Paradoxical sleep: A vigilance state to gate long-term brain plasticity?

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Highlights

  • Paradoxical sleep (PS) facilitates consolidation of hippocampal based forms of memory

  • Long term potentiation (LTP) in the hippocampus is required for memory consolidation

  • PS increases the expression of Zif268, c-Fos, BDNF and Arc in the hippocampus

  • Zif268, c-Fos, BDNF and Arc are required in hippocampal LTP

  • This result suggests molecular mechanisms by which PS enhances memory consolidation

Abstract

Memory consolidation is the process for long-term storage of information and protection against interferences. It has been proposed that long-term potentiation (LTP), the long-lasting enhancement of synaptic transmission, is a cellular model for memory consolidation. Since consolidation of several forms of memory is facilitated by paradoxical sleep (PS) we ask whether PS modulates the cellular and molecular pathways underlying LTP. The long-lasting form of LTP (L-LTP) is dependent on the activation of transcription factors, enzymatic cascades and the secreted neurotrophin BDNF. By using PS deprivation, immunohistochemistry and quantitative real-time polymerase chain reaction (qPCR), we showed that an increase in PS amount (produced by rebound in PS deprived rats) is able to up-regulate the expression level of transcription factors Zif268 and c-Fos as well as Arc and BDNF in the CA1 and CA3 areas of the hippocampus. Several studies involved these factors in dendritic protein synthesis and in long-term structural changes of synapses underlying L-LTP. The present study together with the work of others (Ribeiro et al., 2002) suggest that by this mechanism, a post-learning increase in PS quantity (post-learning PS window) could convert a transient form of LTP to L-LTP.

Introduction

Since its discovery by Dement and Kleitman (1957) and Jouvet, Michel, and Courjon (1959) more than fifty years ago, paradoxical sleep (PS, or REMS for rapid-eye-movement sleep) is an important field of medical and neuroscience research. Several aspects concerning PS, in particular its precise role in cognitive functions are currently eliciting tremendous investigation. Recent studies in human have clearly identified a role for PS in procedural and emotional memory as well as in emotional processing (Rasch and Born, 2013, Walker, 2009). Functional brain imaging studies have also revealed that several cortical areas involved in memory processing are activated by PS such as the amygdaloid complexes and the anterior cingulate cortex (Maquet et al., 1996). In rodents, an overwhelming number of studies also suggest a role for PS in spatial and emotional memory (Hennevin et al., 1995, Smith, 1996). However, only few studies examined the mechanisms by which PS may facilitate these forms of learning and memory.

It has been well established that long-term potentiation (LTP), a major form of long-term synaptic plasticity, is a cellular mechanism required for learning and memory consolidation (Malenka and Bear, 2004, Wang and Morris, 2010, Whitlock et al., 2006). Several decades of electrophysiological and biochemical studies have shown that LTP relies on a small number of key molecular targets such as the glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and N-methyl-d-aspartate receptor (NMDAR) and enzymatic cascades located in dendritic spines of pyramidal cells (Malenka & Bear, 2004). LTP is now commonly divided in two forms, a transient one that rapidly fades over few hours and a late form that can be sustained over several hours, days and even weeks (Govindarajan, Kelleher, & Tonegawa, 2006). This late form of LTP (L-LTP), potentially responsible for synaptic consolidation, requires repeated synaptic activation. During the synaptic consolidation period, which has been hypothesized to precede system consolidation (Frankland & Bontempi, 2005), memory traces could be stored by the reinforcement of existing synaptic connections and the growth of new synaptic connections (Yang et al., 2014). In contrast with transient LTP, L-LTP involves de novo protein synthesis induced by dendritic translation or nuclear transcription under the control of transcription factors. This synthesis of new proteins is under the control of neuronal enzymatic cascades relying on mitogen-activated protein kinases (MAPK) and cAMP-dependent protein kinase (protein kinase A, PKA).

