- Email: [email protected]
Why does serotonergic activity drastically decrease during REM sleep?
Medical Hypotheses 81 (2013) 734–737
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Why does serotonergic activity drastically decrease during REM sleep? q Kohji Sato ⇑ Department of Anatomy & Neuroscience, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashiku, Hamamatsu, Shizuoka 431-3192, Japan
a r t i c l e
i n f o
Article history: Received 16 May 2013 Accepted 21 July 2013
a b s t r a c t Here, I postulate two hypotheses that can explain the missing link between sleep and the serotonergic system in terms of spine homeostasis and memory consolidation. As dendritic spines contain many kinds of serotonin receptors, and the activation of serotonin receptors generally increases the number of spines in the cortex and hippocampus, I postulate that serotonin neurons are down-regulated during sleep to decrease spine number, which consequently maintains the total spine number at a constant level. Furthermore, since synaptic consolidation during REM sleep needs long-term potentiation (LTP), and serotonin is reported to inhibit LTP in the cortex, I postulate that serotonergic activity must drastically decrease during REM sleep to induce LTP and do memory consolidation. Until now, why serotonergic neurons show these dramatic changes in the sleep–wake cycle remains unexplained; however, making these hypotheses, I can confer physiological meanings on these dramatic changes of serotonergic neurons in terms of spine homeostasis and memory consolidation. Ó 2013 Published by Elsevier Ltd.
Introduction Sleep is necessary for evolved-vertebrates, such as reptiles, birds and mammals [1], and its physiological functions are under intense investigations. Recently, the ‘synaptic homeostasis’ hypothesis has been postulated to explain the effect of sleep on brain performance. This hypothesis suggests that staying awake results in a progressive increase in synaptic strength, as the awake brain learns and adapts to an ever-changing environment mostly through synaptic potentiation [2]. However, such increase would soon become unsustainable, because stronger synapses need more energy, more space, more supplies, and cannot be further potentiated, saturating the ability to learn. Thus, according to the synaptic homeostasis hypothesis, sleep may serve an essential function by promoting a homeostatic reduction in synaptic strength down to sustainable levels [3]. Actually, Maret et al. have reported using two-photon techniques that waking results in a net increase in cortical spines, whereas sleep is associated with net spine loss in the mouse cortex [4]. However, the cellular mechanisms about how sleep changes spine number remain unexplored. In addition, sleep has been also believed to play pivotal roles in memory. Sleep promotes primarily the consolidation of memory, whereas memory encoding and retrieval take place most effectively during waking [5]. During slow-wave (SW) sleep, slow oscillations, spindles and ripples coordinate the reactivation and redistribution of hippocampus-dependent memories to neocortical q Grant sponsor: the Ministry of Education, Science and Culture of Japan; Shintenkai. ⇑ Tel./fax: +81 53 435 2582. E-mail address: [email protected]
0306-9877/$ - see front matter Ó 2013 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.mehy.2013.07.041
sites (system consolidation), whereas during rapid eye movement (REM) sleep, local increases in plasticity-related immediate-early gene activity might favor the subsequent synaptic consolidation of memories in the cortex [5]. However, the cellular mechanisms about how to make these two types of consolidations are largely unknown. Many lines of evidence show that monoamines are deeply involved in sleep [6]. For example, in general, the activity of serotonin neurons is strongly related to spontaneous changes in behavioral state, being highest in active waking and lowest during REM sleep [6]. Interestingly, the most dramatic changes in the activity of serotonin neurons occur during sleep. As animals become drowsy and enter SW sleep, neuronal activity slows to approximately 50 percent of the quiet waking level and loses its regularity. Finally, during REM sleep, the activity of most brain serotonin neurons declines dramatically, in many cases falling to zero [6]. However, why serotonin neurons show these dynamic changes in sleep is not elucidated. In this paper, thus, I want to postulate the hypotheses that can explain the missing link between sleep and the serotonergic system in terms of spine homeostasis and memory consolidation.
Hypotheses Recent studies show that dendritic spines contain many kinds of serotonin receptors [7–9]. And interestingly, activation of many different kinds of serotonin receptors generally increases the number of spines in the cortex and hippocampus [10,11]. It means that if serotonin concentrations are high, spinogenesis is promoted, resulting in an increase in spine number. On the other hand, if
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K. Sato / Medical Hypotheses 81 (2013) 734–737
serotonin concentrations are low, spinogenesis is inhibited, resulting in a decrease in spine number. Thus, I want to postulate the following hypothesis first. Hypothesis1. Serotonin neurons are down-regulated during sleep to decrease spine number, which consequently maintains the total spine number at a constant level (Table 1). Next, how about is the missing link between sleep and serotonin in terms of memory consolidation? During REM sleep, local increases in plasticity-related immediate-early gene activity might favor the subsequent synaptic consolidation of memories in the cortex [5]. Synaptic consolidation needs long-term potentiation (LTP) [5], and serotonin is reported to inhibit LTP in the cortex [12–15]. In this way, to induce LTP, serotonin concentration should be kept very lowered during synaptic consolidation. Thus, I want to further postulate the following hypothesis. Hypothesis 2. Serotonergic activity must drastically decrease during REM sleep to induce LTP and do memory consolidation (Table 2).
