Dopamine neurons in the ventral tegmental area modulate rapid eye movement sleep

The discovery of rapid eye movement (REM) sleep is attributed to the landmark observations of Eugene Aserinsky and Nathaniel Kleitman. In 1953, they identified periods of “active sleep” that are marked by REMs that alternate with “quiescent sleep” periods in human infants. Several years later Dement and Kleitman showed that REMs are correlated with specific patterns of brain wave activity and that vivid dreaming occurs during periods of REMs in human adults. Shortly thereafter, Jouvet identified a similar behavioral state in cats, showing that cats also experience periods of REMs that occur during periods of muscle atonia and wake-like cortical activity. REM sleep, or REM sleep-like states, have subsequently been identified in a variety of animals, including marsupials, birds, fish, insects, octopi, and lizards. These observations suggest that REM sleep is conserved across the animal kingdom and imply that REM sleep plays a role in normal biology and physiology. Although REM sleep was initially characterized by REMs, we now know that it is also characterized by a range of physiological features, including reduced amplitude and faster frequency cortical electroencephalogram that is reminiscent of waking, high-amplitude theta waves in the hippocampus, active suppression of skeletal muscle activity (i.e. REM atonia), intermittent muscle twitches, autonomic and respiratory activation, fluctuations in brain/body temperature, and an elevated arousal threshold. Because REM sleep is marked by a waking-like electroencephalogram pattern coupled with skeletal motor atonia, some scientists use the terms “active sleep” or “paradoxical sleep” when referring to REM sleep. Research over the past several decades has shed light on the biological functions of REM sleep and has provided scientists/clinicians with considerable insights into the anatomic bases by which it is regulated. Although Jouvet found that REM sleep is generated by structures in the pons, considerable advances in our understanding of REM sleep mechanisms have emerged over the past two decades. Many of these advances are attributable to the advent of novel neuroscience tools (e.g. optogenetics and genetic sensors) that have enabled high-precision interrogation of the brain circuits and neurochemicals that control REM sleep. For example, we now know that circuits beyond the pons (e.g. medulla, midbrain, and hypothalamus) also influence the timing, duration, and hallmark features of REM sleep. This commentary was sparked by recent findings that a new, but unexpected, cluster of midbrain neurons appears to play a role in REM sleep control. In a recent edition of Science, Hasegawa et al., in their paper entitled Rapid eye movement sleep is initiated by basolateral amygdala dopamine signaling in mice, found that dopamine neurons in the ventral tegmental area and dopamine receptor-expressing neurons in the amygdala influence the timing of REM sleep. Hasegawa et al.’s findings are not only novel but also provocative because dopamine neurons are typically thought, and have previously been shown, to promote arousal. Dopamine neuronal control of REM sleep, therefore, represents a new frontier in the search for the circuits that modulate REM sleep. Based on the novel and provocative nature of Hasegawa et al.’s findings, members of SLEEP’s editorial board felt that it would be useful to engage the opinions and feedback of experts who study REM sleep mechanisms. Below are the commentaries from Drs. Fraigne, Luppi, Mahoney, De Luca, Shiromani, and Weber, wherein discuss the strengths, limitations, and new questions that Hasegawa et al.’s study provides in the field of sleep science. The role of dopamine neurons in regulating sleep–wake states has, until recently, been mostly overlooked [1, 2]. This is despite the fact that the most efficient wake-promoting drugs (e.g. modafinil) enhance arousal via dopamine-dependent mechanisms [3, 4], and that pharmacological manipulation of dopamine receptors influences sleep [5] (both D1 and D2 dopamine receptor agonists cause arousal), and that some dopamine neurons change their activity across the sleep–wake cycle [6]. A recent paper by Hasegawa et al. proposes that dopamine cells in the ventral tegmental area (VTADA) and neurons expressing dopamine receptor D2 in the basolateral amygdala (BLAD2R) gate the onset of rapid eye movement (REM) sleep (Figure 1,A), and that VTADA neurons might play a role in the pathophysiology of cataplexy—a core disease symptom in narcolepsy [7]. My commentary not only aims to highlight Hasegawa et al.’s findings but also aims to raise questions that were not resolved/answered in Hasegawa et al.’s paper. Dopamine control of REM sleep. (A) Hasegawa et al. proposed that dopamine (DA) cells in the ventral tegmental area (VTADA) silence neurons expressing dopamine receptor D2 in the basolateral amygdala (BLAD2R) to engage REM sleep. However, it remains unclear through which pathway they connect with REM-generating neurons of the mesopontine junction. This could be done through activation of GABA-releasing neurons of the central of the amygdala that neurons and the of REM sleep. Hasegawa et al. showed that in the in the occurs a the into REM sleep from sleep by a VTADA neurons in a a of dopamine that dopamine D2 receptors (both and or by of dopamine dopamine D1 The of dopamine is by the of of neurons to through dopamine which be by wake-promoting drugs (e.g. and D2 receptors are also on the and the activity of dopamine and neurons D1 and D2 remains to be a in D1 to could and REM sleep. In et al. the to that VTADA a with and are active in and REM sleep, and their activity the from to REM sleep Based on Hasegawa et al. to which from VTADA neurons