ENHANCEMENT OF HIPPOCAMPAL SHARP-WAVE RIPPLES USING CLOSED-LOOP DEEP BRAIN STIMULATION

Deep brain stimulation (DBS) of the fornix has been trialled as a potential therapy for the treatment of Alzheimer’s disease (AD). However, the continuous delivery of high frequency stimulation, which has been successful in the treatment of other brain disorders, has not consistently reduced cognitive symptoms. In rodents, closed-loop optogenetic stimulation targeting hippocampal sharp-wave ripples (SWRs) has been shown to elongate SWRs, and improve memory reconsolidation and performance. Here we investigated whether such effects could be achieved using closed-loop electrical stimulation of the fornix, potentially providing a clinically tractable approach to memory enhancement. We used real-time tracking of SWRs to deliver a short burst of stimulation pulses to the fornix at the onset of naturally occurring SWRs (SWR-targeted-DBS) in freely moving rats. Stimulation was applied during quiet/rest sleep periods before the performance of a novel object recognition task to probe the effects of stimulation on memory reconsolidation. We compared hippocampal activity and task performance with SWR-targeted-DBS against baseline (no stimulation) and open-loop-replay stimulation, whereby the stimulation train from a closed-loop session was ‘played back’ to the same animal. We found that SWR-targeted-DBS was effective in elongating sharp-wave ripples in the hippocampus. Moreover, while this protocol did not disrupt task performance compared to baseline, open-loop-replay significantly reduced object recognition. Our results demonstrate that closed-loop DBS of the fornix can be used to modulate the properties of SWRs and that the timing of stimulation impacts behavioural performance.