Evaluation of the hypotheses
Table 2 How serotonergic activity regulates memory consolidation. State
Serotonergic activity
LTP
Memory consolidation
Non-REM REM
Moderate Very low
Low High
System consolidation Synaptic consolidation
Sleep and spine homeostasis Recent advances in two-photon techniques enabled us to directly investigate spine homeostasis in vivo. Interestingly, Yang et al. examined the formation and elimination of fluorescently labeled dendritic spines and filopodia of layer 5 pyramidal neurons in the barrel cortex of the mouse during wakefulness and sleep. They observed that the elimination rate of dendritic spines or filopodia was faster during sleep than during wakefulness [20]. Furthermore, Maret et al. have also reported using two-photon techniques that waking results in a net increase in cortical spines, whereas sleep is associated with net spine loss in the mouse sensory motor cortex [4]. These data indicate that the number of dendritic spines is increased during wakefulness, and is decreased during sleep, which consequently maintains the total spine number at a constant level. In other words, sleep is indispensable to keep spine number. The serotonergic system and spine homeostasis
Hypothesis 1. Serotonin neurons are down-regulated during sleep to decrease spine number, which consequently maintains the total spine number at a constant level (Table 1). Sleep and the serotonergic system During prolonged wakefulness, accumulating adenosine inhibits specific anterior hypothalamic and basal forebrain GABA-containing neurons that have been inhibiting the sleep-active ventrolateral pre-optic area (VLPO) neurons during waking. Disinhibited sleep-active GABA neurons of the VLPO and adjacent structures then inhibit monoaminergic neurons, including serotonergic neurons, thereby initiating NREM sleep [16]. The activity of serotonin neurons are also regulated by other GABAergic neurons in the lateral hypothalamus, dorsal gigantocellular reticular nucleus, and ventrolateral periaqueductal gray [17]. During waking these GABAergic neurons also do not work, so the activity of serotonergic neurons is very constant and high. In contrast, during sleep these GABAergic neurons inhibit serotonergic neurons’ activity. As animals become drowsy and enter SW sleep, neuronal activity slows to approximately 50 percent of the quiet waking level and loses its regularity. Finally, during REM sleep, the activity of most brain serotonin neurons declines dramatically, in many cases falling to zero [6]. In addition, based on electrophysiological, neurochemical, genetic and neuropharmacological approaches it is currently accepted that serotonin promotes waking and to inhibit REM sleep [18]. Furthermore, recently, Miyamoto et al. have reported that the serotonergic system enables the basal forebrain/preoptic area to couple the suprachiasmatic nucleus circadian signal to ultradian sleep–wake cycles, thereby providing a potential link between circadian rhythms and psychiatric disorders [19]. Taken together, the dramatic activity changes of serotonergic neurons are deeply involved in the genesis of sleep–wake cycles.
Interestingly, spines contain many kinds of serotonin receptors. For example, serotonin 1A [7], serotonin 1B [8], serotonin 2A [9], serotonin 2C [21], serotonin 3 [22], serotonin 4 [23], serotonin 6 [24], and serotonin 7 [25] receptors are reported to exist in spines. What do serotonin receptors do in spines? Mogha et al. have reported that stimulation of serotonin 1A receptor caused a dramatic increase in PSD-95 expression and dendritic spine and synapse formation through sequential activation of the mitogen-activated protein kinase isozymes Erk1/2 and protein kinase C (PKC) in the hippocampus [10]. In addition, Jones et al. have shown that serotonin 2A receptor activation of serotonin 2A receptor agonist (±)-2,5dimethoxy-4-iodoamphetamine hydrochloride (DOI) induced a transient increase in dendritic spine size in cortical culture neurons through kalirin-7 signaling [11]. Furthermore, administration of the serotonin 4 receptor partial agonist SL65.0155 enhances simultaneous olfactory discrimination performance and potentiates learning-induced dendritic spine growth in the mouse hippocampus [23]. Kobe et al. have also reported that, in organotypic preparations from the hippocampus of juvenile mice, stimulation of serotonin 7 receptor/G12 signaling potentiates formation of dendritic spines, increases neuronal excitability, and modulates synaptic plasticity [26]. These reports clearly indicate that activation of many different kinds of serotonin receptors generally increases the number of spines in the cortex and hippocampus. Taken together, these reports clearly support the hypothesis that serotonin neurons are down-regulated during sleep to decrease spine number, which consequently maintains the total spine number at a constant level. Hypothesis 2. Serotonergic activity must drastically decrease during REM sleep to induce LTP and do memory consolidation (Table 2).
