Sleep loss drives acetylcholine- and somatostatin interneuron–mediated gating of hippocampal activity to inhibit memory consolidation

Abstract

Sleep loss disrupts consolidation of hippocampus-dependent memory. To characterize effects of learning and sleep loss, we quantified activity-dependent phosphorylation of ribosomal protein S6 (pS6) across the dorsal hippocampus of mice. We find that pS6 is enhanced in dentate gyrus (DG) following single-trial contextual fear conditioning (CFC) but is reduced throughout the hippocampus after brief sleep deprivation (SD; which disrupts contextual fear memory [CFM] consolidation). To characterize neuronal populations affected by SD, we used translating ribosome affinity purification sequencing to identify cell type–specific transcripts on pS6 ribosomes (pS6-TRAP). Cell type–specific enrichment analysis revealed that SD selectively activated hippocampal somatostatin-expressing (Sst+) interneurons and cholinergic and orexinergic hippocampal inputs. To understand the functional consequences of SD-elevated Sst+ interneuron activity, we used pharmacogenetics to activate or inhibit hippocampal Sst+ interneurons or cholinergic input from the medial septum. The activation of either cell population was sufficient to disrupt sleep-dependent CFM consolidation by gating activity in granule cells. The inhibition of either cell population during sleep promoted CFM consolidation and increased S6 phosphorylation among DG granule cells, suggesting their disinhibition by these manipulations. The inhibition of either population across post-CFC SD was insufficient to fully rescue CFM deficits, suggesting that additional features of sleeping brain activity are required for consolidation. Together, our data suggest that state-dependent gating of DG activity may be mediated by cholinergic input and local Sst+ interneurons. This mechanism could act as a sleep loss–driven inhibitory gate on hippocampal information processing.

The Engram’s Dark Horse: How Interneurons Regulate State-Dependent Memory Processing and Plasticity

“…Our lab has recently demonstrated that SD also profoundly disrupts principal neuron activity in the hippocampus. We found that SD decreases neuronal activity-driven phosphorylation of ribosomal protein S6 throughout the dorsal hippocampus, suggesting decreased neuronal activity ( Delorme et al, 2021 ). This is consistent with previous findings from our lab, where IEG Arc ’s messenger ribonucleic acid (mRNA) and protein expression is reduced in DG after a period of SD ( Delorme et al, 2019 ).…”

“…VIP+ interneurons inhibit SST+ interneurons in the circuit. Left: During a period of post-learning sleep, principal cells and PV+ interneurons generally become more active ( Ognjanovski et al, 2014 ), while SST+ interneurons are relatively quiescent (due to lower acetylcholine-mediated activation in NREM sleep) ( Delorme et al, 2021 ). Some principal neurons (engram neurons) will become selectively more active, and may form new and/or stronger synaptic connections ( Clawson et al, 2021 ).…”

“…All these features are essential components of sleep-dependent memory consolidation. Right: When learning is followed by SD, SST+ interneurons shown increased activity in response to higher acetylcholine levels ( Delorme et al, 2021 ). VIP+ interneurons may also have reduced activation, reducing inhibitory input to SST+ interneurons.…”

“…VIP+ interneurons may also have reduced activation, reducing inhibitory input to SST+ interneurons. This leads to suppression of firing in surrounding principal neurons ( Delorme et al, 2021 ). As a result, dendritic spines on engram neurons (and other principal neurons) will be reduced and connections between them will be weakened ( Havekes et al, 2016 ; Raven et al, 2019 ; Havekes and Aton, 2020 ), which impairs memory consolidation.…”

“…For example, SST+ interneuron targeted disruption of either eIF2 or mTOR (key regulators of neuronal activity-regulated translation required for structural plasticity) leads to impaired consolidation of multiple hippocampus-dependent forms of memory ( Artinian et al, 2019 ; Sharma et al, 2020 ). A recent study from our lab (described in greater detail below) assessed the effects of chemogenetically activating or inhibiting DG SST+ interneurons over the hours following CFC ( Delorme et al, 2021 ). We found that these manipulations were sufficient to disrupt or enhance CFM consolidation, as evidenced by decreased or increased contextual freezing responses, respectively, 24 h after training.…”