivational 5.4.2. Activation-input-modulation (AIM) model and RAM

and emotional drives at the center of the dreaming state. We sug- The AIM was introduced by Hobson and offers a charac-

gest that activation of the ML-DA system allows the dreamer to terization of the brain states according to three main factors:

become acquainted with diverse conﬁgurations and rewarding val- activation (total and regional brain activity levels), input–output

ues of a simulated internal environment and thereby establish gating (external versus internal source), and modulation or infor-

realistic and adaptive expectations, which could be used in real mation processing mode (cholinergic versus aminergic) (Hobson,

life situations. Thus, dreams not only result from the activation of 1988, 1999). Within the AIM framework, REM sleep and dream-

memory processes during sleep, but they may also contribute to ing are both characterized by high levels of activation, internal

ofﬂine memory consolidation and learning. The latter hypothesis input, and aminergic modulation. More speciﬁcally, dreams result

is supported by recent studies on dreaming (Wamsley et al., 2010), from internally-generated sensory activation originating from the

on the SEEKING system (Alcaro and Panksepp, 2011), and on VTA’s brainstem (ponto-geniculo-occipital waves), later combined with

role in memory and learning (Adcock et al., 2006). memory and cognitive functions. Hence, according to the last revi-

sion of this model, “dreaming is an indispensable — if sometimes

5.4.1. Freud’s psychoanalytic theory of dreams and RAM misleading — subjective informant about what the brain does dur-

In brief, the theory proposed by Freud in 1900, in his book “The ing REM sleep” (Hobson, 2009, p. 805). Moreover, REM sleep and

Interpretation of Dreams” (Freud, 1995), is based on the fundamen- dreaming would provide us with a virtual reality model, which may

tal assumption that the purpose of each dream is a wish-fulﬁllment: support learning and memory, and may inﬂuence the development

dreams are attempts of the unconscious to resolve a, usually dis- and maintenance of waking consciousness.

turbing, conﬂict from the recent or distant past. A censorship Concerning the role of the dopamine system in dreaming, Hob-

mechanism renders dreams altered and incomprehensible, because son has suggested that the relative persistence of dopamine release

the immediate gratiﬁcation of a wish is usually impossible or could during REM sleep could explain some of the cognitive character-

be unwise or unsafe (‘pleasure principle’ opposing the ‘reality prin- istics of dreaming (such as visual hallucinations, bizarreness, and

ciple’). This mechanism makes anxiety-arousing wishes tolerable lack of self-reﬂective awareness), which may resemble psychosis in

for the conscious. Furthermore, because dreams would preserve mental illnesses (Scarone et al., 2008). While both models are not

sleep by giving an acceptable form to the satisfaction of a desire incompatible, a main difference between Hobson’s view and our

(mainly sexual) they are considered by Freud to be the ‘guardians’ proposal in the context of the RAM concerns the functional role of

of sleep. ML-DA system activation during sleep. In particular, the RAM pro-

On the one hand, the RAM supports some of Freud’s claims vides the ﬁrst integrated and detailed description of how activation

about dreaming because it proposes that activation of the SEEKING of the dopamine system and limbic circuits during sleep and dream-

reward-related system (urge for Freud) could generate dreaming ing may contribute to important cognitive and affective functions

(production) and could preserve dream continuation (mainte- pertaining to memory, emotion, and motivation.

nance). In particular, a wish in the Freudian taxonomy could

correspond to the anticipation of a reward, and a threat could corre- 5.4.3. Threat Simulation Theory (TST) and RAM

spond to the anticipation of a punisher that would trigger avoidance The Threat Simulation Theory (TST) was initially proposed by

behavior or seeking of safety (which may typically fail in night- Revonsuo (2000) and then further developed by Revonsuo and

mares). On the other hand, while many bizarre aspects in dreams Valli (2009). According to the TST, the function of dreaming is to

may relate to changes in regional brain activity and in functional allow an organized and selective ofﬂine simulation of threaten-

connectivity between brain regions (see Section 5.1 above), the ing events that would ultimately promote the development and