Sleep and memory consolidation
Table 1 How serotonergic activity regulates the number of spine. State
Serotonergic activity
Number of spine
Awake Sleep
High Low
Increase Decrease
Sleep has been identified as a state that optimizes the consolidation of newly acquired information in memory [5]. Consolidation refers to a process that transforms new and initially labile memories encoded in the awake state into more stable representations
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K. Sato / Medical Hypotheses 81 (2013) 734–737
that become integrated into the network of pre-existing long-term memories [5]. During SW sleep, slow oscillations, spindles and ripples coordinate the reactivation and redistribution of hippocampus-dependent memories to neocortical sites (system consolidation, [27]), whereas during REM sleep, local increases in plasticity-related immediate-early gene activity might favor the subsequent synaptic consolidation of memories in the cortex (synaptic consolidation; [5]). Synaptic consolidation involves the strengthening of memory representations at the synaptic level. LTP is considered a key mechanism of synaptic consolidation. LTP can be induced in the hippocampus during REM sleep but less reliably so during SW sleep [28]. These data suggest that LTP may be more often observed in REM sleep than in SW sleep.
shown to improve the consolidation of fear memories [34]. Furthermore, SSRIs are reported to cause REM sleep deprivation and to impair spatial learning and passive avoidance in mice [35]. These reports indicate that increased concentrations of extracellular serotonin inhibit both REM sleep and memory consolidation as estimated in this theory. Since it has been reported that post-exposure sleep deprivation attenuates traumatic stress responses [36], controlling REM sleep by SSRIs might be a promising strategy for the treatment of post-traumatic stress disorder (PTSD). Until now, why serotonergic neurons show these dramatic changes in the sleep–wake cycle remains unexplained; however, making these hypotheses, I could confer physiological meanings on these dramatic changes of serotonergic neurons in terms of spine homeostasis and memory consolidation.
The serotonergic system and memory consolidation Conflict of interest statement As mentioned before, synaptic consolidation in the cortex needs LTP [5]. Interestingly, serotonin is reported to inhibit the induction of LTP, and decrease GluR1 surface expression in cortical neurons via serotonin 2A receptor [12]. In addition, Moreau et al. have reported that serotonin tends to inhibit both excitatory synapseLTP and inhibitory synapse-LTP, mainly via the activation of serotonin 1A receptor in principal cells within visual cortex microcircuits [13], and postulated that this phenomenon plays pivotal roles to keep the excitatory-inhibitory balance around its control set-point in the cells. Furthermore, Kim et al. have reported that serotonin inhibits the induction of NMDA receptor-dependent LTP via the co-activation of serotonin 1A receptor and serotonin 2 receptor in the rat primary visual cortex [14]. Edagawa et al. have also reported that serotonin plays a role in inhibiting the induction of LTP in the visual cortex, and the inhibitory effect of serotonin is probably mediated by serotonin 1A receptor and serotonin 2 receptor [15]. Taken together, in the cortex, serotonin generally inhibits the induction of LTP. Thus, to induce LTP serotonin should be lowered in the cortex during REM sleep. Consequences of the hypotheses and discussion In this paper, I postulated the two hypotheses that can explain the missing link between sleep and the serotonergic system in terms of spine homeostasis and memory consolidation. As dendritic spines contain many kinds of serotonin receptors [7–9], and the activation of different kinds of serotonin receptors generally increases the number of spines in the cortex and hippocampus [10,11], I postulated the first hypothesis; i.e., serotonergic neurons are down-regulated during sleep to decrease spine number, which consequently maintains the total spine number at a constant level. The clinical relevance of this theory should be discussed in the pathophysiological situations where spine homeostasis is somehow disturbed. For example, in