November 25, 2020

Sleep loss disrupts hippocampal memory consolidation via an acetylcholine- and somatostatin interneuron-mediated inhibitory gate

Sleep loss profoundly disrupts consolidation of hippocampus-dependent memory. To better characterize effects of learning and sleep loss on the hippocampal circuit, we quantified activity-dependent phosphorylation of ribosomal subunit S6 (pS6) across the dorsal hippocampus of mice. We find that pS6 in enhanced in the dentate gyrus (DG) following single-trial contextual fear conditioning (CFC), but is reduced throughout the hippocampus after brief sleep deprivation (SD), a manipulation which disrupts contextual fear memory (CFM) consolidation. To characterize cell populations with activity affected by SD, we used translating ribosome affinity purification (TRAP)-seq to identify cell type-specific transcripts on pS6 ribosomes after SD vs. sleep. Cell type-specific enrichment analysis (CSEA) of these transcripts revealed that hippocampal somatostatin-expressing (Sst+) interneurons, and cholinergic and orexinergic inputs to hippocampus, are selectively activated after SD. We used TRAP targeted to hippocampal Sst+ interneurons to identify cellular mechanisms mediating SD-driven Sst+ interneuron activation. We next used pharmacogenetics to mimic the effects of SD, selectively activating hippocampal Sst+ interneurons while mice slept in the hours following CFC. We find that activation of Sst+ interneurons is sufficient to disrupt CFM consolidation, by gating activity in surrounding pyramidal neurons. Pharmacogenetic inhibition of cholinergic input to hippocampus from the medial septum (MS) promoted CFM consolidation and disinhibited neurons in the DG, increasing pS6 expression. This suggests that state-dependent gating of DG activity is mediated by cholinergic input during SD. Together these data provide evidence for an inhibitory gate on hippocampal information processing, which is activated by sleep loss.

 bioRxiv Subject Collection: Neuroscience

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