Interestingly, it has been shown that several enzymatic cascades involved in long-term synaptic plasticity are regulated by sleep states (Abel et al., 2013, Tononi and Cirelli, 2014). It is known that sleep states modulate synaptic transmission and plasticity in the hippocampus and neocortex (Bramham and Srebro, 1989, Winson and Abzug, 1977). It has been proposed that slow wave sleep (SWS) could contribute to a global synaptic downscaling after wakefulness (Tononi & Cirelli, 2006). In agreement with this Synaptic Homeostasis Hypothesis (SHY), the response to evoked frontal Local Field Potentials (LFP) and AMPAR subtype GluA1 expression are down regulated during sleep (Vyazovskiy, Cirelli, Pfister-Genskow, Faraguna, & Tononi, 2008). Moreover, calcineurin, a protein phosphatase involved in long-term synaptic depression (LTD), is upregulated during sleep while the immediate early gene (IEG) activity-regulated cytoskeleton-associated protein (Arc also known as Arg3.1) and the trophic factor Brain-derived neurotrophic factor (BDNF) are upregulated by wakefulness (Cirelli, Gutierrez, & Tononi, 2004). In this model, the role of PS is unclear, although a recent study suggests that it may contribute to a homeostasis of hippocampal excitability during SWS (Grosmark, Mizuseki, Pastalkova, Diba, & Buzsaki, 2012). Alternatively, several studies suggest that sleep might play an active role and in particular may facilitate long-term synaptic plasticity (Rasch & Born, 2013). This later model suggests that hippocampal sharp-wave ripples (SWR) are associated with hippocampal and neocortical replays which reinforce/induce synaptic potentiation (Replay-Transfer-Potentiation, RTP). SWR-induced replays during SWS may facilitate LTP induction and then PS may convert it into L-LTP. According to this model, experiments using the IEG Zif268 (also known as Egr1, Krox-24, NGF1-A, Zenk), a transcription factor required for L-LTP (Jones et al., 2001), suggest that waves of Zif268 up-regulation propagate during PS from the hippocampus to the neocortex after hippocampal LTP (Ribeiro et al., 2002).

We have shown that the expression level of some AMPAR and NMDAR subtypes is down-regulated in the CA1 area of the dorsal hippocampus by PS deprivation and that this decrease is associated with a reduction of MAPK activity in the same area (Ravassard et al., 2009). Conversely, sleep deprivation impaired L-LTP in the dorsal CA1 area. Therefore, these studies suggest that sleep states, and PS in particular, play an important role in regulating L-LTP and its key molecular targets. However, some questions remain unanswered. Since L-LTP in CA1 pyramidal cells seem to be required for several forms of long-term memory, are these cells activated by sleep states? BDNF, a secreted protein that plays an important role in brain development, is present in adult animals in CA1–CA3 pyramidal cells and is required for converting LTP in L-LTP (Bramham and Messaoudi, 2005, Govindarajan et al., 2006). Is BDNF expression modulated by PS?

To answer these questions, we first used immunohistochemistry and quantitative PCR of the IEG Zif268, c-Fos and Arc acting as indirect markers of neuronal activity and synaptic plasticity (Bramham et al., 2008, Cirelli and Tononi, 2000, Fleischmann et al., 2003, Veyrac et al., 2014). Second, we examined the expression of BDNF in the same hippocampal areas. In these experiments, PS amount was modulated by using a PS deprivation method. After PS deprivation, the animals were subjected to a recovery of their PS debt which induced a selective and sustained increase in PS amount (PS rebound, PSR). Our results suggest that increasing PS by PS rebound up-regulates markers of synaptic plasticity and BDNF in the CA1–CA3 areas of the hippocampus.

Section snippets

Polygraphic recording of vigilance states

All procedures were approved by the institutional animal care and use committee of the University of Lyon 1 (protocol BH2006-09) and were conducted in accordance with the French and European Community guidelines for the use of research animals. Experiments were performed on male Sprague Dawley rats (7–8 weeks old, 250–350 g, Charles River Laboratories, France). Animals were implanted under chloral hydrate anesthesia (400 mg/kg) to monitor electroencephalogram (frontal and parietal EEG) and

Results

First, we sought to identify what neuronal population was activated by PS rebound in the hippocampus. We carried out an immunohistochemical study on three experimental groups of rats undergoing large manipulations of PS amount by comparing control conditions (PSC), PS deprivation (PSD) and PS rebound (PSR) induced by the restoration of PS debt following PS deprivation, to determine whether PS amount was able to modulate Zif268 expression. Using this protocol we previously found (Ravassard et

Discussion

Altogether, our results suggest that the increase in PS amount following PS deprivation selectively up-regulates known biomarkers of long-term synaptic plasticity in the CA1–CA3 areas of the hippocampus. Fig. 5 summarizes the results that we obtained in the present study and previously in Ravassard et al., 2009. We found that both synaptic transmission and plasticity (LTP) were impaired in dorsal CA1 after PSD. The protein expression of their key effectors such as GluR1 and NR1, as well as the

Acknowledgments

P.R. and the project were supported by the Cluster11 Rhône-Alpes grant to P.A.S.; A.M.H was supported by an ARC2 (Région Rhône-Alpes) grant to G.M. We thank Nadine Gay, Catherine Rey and the Plateform ProfileXpert for help with the qPCR analysis.

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    1

    Present address: University of California, Los Angeles, Department of Physics & Astronomy, Department of Neurology, 475 Portola Plaza, Room 5–170 Knudsen Hall, Los Angeles, CA 90095, United States.

    2

    Present address: INSERM U1107, UdA Neuro-Dol Equipe Pharmacologie Fondamentale et Clinique de la Douleur, Facultés de médecine et de pharmacie, 28 place Henri-Dunant, BP38, 63001 Clermont-Ferrand, France.

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