depression, intensive spine loss has been reported [29,30]. Interestingly, serotonin selective reuptake inhibitors (SSRIs), which can increase extracellular serotonin concentrations by inhibiting the serotonin transporter, are generally used to treat this disease. Furthermore, many reports show that SSRIs increase both extracellular serotonin concentrations and the number of dendritic spines [31–33], supporting that spine numbers are exactly regulated by the serotonergic system in the brain as speculated in this theory. Thus, I believe that this theory might shed a new light on the treatment of many psychiatric diseases in which sleep disturbance is observed. In addition, since synaptic consolidation during REM sleep needs LTP [5], and serotonin is reported to inhibit LTP in the cortex [12–15], I postulated the second hypothesis; i.e., serotonergic activity must drastically decrease during REM sleep to induce LTP and do memory consolidation. In human, REM sleep has been
None declared. Acknowledgement The author would like to thank Ms. Chiemi Kawamoto for her excellent technical help. References [1] Ribeiro S, Nicolelis MAL. The evolution of neural systems for sleep and dreaming. In: Jon Kaas (Org.), editor. Evolution of nervous systems. New York: Elsevier; 2006. p. 451–64. V. 3. [2] Tononi G, Cirelli C. Sleep function and synaptic homeostasis. Sleep Med Rev 2006;10:49–62. [3] Bushey D, Tononi G, Cirelli C. Sleep and synaptic homeostasis: structural evidence in Drosophila. Science 2011;332:1576–81. [4] Maret S, Faraguna U, Nelson AB, Cirelli C, Tononi G. Sleep and waking modulate spine turnover in the adolescent mouse cortex. Nat Neurosci 2011;14:1418–20. [5] Diekelmann S, Born J. The memory function of sleep. Nat Rev Neurosci 2010;11:114–26. [6] Jacobs BL, Fornal CA. Activity of brain serotonergic neurons in relation to physiology and behavior. In: Muller CP, Jacobs BL, editors. Handbook of the behavioral neurobiology of serotonin. Amsterdam: Elsevier; 2010. p. 153–62. [7] Kia HK, Brisorgueil MJ, Hamon M, Calas A, Verge D. Ultrastructural localization of 5-hydroxytryptamine1A receptors in the rat brain. J Neurosci Res 1996;46:697–708. [8] Peddie CJ, Davies HA, Colyer FM, Stewart MG, Rodriguez JJ. Dendritic colocalisation of serotonin1B receptors and the glutamate NMDA receptor subunit NR1 within the hippocampal dentate gyrus: an ultrastructural study. J Chem Neuroanat 2008;36:17–26. [9] Miner LA, Backstrom JR, Sanders-Bush E, Seasack SR. Ultrastructural localization of serotonin 2A receptors in the middle layers of the rat prelimbic prefrontal cortex. Neuroscience 2003;116:107–17. [10] Mogha A, Guariglia SR, Debata PR, Wen GY, Banerjee P. Serotonin 1A receptormediated signaling through ERK and PKCa is essential for normal synaptogenesis in neonatal mouse hippocampus. Transl Psychiatry 2012;2:e66. [11] Jones KA, Srivastava DP, Allen JA, Strachan RT, Roth BL, Penzes P. Rapid modulation of spine morphology by the 5-HT2A serotonin receptor through kalirin-7 signaling. Proc Natl Acad Sci U S A 2009;106:19575–80. [12] Xu ZH, Yang Q, Ma L, Liu SB, Chen GS, Wu YM, et al. Deficits in LTP induction by 5-HT2A receptor antagonist in a mouse model for fragile X syndrome. PLoS One 2012;7:e48741. [13] Moreau AW, Amar M, Callebert J, Fossier P. Serotonergic modulation of LTP at excitatory and inhibitory synapses in the developing rat visual cortex. Neuroscience 2013;238:148–58. [14] Kim HS, Jang HJ, Cho KH, Hahn SJ, Kim MJ, Yoon SH, et al. Serotonin inhibits the induction of NMDA receptor-dependent long-term potentiation in the rat primary visual cortex. Brain Res 2006;1103:49–55. [15] Edagawa Y, Saito H, Abe K. Serotonin inhibits the induction of long-term potentiation in rat primary visual cortex. Prog Neuropsychopharmacol Biol Psychiatry 1998;22:983–97. [16] Pace-Schott EF, Hobson JA. The neurobiology of sleep: genetics, cellular physiology and subcortical networks. Nat Rev Neurosci 2002;3:591–605. [17] Luppi PH, Clement O, Fort P. Paradoxical (REM) sleep genesis by the brainstem is under hypothalamic control. Curr Opin Neurobiol 2013;23:1–7. [18] Monti JM. The role of dorsal raphe nucleus serotonergic and non-serotonergic neurons, and of their receptors, in regulating waking and rapid eye movement (REM) sleep. Sleep Med Rev 2010;14:319–27.