Freudian notion of an active censorship that would transform the maintenance of threat-avoidance skills. Supporting the universal-

original or ‘latent’ content of a dream into some ‘apparent’ (usually ity and prevalence of threatening experiences in dreams, being

bizarre) content lacks neurobiological support. Moreover, unlike chased or attacked is the most typical dream theme around the

the Freudian model of dreaming, the RAM also implies that dreams world (Zadra, 1996). Behaviorally and perceptually realistic threat-

can be potentially related to novel events or to some probabilistic ening experiences in a dream would trigger the activation of a

future, and not only to the past. Although, there is evidence for the threat simulation system, and also underlying brain circuits, in

presence of past and current waking concerns in the dream con- particular the amygdala. Such a virtual rehearsal during dream-

tent (Cartwright et al., 2006; Schredl and Hofmann, 2003), dreams ing would lead to improved performance in real life situations and

are usually novel constructions and rarely reproductions of past this training could be used as learning or maintenance of threat

events (Meier, 1993). Actually, while a large proportion of dream avoidance skills (Valli and Revonsuo, 2009). Support for the the-

elements comes from recent memory (Schwartz, 2003), integrated ory comes from the study of dreams in traumatized populations

life episodes are incorporated in no more than 1–2% of dreams who simulate threatening events in their dreams more often than

reports (Fosse et al., 2003). non-traumatized populations (Valli et al., 2005), as well as from the

The RAM proposes that dreaming, by activation of the reward observation that REMSD impairs threat avoidance responses in real

system, exposes and trains the dreamer to motivationally- or life (e.g.Martinez-Gonzalez et al., 2004). The TST therefore suggests

emotionally-relevant stimuli, which may relate to instinctual plausible psychological and biological functions for dreaming and is

1944 L. Perogamvros, S. Schwartz / Neuroscience and Biobehavioral Reviews 36 (2012) 1934–1951

consistent with ﬁndings on the predominance of negative emotions et al. (2007) suggested that a hyperdopaminergic state leads to

in dreams. impaired computation of prediction errors as well as to an aber-

The RAM appears as a useful supplement to the TST because it rant assignment of salience to elements from one’s own experience

explains why emotionally-relevant experiences (including threat- (see Heinz and Schlagenhauf, 2010). Hallucination would reﬂect the

related information, but not exclusively) have a higher probability direct experience of these aberrantly salient experiences, whereas

of being activated during dreaming and have a preferential access attempts to make sense of those experiences would result in delu-

to sleep-related consolidation processes. We propose that the sions.

acquaintance of individuals with diverse stimuli and the establish- Is there a link between increased dopaminergic activity in psy-

ment of realistic and adaptive expectations during dreaming are chotic patients and the characteristics of their dreams and their

served by the SEEKING system. Importantly, this system would also sleep? Studies addressing this question showed that, in these

protect an animal from aversive stimuli or punishment by promot- patients, cognitive bizarreness during wakefulness correlates pos-

ing the seeking of safety (Alcaro et al., 2007; Alcaro and Panksepp, itively with cognitive bizarreness of their dream reports (Scarone

2011; Delgado et al., 2008). Exposure to feared stimuli (e.g. char- et al., 2008). Note that dream experiences in schizophrenic patients

acters, situations, thoughts, memories, physical sensations) in a also appear to be both more bizarre (Noreika et al., 2010) and more

totally safe context during dreaming may resemble exposure ther- violent (Schnetzler and Carbonnel, 1976) than those of healthy con-

apy for anxiety disorders (Pace-Schott et al., 2009). Nightmares trol subjects. In addition, REM density and sleep duration correlate

would by contrast reﬂect the failure of an adaptive fear memory negatively with the global severity of clinical symptoms (measured

extinction process, in the presence of temporary (e.g. daily con- by the Brief Psychiatric Rating Scale total score – BPRS) (Poulin et al.,

cerns) or more persistent (e.g. trauma) increases in affect load 2003), and with positive symptoms (Yang and Winkelman, 2006) in

