Atypical hypnotic compound ML297 restores sleep architecture following emotionally-valenced learning, to promote memory consolidation and hippocampal network activation during recall

Abstract

AbstractSleep plays a critical role in consolidating many forms of hippocampus-dependent memory. While various classes of hypnotic drugs have been developed in recent years, it remains unknown whether, or how, some of them affect sleep-dependent memory consolidation mechanisms. We find that ML297, a recently-developed candidate hypnotic agent targeting a new mechanism (activating GIRK1-subunit containing G-protein coupled inwardly rectifying potassium [GIRK] channels), alters sleep architecture in mice over the first 6 h following a single-trial learning event. Following contextual fear conditioning (CFC), ML297 reversed post-CFC reductions in NREM sleep spindle power and REM sleep amounts and architecture, renormalizing sleep features to what was observed at baseline, prior to CFC. Renormalization of post-CFC REM sleep latency, REM sleep amounts, and NREM spindle power were all associated with improved contextual fear memory (CFM) consolidation. We find that improvements in CFM consolidation due to ML297 are sleep-dependent, and are associated with increased numbers of highly-activated dentate gyrus (DG), CA1, and CA3 neurons during CFM recall. Together our findings suggest that GIRK1 channel activation restores normal sleep architecture - including REM sleep, which is normally suppressed following CFC - and increases the number of hippocampal neurons incorporated into the CFM engram during memory consolidation.Significance StatementBoth REM and NREM sleep are thought to be important for consolidating hippocampus-dependent memories. We find that GIRK1 activator ML297, administered after single-trial fear learning, restores REM sleep that is normally suppressed after learning fearful associations. This restoration is associated with improvements in fear memory storage, resulting in more robust hippocampus activation in the context of subsequent memory recall. Thus this drug, which also has antiepileptic and anxiolytic properties, may be useful for promoting normal, restorative sleep that benefits memory storage.