K. Sato / Medical Hypotheses 81 (2013) 734–737 [19] Miyamoto H, Nakamaru-Ogiso E, Hamada K, Hensch TK. Serotonergic integration of circadian clock and ultradian sleep–wake cycles. J Neurosci 2012;32:14794–803. [20] Yang G, Gan WB. Sleep contributes to dendritic spine formation and elimination in the developing mouse somatosensory cortex. Dev Neurobiol 2012;72:1391–8. [21] Anatasio NC, Lanfranco MF, Bubar MJ, Seitz PK, Stutz SJ, McGinnis AG, et al. Serotonin 5-HT2C receptor protein expression is enriched in synaptosomal and post-synaptic compartments of rat cortex. J Neurochem 2010;113:1504–15. [22] Miquel MC, Emerit MB, Nosjean A, Simon A, Rumajogee P, Brisorgueil MJ, et al. Differential subcellular localization of the 5-HT3-As receptor subunit in the rat central nervous system. Eur J Neurosci 2002;15:449–57. [23] Restivo L, Roman F, Dumuis A, Bockaert J, Marchetti E, Ammassari-Teule M. The promnesic effect of G-protein-coupled 5-HT4 receptors activation is mediated by a potentiation of learning-induced spine growth in the mouse hippocampus. Neuropsychopharmacology 2008;33:2427–34. [24] Gerard C, Martres MP, Lefevre K, Miquel MC, Verge D, Lanfumey L, et al. Immuno-localization of serotonin 5-HT6 receptor-like material in the rat central nervous system. Brain Res 1997;746:207–19. [25] Doly S, Fischer J, Brisorgueil MJ, Verge D, Conrath M. Pre- and postsynaptic localization of the 5-HT7 receptor in rat dorsal spinal cord: immunocytochemical evidence. J Comp Neurol 2005;490:256–69. [26] Kobe F, Guseva D, Jensen TP, Wirth A, Renner U, Hess D, et al. 5-HT7R/G12 signaling regulates neuronal morphology and function in an age-dependent manner. J Neurosci 2012;32:2915–30. [27] Gais S, Albouy G, Boly M, Dang-Vu TT, Darsaud A, Desseilles M, et al. Sleep transforms the cerebral trace of declarative memories. Proc Natl Acad Sci U S A 2007;104:18778–83. [28] Bramham CR. Phasic boosting of medial perforant path-evoked granule cell output time-locked to spontaneous dentate EEG spikes in awake rats. J Neurophysiol 1998;79:2825–32.
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[29] Kassem MS, Lagopoulos J, Stait-Gardner T, Price WS, Chohan TW, Arnold JC, et al. Stress-induced grey matter loss determined by MRI is primarily due to loss of dendrites and their synapses. Mol Neurobiol 2013;47:645–61. [30] Chen Y, Kramar EA, Chen LY, Babayan AH, Andres AL, Gall CM, et al. Impairment of synaptic plasticity by the stress mediator CRH involves selective destruction of thin dendritic spines via RhoA signaling. Mol Psychiatry 2013;18:485–96. [31] Hajszan T, MacLusky NJ, Leranth C. Short-term treatment with the antidepressant fluoxetine triggers pyramidal dendritic spine synapse formation in rat hippocampus. Eur J Neurosci 2005;21:1299–303. [32] Norrholm SD, Ouimet CC. Altered dendritic spine density in animal models of depression and in response to antidepressant treatment. Synapse 2001;42:151–63. [33] Ampuero E, Rubio FJ, Falcon R, Sandval M, Diaz-Veliz G, Gonzalez RE, et al. Chronic fluoxetine treatment induces structural plasticity and selective changes in glutamate receptor subunits in the rat cerebral cortex. Neuroscience 2010;169:98–108. [34] Wagner U, Gais S, Born J. Emotional memory formation is enhanced across sleep intervals with high amounts of rapid eye movement sleep. Learn Mem 2001;8:112–9. [35] Bridoux A, Laloux C, Derambure P, Bordet R, Monaca Charley C. The acute inhibition of rapid eye movement sleep by citalopram may impair spatial learning and passive avoidance in mice. J Neural Transm 2013;120:383–9. [36] Cohen S, Kozlovsky N, Matar MA, Kaplan Z, Zohar J, Cohen H. Post-exposure sleep deprivation facilitates correctly timed interactions between glucocorticoid and adrenergic systems, which attenuate traumatic stress responses. Neuropsychopharmacology 2012;37:2388–404.