(Nielsen and Levin, 2007). drug-naïve patients with schizophrenia. The study of sleep param-

The RAM is therefore in agreement with the TST and extends eters (e.g. REM density) and dream content could thus provide

it by proposing that one of the main functions of dreaming is useful insights into the pathophysiology of early-onset psychosis

to expose the dreamer to rewarding or aversive stimuli, in order and schizophrenia, and may offer a potential biomarker for the evo-

to maintain and improve ofﬂine memory consolidation processes lution of these diseases. Research in this domain has scientiﬁc and

and performance in real life situations, while also contributing clinical relevance, and should be encouraged.

to emotion regulation processes. Because it is responsible for the

appetitive motivational drives (like sex) and exploratory behav- 6.2. Sleep and emotion regulation

iors (like exposure to a potentially harmful/rewarding stimulus),

the engagement of ML-DA circuits, as modeled in the RAM, offers a Emotions in dreams (see Section 5.3) as well as the activation of

plausible neurophysiological and neurocognitive model of dream- cerebral regions specialized in emotional processing during sleep

ing that integrates and complements the fear-related amygdala (see Section 5.1) lend support to the idea that sleep may contribute

mechanisms proposed by the TST. to emotion regulation processes (Cartwright et al., 1998; Desseilles

In summary, the three theories of dreaming reviewed here sug- et al., 2011; Nielsen and Levin, 2007). Although an exhaustive

gest important and distinct emotional and cognitive functions to review on this contribution is beyond the scope of the present

dreaming (i.e. wish fulﬁllment, performance improvement, threat article, below we discuss two instances where sleep relates to emo-

simulation). These functions, including their underlying neurobi- tion regulation: the link between insomnia and depression, and the

ological mechanisms, can be implemented within the framework effects of sleep deprivation on emotional processing.

of the RAM, which thus offers to sleep science an integrative link

between sleep neurophysiology, cognition and dream content. 6.2.1. Insomnia and sleep loss as precursors of depression via

alteration of brain reward networks

Reward-related deﬁcits, such as decreases in the capacity to

6. Clinical context

seek out rewards, in decision-making, and in the ability to experi-

ence pleasure, are core characteristics of depression (Der-Avakian

Activation of the ML-DA reward system during sleep and

and Markou, 2012). A down-regulation of dopamine-related SEEK-

dreaming may constitute a model for the understanding of some

ING resources has been hypothesized in major depressive disease

neuropsychiatric disorders such as psychosis, depression, and com-

(Alcaro and Panksepp, 2011), and a dysfunction in mesolimbic and

pulsive behaviors.

non-mesolimbic reward structures and networks has been docu-

mented (Blood et al., 2010; Nestler and Carlezon, 2006; Pizzagalli

6.1. Psychosis and dreaming et al., 2009; Tremblay et al., 2005). Insomnia is another main symp-

tom of the depressive disorder (Tsuno et al., 2005). Depression may

The notion that psychosis and the dream state may share some be considered as a risk factor for insomnia (Ohayon and Roth, 2003),

common underlying mechanisms has a long history. For example, while insomnia was found to represent an independent major

in the late 19th century, the neurologist Hughlings Jackson claimed: risk of subsequent onset of major depression (Buysse et al., 2008;

“Find out about dreams and you will ﬁnd out about insanity” (cited Johnson et al., 2006; Riemann and Voderholzer, 2003; Roane and

in Gottesmann, 2006). Recently, there has been a renewed interest Taylor, 2008). Because of their reciprocal relationships, insomnia

in the notion that the dreaming state could serve as a neurobiologi- and depression are increasingly considered as comorbid conditions

cal model of psychosis (Gottesmann and Gottesman, 2007; Hobson, that would share some common underlying causal mechanisms

2004; Noreika et al., 2010; Scarone et al., 2008). Both states present (Staner, 2010).

