Sleep deprivation during a specific 3-hour time window post-training impairs hippocampal synaptic plasticity and memory

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Highlights

  • Sleep deprivation for 3 h impairs memory when onset occurs 1 h after training.

  • Sleep deprivation for 3 h impairs LTP when onset occurs 1 h after training.

  • Sleep deprivation for 3 h, beginning immediately after training, does not impair memory.

  • Sleep deprivation for 3 h, beginning immediately after training, does not impair LTP.

Abstract

Sleep deprivation disrupts hippocampal function and plasticity. In particular, long-term memory consolidation is impaired by sleep deprivation, suggesting that a specific critical period exists following learning during which sleep is necessary. To elucidate the impact of sleep deprivation on long-term memory consolidation and synaptic plasticity, long-term memory was assessed when mice were sleep deprived following training in the hippocampus-dependent object place recognition task. We found that 3 h of sleep deprivation significantly impaired memory when deprivation began 1 h after training. In contrast, 3 h of deprivation beginning immediately post-training did not impair spatial memory. Furthermore, a 3-h sleep deprivation beginning 1 h after training impaired hippocampal long-term potentiation (LTP), whereas sleep deprivation immediately after training did not affect LTP. Together, our findings define a specific 3-h critical period, extending from 1 to 4 h after training, during which sleep deprivation impairs hippocampal function.

Introduction

Despite the fact that sleep exposes an organism to increased risk of attack or predation due to time spent unaware of its surroundings, sleep is an evolutionarily conserved phenomenon that is critical for survival. Inadequate sleep contributes to both physical and mental exhaustion and deterioration. Modern society suffers from unprecedented rates of sleep loss. According to the Center for Disease Control, 7–19% of adults in the US report inadequate sleep, and an estimated 70 million Americans suffer from chronic sleep disorders. Although the vital function of sleep has yet to be determined, lack of sleep is detrimental to cognitive function.

One of the most notable negative consequences of sleep loss is impaired memory (Harrison & Horne, 2000). Memory is composed of at least three stages; acquisition, consolidation, and retrieval (Abel & Lattal, 2001). The effects of sleep deprivation have been examined on both the acquisition and consolidation of memory. Early studies explored the effects of sleep deprivation on memory acquisition (Stern, 1971), and it has since been repeatedly demonstrated that chronic sleep deprivation impairs acquisition (learning) (Abel et al., 2013, Chee and Choo, 2004, Durmer and Dinges, 2005, Hagewoud, Havekes, Novati, et al., 2010, Havekes, Canton, et al., 2012, Havekes, Vecsey, et al., 2012, Prince and Abel, 2013, Van Der Werf et al., 2009, Youngblood et al., 1997). More recently, however, multiple laboratories have explored the effects of acute sleep deprivation and sleep fragmentation during consolidation, showing that consolidation benefits from sleep and is hindered by sleep loss (Florian et al., 2011, Graves et al., 2003, Hagewoud, Havekes, Tiba, et al., 2010, Hagewoud, Whitcomb, et al., 2010, Inostroza et al., 2013, Rolls et al., 2011, Vecsey et al., 2009).

Consolidation in hippocampus-dependent memory tasks is particularly sensitive to sleep loss. Sleep deprivation-induced deficits have been described for associative memory tasks such as contextual fear conditioning and for spatial memory tasks such as the Morris water maze task and the object-place recognition (OPR) task, which is used in the present study (Binder et al., 2012, Florian et al., 2011, Graves et al., 2003, Smith and Rose, 1996, Smith and Rose, 1997). OPR, in particular, is an ideal paradigm for examining the effects of sleep deprivation on hippocampal function because it is comparable to tasks that test declarative memory in humans, it is dependent on the hippocampus, and it is not aversive (Bussey et al., 2000, Mumby et al., 2002, Oliveira et al., 2010, Shrager et al., 2007, Winters et al., 2004, Winters et al., 2008).