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Why does serotonergic activity drastically decrease during REM sleep? q Kohji Sato ⇑ Department of Anatomy & Neuroscience, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashiku, Hamamatsu, Shizuoka 431-3192, Japan
a r t i c l e
i n f o
Article history: Received 16 May 2013 Accepted 21 July 2013
a b s t r a c t Here, I postulate two hypotheses that can explain the missing link between sleep and the serotonergic system in terms of spine homeostasis and memory consolidation. As dendritic spines contain many kinds of serotonin receptors, and the activation of serotonin receptors generally increases the number of spines in the cortex and hippocampus, I postulate that serotonin neurons are down-regulated during sleep to decrease spine number, which consequently maintains the total spine number at a constant level. Furthermore, since synaptic consolidation during REM sleep needs long-term potentiation (LTP), and serotonin is reported to inhibit LTP in the cortex, I postulate that serotonergic activity must drastically decrease during REM sleep to induce LTP and do memory consolidation. Until now, why serotonergic neurons show these dramatic changes in the sleep–wake cycle remains unexplained; however, making these hypotheses, I can confer physiological meanings on these dramatic changes of serotonergic neurons in terms of spine homeostasis and memory consolidation. Ó 2013 Published by Elsevier Ltd.
Introduction Sleep is necessary for evolved-vertebrates, such as reptiles, birds and mammals [1], and its physiological functions are under intense investigations. Recently, the ‘synaptic homeostasis’ hypothesis has been postulated to explain the effect of sleep on brain performance. This hypothesis suggests that staying awake results in a progressive increase in synaptic strength, as the awake brain learns and adapts to an ever-changing environment mostly through synaptic potentiation [2]. However, such increase would soon become unsustainable, because stronger synapses need more energy, more space, more supplies, and cannot be further potentiated, saturating the ability to learn. Thus, according to the synaptic homeostasis hypothesis, sleep may serve an essential function by promoting a homeostatic reduction in synaptic strength down to sustainable levels [3]. Actually, Maret et al. have reported using two-photon techniques that waking results in a net increase in cortical spines, whereas sleep is associated with net spine loss in the mouse cortex [4]. However, the cellular mechanisms about how sleep changes spine number remain unexplored. In addition, sleep has been also believed to play pivotal roles in memory. Sleep promotes primarily the consolidation of memory, whereas memory encoding and retrieval take place most effectively during waking [5]. During slow-wave (SW) sleep, slow oscillations, spindles and ripples coordinate the reactivation and redistribution of hippocampus-dependent memories to neocortical q Grant sponsor: the Ministry of Education, Science and Culture of Japan; Shintenkai. ⇑ Tel./fax: +81 53 435 2582. E-mail address: [email protected]
0306-9877/$ - see front matter Ó 2013 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.mehy.2013.07.041
sites (system consolidation), whereas during rapid eye movement (REM) sleep, local increases in plasticity-related immediate-early gene activity might favor the subsequent synaptic consolidation of memories in the cortex [5]. However, the cellular mechanisms about how to make these two types of consolidations are largely unknown. Many lines of evidence show that monoamines are deeply involved in sleep [6]. For example, in general, the activity of serotonin neurons is strongly related to spontaneous changes in behavioral state, being highest in active waking and lowest during REM sleep [6]. Interestingly, the most dramatic changes in the activity of serotonin neurons occur during sleep. As animals become drowsy and enter SW sleep, neuronal activity slows to approximately 50 percent of the quiet waking level and loses its regularity. Finally, during REM sleep, the activity of most brain serotonin neurons declines dramatically, in many cases falling to zero [6]. However, why serotonin neurons show these dynamic changes in sleep is not elucidated. In this paper, thus, I want to postulate the hypotheses that can explain the missing link between sleep and the serotonergic system in terms of spine homeostasis and memory consolidation.
Hypotheses Recent studies show that dendritic spines contain many kinds of serotonin receptors [7–9]. And interestingly, activation of many different kinds of serotonin receptors generally increases the number of spines in the cortex and hippocampus [10,11]. It means that if serotonin concentrations are high, spinogenesis is promoted, resulting in an increase in spine number. On the other hand, if
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K. Sato / Medical Hypotheses 81 (2013) 734–737
serotonin concentrations are low, spinogenesis is inhibited, resulting in a decrease in spine number. Thus, I want to postulate the following hypothesis first. Hypothesis1. Serotonin neurons are down-regulated during sleep to decrease spine number, which consequently maintains the total spine number at a constant level (Table 1). Next, how about is the missing link between sleep and serotonin in terms of memory consolidation? During REM sleep, local increases in plasticity-related immediate-early gene activity might favor the subsequent synaptic consolidation of memories in the cortex [5]. Synaptic consolidation needs long-term potentiation (LTP) [5], and serotonin is reported to inhibit LTP in the cortex [12–15]. In this way, to induce LTP, serotonin concentration should be kept very lowered during synaptic consolidation. Thus, I want to further postulate the following hypothesis. Hypothesis 2. Serotonergic activity must drastically decrease during REM sleep to induce LTP and do memory consolidation (Table 2).
