AbstractSpatial learning is impaired in preclinical Alzheimer’s disease (AD). We reported similar impairments in 3xTg-AD mice learning a spatial reorientation task. Memory reactivation during sleep is critical for learning related plasticity, and memory consolidation is correlated with hippocampal sharp wave ripple (SWR) density, cortical delta waves (DWs), and their temporal coupling - postulated as a physiological substrate of memory consolidation. Finally, hippocampal-cortical dyscoordination is prevalent in individuals with AD. Thus, we hypothesized impaired memory consolidation mechanisms in hippocampal-cortical networks could account for spatial memory deficits. We assessed sleep architecture, SWR/DW dynamics and memory reactivation in a mouse model of tauopathy and amyloidosis implanted with a recording array targeting isocortex and hippocampus. Mice underwent daily recording sessions of rest-task-rest while learning the spatial reorientation task. We assessed memory reactivation by matching activity patterns from the approach to the unmarked reward zone to patterns during slow wave sleep (SWS). AD mice had more SWS, but reduced SWR density. The increased SWS compensated for reduced SWR density so there was no reduction in SWR number. Conversely, DW density was not reduced so the number of DWs was increased. In control mice hippocampal SWR-cortical DW coupling was strengthened in post-task-sleep and was correlated with performance on the spatial reorientation task the following day. However, in AD mice SWR-DW coupling was reduced and not correlated with behavior, suggesting behavioral decoupling. Thus, reduced SWR-DW coupling may cause impaired learning in AD and may serve as a biomarker for early AD related changes.Significance StatementUnderstanding the relationship between network dynamics and cognition early in Alzheimer’s disease progression is critical for identifying therapeutic targets for earlier treatment. We assessed hippocampal-cortical interactions during sleep in AD mice as a potential cause of early spatial learning and memory deficits. We identified compensatory sleep changes in AD mice, that ameliorated some brain dysfunction. Despite the compensatory changes, impaired spatial navigation and impaired hippocampal–cortical (sharp wave ripple-delta wave) interactions were apparent in AD mice. In control but not AD mice hippocampal-cortical interactions were correlated with performance on the spatial task, the following day, suggesting a potential mechanism of impaired consolidation in AD mice. Thus, changes in hippocampal-cortical brain dynamics during sleep may underlie early memory deficits in AD.
Impaired Spatial Reorientation in the 3xTg-AD Mouse Model of Alzheimer’s Disease