phenomenological similarities, including sensory hallucinations, Sleep restriction induces neuroendocrine disturbances, in par-

bizarre imagery, diminished reﬂectiveness, and intensiﬁcation of ticular HPA (hypothalamic–pituitary–adrenal) axis stimulation

emotion (Scarone et al., 2008). At the brain level, dreaming and (Novati et al., 2008; Spiegel et al., 1999), that are also observed in

psychosis are characterized by dlPFC deactivation, a breakdown depression (Holsboer, 2000). Such ‘hyperarousal mechanism’, sim-

of cortical connectivity, and speciﬁc neurochemical variations (in ilar to what is usually observed in insomnia, may partially but not

particular hyperdopaminergia). totally explain a direct causality between insomnia and depres-

Hyperactivation of the dopaminergic reward system seems to sion. Activation of reward networks during sleep as proposed here

be present in both psychosis and dreams. Kapur (2003) and Corlett could be a supplementary mechanism explaining why disturbances

L. Perogamvros, S. Schwartz / Neuroscience and Biobehavioral Reviews 36 (2012) 1934–1951 1945

in sleep quality or quantity may precede clinical depression and sleep disturbances, could lead to compensatory drug and food seek-

participate in its occurrence. Indeed, chronically disrupted sleep ing in vulnerable subjects (Alcaro and Panksepp, 2011; Koob, 2009;

and insufﬁcient sleep time (<6 h), known to produce cognitive per- Zellner et al., 2011), as shown in animals (Puhl et al., 2009) and

formance deﬁcits (Van Dongen et al., 2003) and negative affective humans (Benedict et al., 2012). Disturbances of circadian (Forbes

states (Banks and Dinges, 2007; Meerlo et al., 2008; Zohar et al., et al., 2012; Hasler et al., 2012) and neuroendocrine (Van Cauter

2005), may alter reward processing in a way that would precipitate et al., 2008) mechanisms may also be implicated in these inter-

a depressive, reward-deﬁcient symptomatology (anhedonia, abou- actions. Future longitudinal studies could also be useful to further

lia, impaired decision making) (Der-Avakian and Markou, 2012). substantiate and clarify these links between sleep disturbances and

A probable down-regulation of reward and emotional processes, compulsive behaviors like addictions.

especially during NREM sleep should be further investigated, since

decreased slow wave sleep and slow wave activity may charac-

terize both primary insomnia (Merica et al., 1998) and depression 7. Limitations and testability of the model

(Armitage, 2007). Longitudinal studies examining the effects of

chronic sleep restriction in reward networks and correlating them In this article, we propose that reward-related mechanisms con-

with mood disturbances are needed in order to further establish tribute to the generation of both REM sleep and dreaming. However,

a causal relationship between insomnia and depressive disorder. we do not claim that the same pathways within the ML-DA system

Similar evidence is also needed for the hypomanic/manic phases fulﬁll both functions, as it is well established that REM sleep and

of bipolar disorder, which have been also causally associated with dreaming are dissociated states (Solms, 2000; Oudiette et al., 2012).

sleep disturbances, like sleep reduction (Plante and Winkelman, The REM sleep generator is located in the brainstem (Luppi et al.,

2008; Wehr et al., 1987) and circadian dysregulations (Roybal et al., 2011), whereas the dream generator probably implicates mesolim-

2007; Harvey, 2008). bic/mesocortical networks (Solms, 2000). Accordingly, the RAM

claims that the activation of emotionally-relevant information such

6.2.2. Evidence from sleep deprivation studies as reward can potentially favor the generation of both REM sleep

Further evidence from SD studies in non-depressed subjects and dreaming, while this most probably happens via dissociated

supports the role of sleep in waking emotion regulation processes. mechanisms. Whereas dreaming is inﬂuenced by ascending ML-

SD can lead to reduced disappointment in response to losses in DA mechanisms (e.g. SEEKING system; see Section 5.1 and Fig. 2),

a gambling task, together with decreased activity in the insular reward-induced REM sleep would primarily implicate descending

cortex (Venkatraman et al., 2007), which is thought to process projections from the hippocampus to the midbrain, and from the

the emotional signiﬁcance of a stimulus, including the somatic midbrain to the REM sleep generator (see Section 4 and Fig. 4).

affective response (e.g. autonomic changes in blood pressure) and Therefore, we conjecture that disconﬁrmation of the former mech-

introspective awareness (Critchley, 2005; Ernst and Paulus, 2005; anism would not mean disconﬁrmation of the latter, and vice versa.