Evaluation of the hypotheses
Table 2 How serotonergic activity regulates memory consolidation. State
Serotonergic activity
LTP
Memory consolidation
Non-REM REM
Moderate Very low
Low High
System consolidation Synaptic consolidation
Sleep and spine homeostasis Recent advances in two-photon techniques enabled us to directly investigate spine homeostasis in vivo. Interestingly, Yang et al. examined the formation and elimination of fluorescently labeled dendritic spines and filopodia of layer 5 pyramidal neurons in the barrel cortex of the mouse during wakefulness and sleep. They observed that the elimination rate of dendritic spines or filopodia was faster during sleep than during wakefulness [20]. Furthermore, Maret et al. have also reported using two-photon techniques that waking results in a net increase in cortical spines, whereas sleep is associated with net spine loss in the mouse sensory motor cortex [4]. These data indicate that the number of dendritic spines is increased during wakefulness, and is decreased during sleep, which consequently maintains the total spine number at a constant level. In other words, sleep is indispensable to keep spine number. The serotonergic system and spine homeostasis
Hypothesis 1. Serotonin neurons are down-regulated during sleep to decrease spine number, which consequently maintains the total spine number at a constant level (Table 1). Sleep and the serotonergic system During prolonged wakefulness, accumulating adenosine inhibits specific anterior hypothalamic and basal forebrain GABA-containing neurons that have been inhibiting the sleep-active ventrolateral pre-optic area (VLPO) neurons during waking. Disinhibited sleep-active GABA neurons of the VLPO and adjacent structures then inhibit monoaminergic neurons, including serotonergic neurons, thereby initiating NREM sleep [16]. The activity of serotonin neurons are also regulated by other GABAergic neurons in the lateral hypothalamus, dorsal gigantocellular reticular nucleus, and ventrolateral periaqueductal gray [17]. During waking these GABAergic neurons also do not work, so the activity of serotonergic neurons is very constant and high. In contrast, during sleep these GABAergic neurons inhibit serotonergic neurons’ activity. As animals become drowsy and enter SW sleep, neuronal activity slows to approximately 50 percent of the quiet waking level and loses its regularity. Finally, during REM sleep, the activity of most brain serotonin neurons declines dramatically, in many cases falling to zero [6]. In addition, based on electrophysiological, neurochemical, genetic and neuropharmacological approaches it is currently accepted that serotonin promotes waking and to inhibit REM sleep [18]. Furthermore, recently, Miyamoto et al. have reported that the serotonergic system enables the basal forebrain/preoptic area to couple the suprachiasmatic nucleus circadian signal to ultradian sleep–wake cycles, thereby providing a potential link between circadian rhythms and psychiatric disorders [19]. Taken together, the dramatic activity changes of serotonergic neurons are deeply involved in the genesis of sleep–wake cycles.
Interestingly, spines contain many kinds of serotonin receptors. For example, serotonin 1A [7], serotonin 1B [8], serotonin 2A [9], serotonin 2C [21], serotonin 3 [22], serotonin 4 [23], serotonin 6 [24], and serotonin 7 [25] receptors are reported to exist in spines. What do serotonin receptors do in spines? Mogha et al. have reported that stimulation of serotonin 1A receptor caused a dramatic increase in PSD-95 expression and dendritic spine and synapse formation through sequential activation of the mitogen-activated protein kinase isozymes Erk1/2 and protein kinase C (PKC) in the hippocampus [10]. In addition, Jones et al. have shown that serotonin 2A receptor activation of serotonin 2A receptor agonist (±)-2,5dimethoxy-4-iodoamphetamine hydrochloride (DOI) induced a transient increase in dendritic spine size in cortical culture neurons through kalirin-7 signaling [11]. Furthermore, administration of the serotonin 4 receptor partial agonist SL65.0155 enhances simultaneous olfactory discrimination performance and potentiates learning-induced dendritic spine growth in the mouse hippocampus [23]. Kobe et al. have also reported that, in organotypic preparations from the hippocampus of juvenile mice, stimulation of serotonin 7 receptor/G12 signaling potentiates formation of dendritic spines, increases neuronal excitability, and modulates synaptic plasticity [26]. These reports clearly indicate that activation of many different kinds of serotonin receptors generally increases the number of spines in the cortex and hippocampus. Taken together, these reports clearly support the hypothesis that serotonin neurons are down-regulated during sleep to decrease spine number, which consequently maintains the total spine number at a constant level. Hypothesis 2. Serotonergic activity must drastically decrease during REM sleep to induce LTP and do memory consolidation (Table 2).