Several studies have assessed whether sleep deprivation during specific time windows after training affects long-term memory (Graves et al., 2003, Palchykova et al., 2006, Smith and Rose, 1997). In these studies, a sleep deprivation sensitive window, within the first 4–6 h of consolidation, has been demonstrated in the consolidation of contextual memory, object recognition memory, and spatial memory. Memory is resistant to the effects of sleep deprivation if animals are sleep deprived after this window (Graves et al., 2003, Palchykova et al., 2006, Smith and Rose, 1997). These findings suggest that there is a critical period during which memory is vulnerable to the effects of sleep deprivation. However, little work has been conducted to examine the precise timing of this sensitive time window. The aim of this study was to define the temporal parameters for the impact of sleep deprivation on memory consolidation.

Aside from the effects of sleep deprivation on behavioral measures of memory, sleep deprivation also disrupts synaptic plasticity, a neural correlate of memory. Campbell and colleagues demonstrated that 12 h of sleep deprivation impairs hippocampal long-term plasticity (LTP), a form of synaptic plasticity (Campbell, Guinan, & Horowitz, 2002). LTP deficits have been observed in vitro after 4–5 h of sleep deprivation as well (Kopp et al., 2006, Vecsey et al., 2009). The impact of short periods of sleep deprivation is specific to late-phase LTP (L-LTP), which requires protein synthesis and the cyclic adenosine mono-phosphate (cAMP) signaling pathway (Vecsey et al., 2009). Critically, however, the effects of sleep deprivation on hippocampal LTP during a period of active memory consolidation have not previously been examined. By assessing hippocampal LTP following training, in the sensitive window for sleep deprivation, we aimed to more accurately determine the effects of sleep and sleep loss on hippocampal plasticity associated with memory consolidation.

Previously, we demonstrated that as little as 6 h of sleep deprivation immediately after task training disrupts long-term spatial memory in OPR (Florian et al., 2011). Here we aim to better define the critical period during which sleep is essential for hippocampal memory consolidation. By sleep depriving mice during two different time windows, we demonstrate that as few as 3 h of sleep deprivation during consolidation can affect both long-term memory and LTP.

Section snippets

Subjects

One hundred C57BL/6J adult male mice (2–4 months of age) were pair housed and kept on a 12 h/12 h light/dark schedule with lights on at 7:00 AM (ZT 0). Food and water were available ad libitum throughout the experiments. All experiments were approved by the Institution of Animal Care and Use Committee of the University of Pennsylvania and were carried out in accordance with all National Institutes of Health guidelines.

Sleep deprivation

To assess the effects of sleep deprivation (SD) on memory, mice (n = 58) were

Delayed sleep deprivation during hours ZT 2-5 after object place recognition (OPR) training impairs long-term memory

We first examined the impact of two periods of SD during the consolidation of spatial memory. We subjected separate groups of mice to one of two overlapping 3-h SD periods during the first 4 h of consolidation. We chose to examine these overlapping sleep deprivation time points because we had already discovered that 4 h of immediate sleep deprivation (ZT 1-5) was sufficient to impair memory compared to the NSD control group. This observation suggests that the critical time window necessary for

Discussion

Our study investigated whether there is a critical time window for sleep deprivation during memory consolidation to impair hippocampus-dependent long-term memory and plasticity. We found that as little as 3 h of SD following learning impairs spatial memory in mice. More importantly, we observed that the timing of sleep loss is critical. When the onset of SD was delayed for an hour after learning, hippocampus-dependent memory consolidation was impaired compared to when mice were sleep deprived

Acknowledgments

We thank Morgan Bridi, Alan Park, and Dr. Marcel Estevez for help with the electrophysiology. We thank Dr. Nicola Grissom and Christopher Angelakos for input in editing process of this paper. The research was supported by NIH (P01AG017628 to T.A.; Principal Investigator Allan Pack) and NHLBI Training in Sleep and Sleep Disorders (T32HL007953; Principal Investigator Allan Pack).

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