Singer et al., 2009). Because the insular cortex is activated during It should be also noted that, while reward-related dopaminergic

both NREM (Nofzinger et al., 2002) and REM sleep (Maquet et al., activity would facilitate the generation of REM sleep, it does not

2000), one could hypothesize that SD interferes with emotional seem necessary for REM sleep to occur. Other non-dopaminergic

functions subserved by the insula. In addition, SD causes an ampli- mechanisms and structures (Boissard et al., 2003; Luppi et al.,

ﬁed response of amygdala to negative emotional stimuli, paralleled 2011), that are not described in this article, are also implicated in

with a hypoactivity of the mPFC, suggesting a failure of top-down the generation and maintenance of REM sleep. Similarly, dream-

cortical control from the mPFC on the amygdala (Yoo et al., 2007). ing is not exclusively dopamine-driven, and may for example also

This latter result indicates that sleep is necessary for the functional imply other components of the SEEKING system, such as ascending

integrity of amygdala–PFC circuit, which is responsible for adapted noradrenergic and descending glutamatergic inﬂuences (Panksepp,

emotional responses during waking life. As a complement to this 1998). Moreover, dopamine alone certainly does not account for the

ﬁnding, a recent study supports that SD ampliﬁes the reactivity whole range of cognitive and emotional processes occurring dur-

of reward networks in healthy volunteers, when exposed to pos- ing sleep. Other neuromodulatory systems with many of which the

itive emotional stimuli (Gujar et al., 2011). These recent studies dopamine system interacts also contribute to these functions.

demonstrate that combining behavioral and brain imaging mea- Another limitation of the RAM model is that many of the exper-

sures signiﬁcantly improve our understanding for the effects of SD iments supporting the role of dopamine in sleep/dream generation

on waking emotional processing and reward functions. These stud- and the activation of reward structures (VTA, striatum) during

ies thus offer a very promising approach for future experiments that sleep were performed in animals (mainly rodents). However, as we

could be applied to both controls and patients. have shown above, animal data are mostly consistent with existing

human pharmacological studies (Ferreira et al., 2002; Jama et al.,

6.3. Sleep and compulsive behaviors 2009; Micallef et al., 2009; Ott et al., 2004; Pinter et al., 1999; Staedt

et al., 1997; Ye et al., 2011), clinical (D’Agostino et al., 2010; Gaillard

Compulsive behaviors like drug addictions are characterized and Moneme, 1977; Sharf et al., 1978; Solms, 1997), and with SD

by an inability to reduce the occurrence of an approach behav- studies (Gujar et al., 2011; Holm et al., 2009; McKenna et al., 2007;

ior toward a primary or secondary reward (e.g. food, drug), and Menz et al., 2012; Venkatraman et al., 2007; Volkow et al., 2012).

by a negative emotional state when the access to the reward is More research is thus awaited to further conﬁrm a similar recruit-

precluded. It is now well established that compulsive behaviors ment of the reward system in human sleep and its implication in

may relate to a dysregulation of the hedonic (OFC, insula), emo- dreaming and REM sleep generation.

tional (amygdala) and motivational (VTA, NAcc) components of the In this article, we have proposed a model for sleep and dreaming

reward networks (Koob, 2009; Koob and Volkow, 2010). which is inspired and supported by a rich and comprehensive set of

Recent ﬁndings suggest that sleep problems like insomnia experimental data. Beyond the integration of existing data, the RAM

may developmentally precede and predict early onset of alcohol, aims at improving our knowledge about the inﬂuence of the ML-

cigarette and marijuana use in adolescents and young adults (Roane DA system on memory, sleep and dreaming processes by fostering

and Taylor, 2008; Shibley et al., 2008; Wong et al., 2004, 2009). new research in this domain. The speciﬁc hypotheses put forward

Here, we propose that a disruption of brain reward and SEEKING in the model are therefore amenable to experimental conﬁrmation

networks, as well as ineffective emotion regulation processes due to or falsiﬁcation, as we suggest hereafter.

