A hypothalamo-septo-hippocampal circuit for REM sleep-dependent consolidation of social memory

Abstract REM sleep constitutes a critical window for memory consolidation, yet the brain circuits orchestrating this process remain incompletely defined. Here, we identify a lateral supramammillary nucleus (SuM)-medial septum (MS) projection as a REM sleep-specialized pathway essential for hippocampal memory consolidation. Fiber photometry and optrode recordings revealed that lateral SuM-MS projecting neurons were selectively active during REM sleep. REM-specific optogenetic silencing of this projection impaired consolidation of both social and contextual fear memories. Crucially, silencing of its downstream target, the MS-CA2 pathway, during REM sleep selectively disrupted social memory while sparing contextual fear memory. This functional dissection establishes a hypothalamo-septo-hippocampal circuit (lateral SuM-MS-CA2) dedicated to social memory processing, in parallel to the recently-described direct SuM-CA2 pathway. These results also position the SuM as a REM sleep-hub that routes information via parallel septal pathways to consolidate distinct memory modalities.