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

Associated faculty or student(s): Publication Date:
Tuesday, August 10, 2021

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.Hippocampal plasticity and memory storage are gated by vigilance states. In both human subjects and animal models, sleep loss disrupts consolidation of multiple types of hippocampus-dependent memories (12). This effect has been extensively studied in mice in which as little as a few hours of experimental sleep deprivation (SD) can disrupt hippocampally mediated consolidation of object–place memory (35) and contextual fear memory (CFM) (67). Recent work has characterized biochemical pathways involved in memory consolidation which are disrupted in the hippocampus by SD (4589). However, much less is known about how SD affects hippocampal microcircuit function.SD disrupts patterns of hippocampal network activity which are associated with memory consolidation. For example, SD interferes with network activity changes induced in hippocampal area CA1 by prior learning (contextual fear conditioning, or CFC); these post-CFC changes predict successful CFM consolidation, and their loss predicts consolidation disruption (710). The reason for this SD-mediated disruption is unknown. Recently, activity-dependent regulation of protein translation machinery within the dorsal hippocampus was found to be essential for sleep-dependent memory consolidation (9). SD interferes with biochemical pathways which drive increased protein synthesis following learning (911). This suggests a link between state-dependent changes in network activity and biosynthetic events occurring in the first few hours following learning (1215), which are necessary for appropriate CFM consolidation.To better characterize the link between neuronal activity and protein synthesis in the hippocampus during CFM consolidation, we characterized effects of learning and subsequent sleep or SD on activity-dependent phosphorylation of ribosomal protein S6 (pS6). S6 is phosphorylated in an activity-dependent manner by ERK, PKA, and mTOR kinase pathways in neurons and thus is a cellular marker of activated neurons (16). We find that CFC increases S6 phosphorylation at a terminal serine residue (pS6 Ser244-247) and that SD reduces pS6 Ser244-247 throughout the dorsal hippocampus. To identify cell populations differentially expressing pS6 after sleep versus SD, we used a pSer244-247 as an affinity tag for translating ribosome affinity purification (pS6-TRAP). We then identified modules of cell type–specific transcripts with expression correlated to wake time in sleeping and SD mice and verified these findings with qPCR. These analyses indicate that SD selectively activates (i.e., leads to increased S6 phosphorylation in) hippocampal somatostatin-expressing (Sst+) interneurons and orexinergic (lateral hypothalamic) and cholinergic (MS) neurons, which send input to the hippocampus. We used TRAP in Sst+ interneurons (Sst-TRAP) to verify that activity-dependent transcripts are increased in these neurons with SD. To assess how increased activity in the hippocampus Sst+ interneuron population during SD affects memory consolidation, we used pharmacogenetics to selectively activate these neurons in the hours following CFC. We find that mimicking the effects of SD on Sst+ interneuron activity is sufficient for disruption of CFM consolidation in freely sleeping mice and that inactivation of Sst+ interneurons during post-CFC sleep augments CFM consolidation. Lastly, we tested the hypothesis that state-dependent regulation of the dorsal hippocampal network is mediated by changes in activity of MS cholinergic neurons. We find that pharmacogenetic activation of MS cholinergic inputs to the hippocampus following CFC impairs sleep-dependent CFM consolidation. In contrast, pharmacogenetic inhibition of these cholinergic inputs during sleep promotes CFM consolidation and increases S6 phosphorylation in the dorsal hippocampus. Together, these data provide evidence for a state-dependent gate on network activity in the hippocampus, regulated by Sst+ interneurons and MS cholinergic input, which likely contributes to SD-induced disruption of memory consolidation.

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