1946 L. Perogamvros, S. Schwartz / Neuroscience and Biobehavioral Reviews 36 (2012) 1934–1951

One central hypothesis of the RAM is that activation of the reward system during sleep and dreaming contributes to adaptive

ML-DA reward system during sleep enhances the overnight con- memory processes, leading to subsequent performance improve-

solidation of rewarded or emotionally-relevant memories. This ment during wakefulness.

hypothesis can be directly addressed by studying the inﬂuence By developing a new model for sleep and dreaming, our aim

of a pharmacological manipulation of dopamine activity during was to allow the integration of prominent hypotheses about ofﬂine

sleep on the consolidation of recent rewarded versus non-rewarded cognitive and emotional processes during sleep, including memory

memories in healthy volunteers (e.g. using dopamine D2/D3 recep- consolidation, threat simulation, and performance improvement.

tor agonists versus antagonists, Pessiglione et al., 2006; Ye et al., In addition, this model can be applied to clinical conditions and pro-

2011). The model predicts that an increase in dopamine activ- vide insights into the pathophysiology of disorders like depression,

ity boosts (while a decrease would suppress) the advantage of schizophrenia and addiction. Moreover, because sleep curtailment

rewarded over non-rewarded stimuli for consolidation during emerges as a major health problem, with disastrous socioeconomic

sleep. A similar pharmacological approach could be used to test the and public safety consequences, demonstrating that sleep affects

hypothesis that ML-DA activation inﬂuences the regulation of REM learning and emotion regulation may be useful to promote mea-

sleep, by investigating the effects increased or decreased dopamine sures aiming at preventing sleep restriction (and its consequences),

during sleep on polysomnographic parameters (e.g. REM density particularly in the most vulnerable populations, such as for example

and duration). psychiatric patients or children.

The notion that motivationally-relevant information is prior- We think that the RAM provides a timely and useful integra-

itized for subsequent reprocessing during sleep can be directly tion of neurophysiological, clinical, and neuroimaging approaches

assessed by measuring changes in brain activity or connectivity to sleep and dreaming. This integration has become possible thanks

during sleep (fMRI or PET) following a learning task involving to recent neuroscientiﬁc evidence about the activation of the ML-

rewards or not, with the prediction that ML-DA regions and their DA system during sleep and reward processing. The RAM thus offers

connectivity with the hippocampus should be enhanced. This imag- a comprehensive model that combines different levels of descrip-

ing approach in humans would somehow mimic the study by tion, from the basic neurobiology of reward and sleep functions

Lansink et al. in rats (Lansink et al., 2008), and is methodologi- to affective and cognitive levels encompassing dreaming and con-

cally feasible (e.g. Bergmann et al., 2012; Peigneux et al., 2004; van sciousness in humans.

Dongen et al., 2011). A similar brain imaging approach could be

applied to test for the role of the ML-DA activation in the generation

Acknowledgements

and the motivational content of dreams, for example by performing

correlation analyses at the individual level between dream param-

This work is supported by grants from the Swiss National Science

eters (quantity of dream recall, motivational content of the dream

Foundation, the Swiss Center for Affective Sciences, the Mercier

reports) and measures of brain activity or connectivity during sleep

Foundation, and the Boninchi Foundation.

(Schwartz and Maquet, 2002).

The contribution of ML-DA activity during sleep may also be

investigated by studying the effects of SD and insomnia on emo-

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