Acute sleep deprivation induces ECM-associated transcription and MMP12-sensitive perivascular remodeling

Sleep deprivation (SD) disrupts brain homeostasis, but whether acute sleep loss alters extracellular matrix (ECM) programs and the structural organization of the perivascular interface remains unclear.

We integrated re-analysis of three public 6-h SD transcriptomic datasets with cisterna magna tracer studies, collagen IV and hyaluronan-binding protein 2 (HABP2) imaging, cellular localization of matrix metalloproteinase-12 (MMP12), transmission electron microscopy, pharmacological MMP12 inhibition, and continuous EEG/EMG recording during ZT0-ZT6 and recovery, with manual sleep-wake scoring in 4-s epochs.

Across GSE256140, GSE78215, and GSE128770, acute SD was associated with increased ECM-related transcription. In GSE256140, the most prominent differential response occurred in excitatory neurons, and six of 18 upregulated genes were annotated to the extracellular matrix term. SD increased tracer displacement relative to collagen IV, broadened collagen IV- and HABP2-positive perivascular bands, and expanded an ECM-associated perivascular compartment at the ultrastructural level. Cortical MMP12 immunoreactivity was associated most strongly with NeuN-positive structures, followed by Iba1-positive structures, with limited enrichment in GFAP-positive regions. MMP408 attenuated the SD-associated redistribution of tracer and normalized widening of the perivascular compartment, but did not significantly restore the narrowed endothelial-basement membrane complex. During ZT0-ZT6, rotating-bar SD increased wakefulness and reduced NREM and REM sleep. Recovery NREM sleep was increased in both SD groups, whereas NREM spectral profiles and relative delta power did not differ significantly among the four groups.

Acute SD engages an ECM-associated transcriptional response and produces structural reorganization of the perivascular interface. The pharmacological findings identify an MMP12-sensitive component of this remodeling without establishing a single cellular source of MMP12. These results connect sleep loss to ECM and perivascular structural plasticity while separating these changes from the magnitude of early recovery sleep.