Maternal sleep deprivation reshapes offspring hippocampal development through a Trem2-centered microglial program revealed by single-nucleus and spatial transcriptomics.
Abstract
Maternal sleep deprivation during late pregnancy is common and has been linked to increased neuropsychiatric risk in offspring, but the mechanisms by which it shapes developing hippocampal circuits remain unclear. The triggering receptor expressed on myeloid cells 2 (Trem2) is a key genetic risk factor for neurodegenerative disease and regulator of microglial survival and synaptic refinement, but it is unknown whether perinatal environmental stressors, such as maternal sleep loss, reprogram Trem2-associated microglial states in the developing hippocampus. Here, we combine single-nucleus RNA sequencing and spatial transcriptomics to generate a lifespan atlas of hippocampal cell populations in rat dams and offspring exposed to late-pregnancy maternal sleep deprivation (LSD) across postnatal day (P)1, 7, 14, and 56. LSD induces widespread, cell-type-specific transcriptional alterations across oligodendrocytes, astrocytes, and excitatory and inhibitory neurons, with a convergent and persistent disruption of microglial states characterized by downregulation of Trem2 and enrichment of gene modules shared with human neuropsychiatric and neurodegenerative risk loci. Behaviourally, LSD offspring display long-lasting deficits in Morris water maze performance, altered anxiety-related and exploratory behaviors in the open field and elevated plus maze, and impaired hippocampal long-term potentiation (LTP). AAV-mediated hippocampal Trem2 restoration, accompanied by recovery of Trem2 signal in Iba1-positive microglia, partially attenuates inflammatory remodeling and ameliorates LTP and behavioural abnormalities. Our findings identify maternal sleep deprivation as an early-life insult that programs a Trem2-centred microglial axis shaping hippocampal circuits and long-lasting cognitive and behavioral alterations, and suggest microglial Trem2 as a candidate target for mitigating neuropsychiatric risk associated with adverse sleep in pregnancy.
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