期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：32
DOI：10.1073/pnas.2019318118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Sleep loss disrupts long-term storage of episodic and spatial memories that require activity in the hippocampus. We find that sleep deprivation in mice leads to selective disruption of activity-dependent phosphorylation of ribosomal protein S6 in the hippocampus, which is normally increased in the hippocampus after learning. We used an unbiased approach to profile messenger RNAs associated with phosphorylated ribosomes and found evidence that cholinergic hippocampal inputs and somatostatin-containing hippocampal neurons are selectively activated with sleep deprivation. We find functional evidence supporting the idea that during sleep loss, activity in these two cell populations may act as an inhibitory gate, reducing the activity of dentate gyrus neurons. We find that this inhibitory gating mechanism is capable of disrupting memory consolidation.
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.
