Abstract
Clinical populations have memory deficits linked to sleep oscillations that can potentially be treated with sleep medications. Eszopiclone and zolpidem (two non-benzodiazepine hypnotics) both enhance sleep spindles. Zolpidem improved sleep-dependent memory consolidation in humans, but eszopiclone did not. These divergent results may reflect that the two drugs have different effects on hippocampal ripple oscillations, which correspond to the reactivation of neuronal ensembles that represent previous waking activity and contribute to memory consolidation. We used extracellular recordings in the CA1 region of rats and systemic dosing of eszopiclone and zolpidem to test the hypothesis that these two drugs differentially affect hippocampal ripples and spike activity. We report evidence that eszopiclone makes ripples sparser, while zolpidem increases ripple density. In addition, eszopiclone led to a drastic decrease in spike firing, both in putative pyramidal cells and interneurons, while zolpidem did not substantially alter spiking. These results provide an explanation of the different effects of eszopiclone and zolpidem on memory in human studies and suggest that sleep medications can be used to regulate hippocampal ripple oscillations, which are causally linked to sleep-dependent memory consolidation.
Highlights
Noninvasive interventions of sleep oscillations can be used to normalize or enhance memory function (Malkani and Zee, 2020; Manoach et al, 2020; Winkelman and Lecea, 2020)
We saw no significant difference in the average sleep bout duration between vehicle, eszopiclone or zolpidem sessions (10.98, 12.46 and 11.55 min respectively; vehicle/eszopiclone, F (1,13) 1.46; p 0.25; vehicle/zolpidem, F (1,13) 0.26, p 0.62), nor in the average number of bouts per hour (2.92 bouts/hour, 2.93 bouts/hour and 3.01 bouts/hour respectively; vehicle/ eszopiclone, F (1,13) 1.41; p 0.26; vehicle/zolpidem, F (1,13) 1.96, p 0.19; Supplementary Figure S3A)
The normalized sleep ripple power during recovery was not significantly different compared to vehicle (19% below baseline in eszopiclone and 50% above baseline with zolpidem; vehicle/ eszopiclone, F (1,13) 2.53; p 0.14; vehicle/zolpidem, F (1,13) 3.77, p 0.07). These results suggest that eszopiclone has an acute adverse effect on ripple power, while zolpidem increases hippocampus ripple activity
Summary
Noninvasive interventions of sleep oscillations can be used to normalize or enhance memory function (Malkani and Zee, 2020; Manoach et al, 2020; Winkelman and Lecea, 2020). Eszopiclone and zolpidem, two non-benzodiazepine sedative hypnotics that are prescribed to treat insomnia (Richey and Krystal, 2011; Matheson and Hainer, 2017; Liang et al, 2019; Krystal, 2020), are among the candidates to normalize sleep oscillations and memory (Kaestner et al, 2013). Eszopiclone increased spindles in humans but failed to enhance overnight memory consolidation (Wamsley et al, 2013; Mylonas et al, 2020). We hypothesized that the contrasting effects of these drugs on memory consolidation were due to differential effects in hippocampal function
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