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

Abstract

Sleep 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 GIRK1/2-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 GIRK1/2 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.

Sleep-dependent engram reactivation during hippocampal memory consolidation is associated with subregion-specific biosynthetic changes

“…We (11–13) and others (9, 10) have previously shown that sleep deprivation (SD) over the hours immediately following CFC results in disrupted CFM consolidation. We confirmed these disruptive effects in the cfos::tdTomato mouse line.…”

“…In both animal models and human subjects, sleep deprivation (SD) negatively impacts consolidation of hippocampus-dependent memories (5)(6)(7). For example, in mice, consolidation of contextual fear memory (CFM), a canonical form of Pavlovian conditioning (8) is disrupted by SD in the first 5-6 h following single-trial contextual fear conditioning (CFC; pairing exploration of a novel context with a foot shock) (9)(10)(11)(12)(13). Recent studies have shown that SD can alter basic features of hippocampal network function, including oscillatory patterning of network activity (11), intracellular signaling (10,14,15), transcription and translation (12,(16)(17)(18)(19), and excitatoryinhibitory balance (20,21).…”

Enriched binocular experience followed by sleep optimally restores binocular visual cortical responses in a mouse model of amblyopia

“…No novel objects or additional sensory stimuli were provided, to limit sensory-based neocortical plasticity during sleep deprivation procedures 101 . To estimate the amount of sleep lost in BR + SD mice, BR + Sleep mice were visually monitored every 5 min over the first 4 h following visual enrichment for assumption of sleep postures, similar to previous studies 83,[102][103][104] . As previously described, similar procedures used for sleep deprivation in adult mice 105 and critical period cats 8 either have no significant effect on serum cortisol, or increases it to a degree that is orders of magnitude lower than that capable of disrupting ODP 106 .…”

Neuromodulation via muscarinic acetylcholine pathway can facilitate distinct, complementary, and sequential roles for NREM and REM states during sleep-dependent memory consolidation

“…Together, these findings suggest that NREM-associated suppression of ACh input to hippocampus is an essential feature for sleep-dependent memory consolidation. However, there are accumulating data suggesting that REM -a high-ACh brain state -also plays an important role in consolidation of hippocampus-dependent memories (59)(60)(61)(62). Yet it remains unclear whether NREM and REM play overlapping, distinct, or complementary roles in the storage of information in neural networks.…”