Experience-dependent upregulation of multiple plasticity factors in the hippocampus during early REM sleep

Abstract

Sleep is beneficial to learning, but the underlying mechanisms remain controversial. The synaptic homeostasis hypothesis (SHY) proposes that the cognitive function of sleep is related to a generalized rescaling of synaptic weights to intermediate levels, due to a passive downregulation of plasticity mechanisms. A competing hypothesis proposes that the active upscaling and downscaling of synaptic weights during sleep embosses memories in circuits respectively activated or deactivated during prior waking experience, leading to memory changes beyond rescaling. Both theories have empirical support but the experimental designs underlying the conflicting studies are not congruent, therefore a consensus is yet to be reached. To advance this issue, we used real-time PCR and electrophysiological recordings to assess gene expression related to synaptic plasticity in the hippocampus and primary somatosensory cortex of rats exposed to novel objects, then kept awake (WK) for 60 min and finally killed after a 30 min period rich in WK, slow-wave sleep (SWS) or rapid-eye-movement sleep (REM). Animals similarly treated but not exposed to novel objects were used as controls. We found that the mRNA levels of Arc, Egr1, Fos, Ppp2ca and Ppp2r2d were significantly increased in the hippocampus of exposed animals allowed to enter REM, in comparison with control animals. Experience-dependent changes during sleep were not significant in the hippocampus for Bdnf, Camk4, Creb1, and Nr4a1, and no differences were detected between exposed and control SWS groups for any of the genes tested. No significant changes in gene expression were detected in the primary somatosensory cortex during sleep, in contrast with previous studies using longer post-stimulation intervals (>180 min). The experience-dependent induction of multiple plasticity-related genes in the hippocampus during early REM adds experimental support to the synaptic embossing theory.

Memory corticalization triggered by REM sleep: mechanisms of cellular and systems consolidation

“…Neuronal firing rates during REM sleep showed robust temporal dependence across brain regions: while changes in cortical firing rates during object exploration predicted hippocampal firing rates during REM sleep in the first hour post-experience, changes in hippocampal firing rates during object exploration predicted cortical firing rates during REM sleep in the third hour post-experience. Along with other lines of evidence [157,158,165,173], this corroborates the hypothesis that REM sleep is important for the stabilization of memory traces within cortico-cortical connections, specially in supragranular and infragranular layers [65].…”

“…More recently, these results were extended to the IEG Fos and two major phosphatases related to LTD [174,175], Ppp2ca and Ppp2r2d (Fig. 2c) [165]. This result offers direct support to the notion that sleep-dependent memory processing is a complex, multifaceted process comprising both synaptic potentiation and synaptic depression, as proposed by the Synaptic Embossing Theory.…”

“…Memory reactivation during SWS has been proposed to serve as the first step to activity-dependent memory consolidation [153,154], but at present it is unclear how it relates to protein synthesis able to stabilize long-lasting memory traces [58,155,156]. Indeed, studies of gene expression during sleep have demonstrated that REM sleep, not SWS, triggers the calcium-dependent phosphorylation events and transcriptional upregulation of gene expression related to LTP and LTD and, ultimately, to synaptic remodeling [157][158][159][160][161][162][163][164][165]. Importantly, these effects are experiencedependent, i.e., only occur in animals/brain regions affected by novel experience during waking.…”

“…The transcription factor Zif-268 binds promoter regions of hundreds of genes, and leads to the transcriptional upregulation of synapsins I and II, for instance [43]. The gene Arc, which encodes an effector protein directly related to the remodeling of dendritic spines [166], and other IEG involved in learning, such as Fos, CREB and phosphatases Ppp2ca and Ppp2r2d [41,[167][168][169][170][171][172], are also transcriptionally upregulated by REM sleep [159,161,165]. Importantly, similar experiencedependent activation was observed for calcium-dependent kinases upstream of IEG regulation [127,159].…”

System Consolidation During Sleep – A Common Principle Underlying Psychological and Immunological Memory Formation

“…In addition, the underlying plastic synaptic processes that enable representational transformations at the neuronal level are established during SWS [24,25]. However, other studies have suggested that some aspects of memory abstraction and the underlying synaptic plasticity involve REM sleep (e.g., [115][116][117]). The issue is complicated by observations indicating that the presumed abstraction process develops more or less slowly, depending on the stimulus material and preexisting knowledge, and thus may manifests itself at retrieval only with some delay, and not immediately after the experimental sleep period [118,119].…”