Rescuing impaired cortical‐hippocampal interactions during sleep with 40Hz stimulation targeted to hippocampus in 3xTg‐AD/PVcre mice

Abstract

AbstractBackgroundIn preclinical Alzheimer’s disease (AD), spatial learning and memory is impaired. We previously reported similar impairments in 6‐month 3xTg‐AD female mice on a virtual spatial reorientation task that requires learning to use landmarks for spatial orientation. Memory replay during sleep is critical for learning related plasticity, and hippocampal‐cortical dysfunction during sleep is a potential mechanism for memory impairments in AD. Consistent with this, we previously found that prior to emergence of significant pathology there were deficits in hippocampal‐parietal cortex (PC) coordination during sleep which predicted performance on the virtual spatial reorientation task. Gamma‐stimulation (40Hz) has been shown to clear AD pathology in mice, and improve functional connectivity in preclinical AD patients. Thus, we assessed hippocampal‐PC coordination in 6‐month female 3xTg‐AD/PVcre (4xTg) mice that were learning the same spatial reorientation task.MethodWe implanted a 16‐tetrode recording array targeting PC and hippocampus and an optical fiber aimed at hippocampus. Daily recording sessions of rest‐task‐rest commenced as mice learned to locate the unmarked reward zone. During the same surgery, cre‐dependent AAV was used to express channel rhodopsin 2 in hippocampal interneurons. This allowed for daily stimulation sessions after recording sessions, with either 40Hz or SHAM hippocampal stimulation. We assessed sleep quality metrics, and cortical spindles, and delta waves (DW) in PC during slow wave sleep. In hippocampus we assessed markers of memory replay (SWRs) during SWS.ResultAnimals with 40Hz entrainment showed increased REM sleep compared to SHAM animals. There was also a significant increase in SWR rate from pre‐ to post‐sleep, opposite a decrease in post‐sleep in SHAM mice; however, there was no difference in the absolute number or rate of DW or . Finally, in SHAM stimulated mice SWR‐DW temporal‐correlations were significantly reduced, similar to our previous findings in 3xTg‐AD mice; while in the 40Hz mice, this phase locking was rescued. .ConclusionThus, 40Hz stimulation of hippocampus may rescue learning and memory related functional interactions in the hippocampal‐PC network during sleep and as a consequence at least partially rescue impairments in spatial navigation.