are for the dopamine on REM sleep [7]. VTADA neurons to the the the the and the has the neurons in the which of these might modulate REM sleep, they a dopamine on a dopamine receptor D2 This for of dopamine in the field of VTADA including the through states of and REM sleep. found that dopamine in the and a into REM sleep (Figure it in the and a role of VTADA Hasegawa et al. VTADA a and that activation of VTADA in the from to REM sleep [7]. a that cells through a they D2 receptor-expressing neurons in the and found that also from to REM sleep [7]. that dopamine from the in the neurons which cause and structures that REM sleep. These the of muscle is a of have previously that occurs through the of the that REM sleep muscle atonia These are by by in and in and we and have that is through the activation of cells in the central of the amygdala we have also that pharmacological activation of dopamine D2 receptors in the of the by Hasegawa et al. of the could also was and their that dopamine in the of in the of in the mechanisms of Hasegawa et al. found that of VTADA during dopamine in the and some behavioral that This is was in animals, which found that cells in with an of which similar and have previously identified similar behavioral in This was through manipulation of neurons of the cells of the signaling or activation of tegmental neurons behavioral and REM sleep be and to be by cortical and motor activity a behavioral For example, is characterized by a of muscle that is and by motor a specific cortical activity that from is in REM sleep, and an to be by (e.g. The by Hasegawa et al. to be to the mechanisms that these The by Hasegawa et al. that VTADA neurons modulate the timing of REM sleep through their with neurons some of their with and their the that VTADA dopamine in the REM sleep. it is that dopamine in the a the onset of REM sleep the from the onset of of VTADA or of until the onset of REM sleep is a the into REM sleep which occurs only the of dopamine in the during sleep (Figure when is that the not dopamine to (i.e. in the into REM sleep. it is that the dopamine in the to REM sleep onset from of dopamine neurons to cells in the (both the and dopamine (e.g. also to the is also that the of manipulation (i.e. by Hasegawa et al. not the of most dopamine VTADA neurons in a with the of dopamine that dopamine D2 receptors or by of dopamine dopamine D1 receptors (Figure [6]. VTADA neurons during REM sleep similar to is and [6]. The in the Hasegawa et al. study (i.e. the pattern of VTADA from to In it would be to the with or by that and rapid (e.g. to the on REM sleep and the of neurons (i.e. in the also remains unclear neurons are with the circuits that REM sleep because these neurons not to the amygdala (Figure Hasegawa et al. suggest that of might the to with we and have previously that activation of GABA-releasing neurons and that these neurons to and that in connect with cells (Figure activation of cells neurons and which cause muscle atonia during REM sleep and However, during our activation of neurons only but not REM sleep, that circuits are to of REM sleep. by and has that the state of is from the state of REM sleep For example, we showed that the during is the theta activity during REM sleep, and that muscle in REM sleep are during of of and of their which is from during REM sleep would be of to a similar dopamine in the REM sleep from sleep or cause a when initiated during it remains to be the circuits in states are Many play a role in REM sleep and it is that has to be with our understanding of the that REM sleep. the a activation of specific pathway REM sleep with a and of is to REM sleep by In Hasegawa et al. that dopamine in the not with of REM sleep (e.g. REM sleep or it be to these the to REM sleep a that the timing of REM sleep. REM sleep is characterized by the fact that REM sleep is during REM sleep periods and an of to the REM sleep The by Hasegawa et al. is by our that of a in pharmacological on REM sleep or The use of in also but in the was in the VTADA or These and the activity of dopamine neurons (Figure This that the in in these was to a in dopamine the activation of dopamine the findings by Hasegawa et al. to be with showing that or through of dopamine neurons arousal. The most wake-promoting drugs (e.g. modafinil) arousal by dopamine to dopamine the of dopamine in the which dopamine receptors (Figure of the D1 receptor pathway with D1 agonists to arousal of D2 agonists D2 arousal and in and REM sleep the study by et al., which that VTADA neurons are active during and REM sleep, also showed that activation of VTADA neurons arousal from sleep and of sleep was not only when dopamine were but also when the of dopamine from in the This was most by the activation of which are also active during and REM sleep (Figure it is that of by Hasegawa et al. on is the use of and the of dopamine through D1 or D2 mechanisms. This could be similar to a D1 to D2 in the or promote In recent et al. showed that a (i.e. of the D1 receptors and a (i.e. D2 receptor and in the of the VTADA role in sleep–wake control of VTADA and dopamine in or might the through which or REM sleep are (Figure In study new into our understanding of REM sleep control and the of the dopamine in sleep–wake [7]. 