SLEEP FRAGMENTATION DIFFERENTIALLY ALTERS HIPPOCAMPAL NETWORK DYNAMICS AND MEMORY IN WILD-TYPE AND APP-PS1 MICE

Dementia in Alzheimer’s disease (AD) cannot be explained solely by beta-amyloid and TAU pathology. Additional AD-associated factors, such as sleep hygiene, significantly influence disease outcome. Here, we hypothesize that sleep fragmentation (SF) contributes to disease progression by impairing sleep-dependent network processes involved in memory formation and consolidation.
To test this hypothesis, we compared wild-type (WT) and APP-PS1 mice using hippocampal electrophysiology in freely-moving animals during sleep and memory processing, combined with behavioral assessment in the open field and novel object recognition tasks, both before and after a 5-day SF protocol.
At baseline, APP-PS1 mice exhibited fragmented sleep architecture, together with memory deficits and hippocampal network dysfunction characterized by hyperactivity, hypersynchronization, altered oscillatory coupling - particularly during sharp-wave ripple events associated with memory consolidation - and reduced spatial coding efficiency of place cells.
SF impaired memory in both groups, with larger decline in WT mice. These behavioral deficits were accompanied by genotype-specific electrophysiological changes: WT mice showed degraded spatial coding in place cells, whereas APP-PS1 mice exhibited a further exacerbation of hippocampal hyperactivity and excitation/inhibition imbalance.
These findings suggest that cognitive deficits in APP-PS1 mice reflect chronic alterations in sleep quality and hippocampal circuit dynamics, where increased neuronal activity and synchronization interfere with information consolidation. Moreover, sleep fragmentation differentially affects memory depending on baseline circuit state, inducing dementia-like dysfunction in healthy brains and accelerating pathological processes in AD animals.
Together, these results support the role of sleep disruption as a key modulator of hippocampal circuit’s vulnerability to AD progression.