Sleep and memory consolidation
Table 1 How serotonergic activity regulates the number of spine. State
Serotonergic activity
Number of spine
Awake Sleep
High Low
Increase Decrease
Sleep has been identified as a state that optimizes the consolidation of newly acquired information in memory [5]. Consolidation refers to a process that transforms new and initially labile memories encoded in the awake state into more stable representations
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K. Sato / Medical Hypotheses 81 (2013) 734–737
that become integrated into the network of pre-existing long-term memories [5]. During SW sleep, slow oscillations, spindles and ripples coordinate the reactivation and redistribution of hippocampus-dependent memories to neocortical sites (system consolidation, [27]), whereas during REM sleep, local increases in plasticity-related immediate-early gene activity might favor the subsequent synaptic consolidation of memories in the cortex (synaptic consolidation; [5]). Synaptic consolidation involves the strengthening of memory representations at the synaptic level. LTP is considered a key mechanism of synaptic consolidation. LTP can be induced in the hippocampus during REM sleep but less reliably so during SW sleep [28]. These data suggest that LTP may be more often observed in REM sleep than in SW sleep.
shown to improve the consolidation of fear memories [34]. Furthermore, SSRIs are reported to cause REM sleep deprivation and to impair spatial learning and passive avoidance in mice [35]. These reports indicate that increased concentrations of extracellular serotonin inhibit both REM sleep and memory consolidation as estimated in this theory. Since it has been reported that post-exposure sleep deprivation attenuates traumatic stress responses [36], controlling REM sleep by SSRIs might be a promising strategy for the treatment of post-traumatic stress disorder (PTSD). Until now, why serotonergic neurons show these dramatic changes in the sleep–wake cycle remains unexplained; however, making these hypotheses, I could confer physiological meanings on these dramatic changes of serotonergic neurons in terms of spine homeostasis and memory consolidation.
The serotonergic system and memory consolidation Conflict of interest statement As mentioned before, synaptic consolidation in the cortex needs LTP [5]. Interestingly, serotonin is reported to inhibit the induction of LTP, and decrease GluR1 surface expression in cortical neurons via serotonin 2A receptor [12]. In addition, Moreau et al. have reported that serotonin tends to inhibit both excitatory synapseLTP and inhibitory synapse-LTP, mainly via the activation of serotonin 1A receptor in principal cells within visual cortex microcircuits [13], and postulated that this phenomenon plays pivotal roles to keep the excitatory-inhibitory balance around its control set-point in the cells. Furthermore, Kim et al. have reported that serotonin inhibits the induction of NMDA receptor-dependent LTP via the co-activation of serotonin 1A receptor and serotonin 2 receptor in the rat primary visual cortex [14]. Edagawa et al. have also reported that serotonin plays a role in inhibiting the induction of LTP in the visual cortex, and the inhibitory effect of serotonin is probably mediated by serotonin 1A receptor and serotonin 2 receptor [15]. Taken together, in the cortex, serotonin generally inhibits the induction of LTP. Thus, to induce LTP serotonin should be lowered in the cortex during REM sleep. Consequences of the hypotheses and discussion In this paper, I postulated the two hypotheses that can explain the missing link between sleep and the serotonergic system in terms of spine homeostasis and memory consolidation. As dendritic spines contain many kinds of serotonin receptors [7–9], and the activation of different kinds of serotonin receptors generally increases the number of spines in the cortex and hippocampus [10,11], I postulated the first hypothesis; i.e., serotonergic neurons are down-regulated during sleep to decrease spine number, which consequently maintains the total spine number at a constant level. The clinical relevance of this theory should be discussed in the pathophysiological situations where spine homeostasis is somehow disturbed. For example, in depression, intensive spine loss has been reported [29,30]. Interestingly, serotonin selective reuptake inhibitors (SSRIs), which can increase extracellular serotonin concentrations by inhibiting the serotonin transporter, are generally used to treat this disease. Furthermore, many reports show that SSRIs increase both extracellular serotonin concentrations and the number of dendritic spines [31–33], supporting that spine numbers are exactly regulated by the serotonergic system in the brain as speculated in this theory. Thus, I believe that this theory might shed a new light on the treatment of many psychiatric diseases in which sleep disturbance is observed. In addition, since synaptic consolidation during REM sleep needs LTP [5], and serotonin is reported to inhibit LTP in the cortex [12–15], I postulated the second hypothesis; i.e., serotonergic activity must drastically decrease during REM sleep to induce LTP and do memory consolidation. In human, REM sleep has been
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