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In they also found neurons in the central amygdala and it is these neurons are to the neurons not to the ventral hippocampus, and central amygdala would have been the across the brain to the structures in the pons are and during REM sleep are also In the of their the found that was also a in in the when were which was by they the in the and a of an in were when the neurons expressing D2 of in the the of that neurons to the are to the and and Hasegawa et are the amygdala has been previously in the of it is not the for REM sleep. the amygdala has been in and reduced in but on REM sleep amygdala in not a in REM sleep it has been that neurons have similar of activity during and REM sleep their and sleep with in REM sleep The in REM was to an in the of not their the of neurons by optogenetics an to These that dopamine from neurons is to REM sleep and are the role of in REM sleep In the provided by Hasegawa et al. are in that the by dopamine of neurons via D2 receptors neurons and neurons in the central that neurons play a role in REM sleep and However, are a of that and the central amygdala not play a role in REM sleep In the fact that the of and REM sleep and that they a REM sleep similar to that of REM sleep that neurons are not a core of the REM sleep but are to The to REM sleep that the is not to a of central amygdala neurons to the core REM-generating in the in a the would have been The fact that the is a core for that the is with the of REM sleep. a of that REM sleep plays a role in is to that by on a in the neurons that are for regulating a during REM sleep. that during REM sleep and is by neurons and their to the ventral or these it might be that a is to the REM sleep that or REM sleep is to the are to This be from a to which brain or cause the into the state of rapid eye movement (REM) sleep, or a to are the of REM sleep for the in terms of or of brain we discuss the recent findings from Hasegawa et al. on the role of ventral tegmental area dopamine (VTADA) neurons in REM sleep and the on the of sleep. VTADA neurons have been to activity during REM sleep, and sleep and during sleep and but neuronal of the have been to have a role in and sleep In Hasegawa et al. an pathway by which the of the basolateral amygdala from neurons that the dopamine (DA) the onset of REM sleep. 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A of sleep is the rapid eye movement (REM) and sleep, the or sleep Research over the past has identified in the of REM sleep an of This has in an of the REM sleep and and their However, the mechanisms or signaling that when REM sleep is initiated and the sleep cycle are A recent study has identified in the of REM dopamine receptor D2 neurons in the basolateral amygdala a receptor for dopamine Hasegawa et al. the in the and found that the sleep to signaling in the is in REM sleep the the of neurons from the midbrain ventral tegmental area to the For activation, the the in which a of of when by a of the the of REM sleep. In of the REM sleep. The neurons expressing and that of agonists and into the amygdala REM sleep Hasegawa et al. in that activation of in the a of to of of neurons in REM sleep, their activation reduced REM sleep. these that neurons in the REM sleep, their by from the a of which in to an in REM sleep. have a role of the amygdala in a of muscle atonia into of narcolepsy Hasegawa et al. signaling in the also be in the receptor the the in the in the a of to in and neurons in the of in mice, in the during could a because it that in the mechanisms in In to and for the role of neurons in the of REM sleep, the proposed that their findings a novel for the of the sleep that the in which the and the (Figure and in Hasegawa et sleep and REM sleep. The showed that a to the a of the the of the during and in Hasegawa et the was by REM sleep only a of that is the has to The that a to a of neurons in the the (Figure and in Hasegawa et the light and the not REM sleep in a but the of the promote a state to sleep and the of REM sleep in REM sleep was to an of REM sleep In it be an for to or signaling a of neurons enhance REM sleep. For example, in to a of an for receptors into the amygdala has been to also REM sleep the neurons in the with REM sleep neurons in the and to REM sleep and remains an for A pathway the of neurons in the central of the amygdala by the activation of the central of the amygdala neurons has been previously to promote through the of REM neurons in the midbrain the that neurons by the REM the that the neurons and the in and during to REM sleep insights into the neurons are with REM sleep the of the a to REM sleep is similar to the activity pattern for REM sleep neurons in and which are typically during the sleep to REM sleep that the in the in with REM it remains an for a in the REM sleep with specific neurons REM sleep, or a in which REM sleep. In the study by Hasegawa et al. a novel for the of REM sleep and an role of in REM sleep control and findings are of to for the of narcolepsy and to neurons are and the brain regulating REM sleep. The commentaries from Drs. Fraigne, Luppi, Mahoney, De Luca, Shiromani, and highlight the strengths, limitations, and new insights that Hasegawa et al.’s findings in the field of sleep and our understanding of rapid eye movement (REM) sleep control. A that emerged was that Hasegawa et al.’s study to the of that REM sleep is by a of circuits the Research over the years has identified neurons in the medulla, pons, and midbrain in REM sleep control. Hasegawa et al.’s now that dopamine neurons in the ventral tegmental area and dopamine receptor-expressing neurons in the basolateral amygdala also to the of REM sleep. by dopamine receptor-expressing neurons in the basolateral amygdala with the neurons that REM Although it has been years that structures in the pons REM sleep, the neurons for REM sleep Although that neurons in the tegmental that the are for REM sleep the of these remains that REM-generating neurons be or in a central in sleep biology neurons REM not only sleep scientists to REM sleep is generated but it also for a of the of the of circuits that have been identified to Rapid eye movement sleep is initiated by basolateral amygdala dopamine signaling in et al. Science,

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