Sleep loss disrupts Arc expression in dentate gyrus neurons

Abstract

Sleep loss affects many aspects of cognition, and memory consolidation processes occurring in the hippocampus seem particularly vulnerable to sleep loss. The immediate-early gene Arc plays an essential role in both synaptic plasticity and memory formation, and its expression is altered by sleep. Here, using a variety of techniques, we have characterized the effects of brief (3-h) periods of sleep vs. sleep deprivation (SD) on the expression of Arc mRNA and Arc protein in the mouse hippocampus and cortex. By comparing the relative abundance of mature Arc mRNA with unspliced pre-mRNA, we see evidence that during SD, increases in Arc across the cortex, but not hippocampus, reflect de novo transcription. Arc increases in the hippocampus during SD are not accompanied by changes in pre-mRNA levels, suggesting that increases in mRNA stability, not transcription, drives this change. Using in situ hybridization (together with behavioral observation to quantify sleep amounts), we find that in the dorsal hippocampus, SD minimally affects Arc mRNA expression, and decreases the number of dentate gyrus (DG) granule cells expressing Arc. This is in contrast to neighboring cortical areas, which show large increases in neuronal Arc expression after SD. Using immunohistochemistry, we find that Arc protein expression is also differentially affected in the cortex and DG with SD - while larger numbers of cortical neurons are Arc+, fewer DG granule cells are Arc+, relative to the same regions in sleeping mice. These data suggest that with regard to expression of plasticity-regulating genes, sleep (and SD) can have differential effects in hippocampal and cortical areas. This may provide a clue regarding the susceptibility of performance on hippocampus-dependent tasks to deficits following even brief periods of sleep loss.

Sleep loss disrupts hippocampal memory consolidation via an acetylcholine- and somatostatin interneuron-mediated inhibitory gate

“…We verified that S6 phosphorylation is neuronal activity-driven, consistent with previous reports (Pirbhoy et al, 2016), by quantifying co-expression of the activity-regulated protein Arc in pS6+ neurons. Consistent with our previous findings (Delorme et al, 2019), 3-h SD reduced numbers of both Arc+ and pS6+ neurons in the DG. Arc and pS6 were co-localized to a similar extent in DG of both Sleep and SD mice ( Figure 1D), with 77 ± 3.2% of Arc+ DG neurons also being pS6+, and 54 ± 2.8% of pS6+ neurons also being Arc+ (mean ± SEM from n = 10 mice).…”

“…Here we present converging lines of evidence that indicate SD disrupts activity in the dorsal hippocampus, and disrupts memory consolidation, via a Sst+ interneuron-mediated inhibitory gate. First, we find that, similar to Arc mRNA and Arc protein (Delorme et al, 2019), activity-dependent expression of pS6 in dorsal hippocampus increases across a brief period of sleep ( Figure S1), but is reduced by a period of SD (Figure 1). This effect of SD is enhanced by prior learning (Figure 1, Figure S1), and seems to occur selectively in the hippocampus -it is not seen in the neocortex ( Figure S2).…”

“…Because selective activation of Sst+ interneurons in the hippocampus is characteristic of SD, we conclude that this mechanism may explain the sleep-dependence of CFM consolidation (Graves et al, 2003;Ognjanovski et al, 2018;Vecsey et al, 2009). It may also explain other effects of SD on the dorsal hippocampal network, including disruption of longterm potentiation (LTP) (Havekes et al, 2016;Vecsey et al, 2009), reduction of plasticityassociated gene expression (Delorme et al, 2019), and decreases in dendritic spine density on pyramidal neurons (Havekes et al, 2016;Raven et al, 2019). CFM consolidation itself relies on intact network activity in dorsal hippocampus (Daumas et al, 2005), and is associated with increased network activity in structures such as CA1 (Ognjanovski et al, 2018;Ognjanovski et al, 2014), and regularization of spike-timing relationships during post-CFC sleep (Ognjanovski et al, 2018;Ognjanovski et al, 2014;Ognjanovski et al, 2017).…”

Sleep loss drives brain region- and cell type-specific alterations in ribosome-associated transcripts involved in synaptic plasticity and cellular timekeeping

“…3-5 month old mice were individually housed one week prior to all experiments (with beneficial enrichment), and were habituated to handling for five days prior to experiments. Following habituation, and beginning at lights on (ZT0), mice were either allowed ad lib sleep in their home cage or were sleep deprived by gentle handling (Delorme et al, 2019;Durkin and Aton, 2016;Durkin et al, 2017). For sleeping animals, sleep behavior was visually scored at 5-min or 2-min intervals (for 6-h and 3-h SD, respectively), based on immobility and assumption of characteristic sleep postures.…”

Learning and Sleep Have Divergent Effects on Cytosolic and Membrane-Associated Ribosomal mRNA Profiles in Hippocampal Neurons

“…Many forms of hippocampus-dependent memory are disrupted (in human subjects and animal models) by either pre-or post-learning sleep loss (Havekes and Abel, 2017;Krause et al, 2017;Puentes-Mestril and Aton, 2017;Rasch and Born, 2013). Indeed, sleep loss seems to disrupt plasticity mechanisms within the hippocampus more dramatically than in other brain areas (Delorme et al, 2019;Raven et al, 2019). The underlying mechanisms by which sleep loss leads to these changes (and disrupts memory mechanisms) have remained elusive.…”