Hippocampal Sharp-Wave Ripple and Replay Mechanisms Underlying Long-Term Memory

Project summary The mammalian brain has the remarkable capacity to store and retrieve memories. In particular, salient events called sharp-wave ripples (SWRs) are implicated in the consolidation and recall of memories in the hippocampus. These events are high frequency oscillations caused by synchronous depolarizations across both hippocampal hemispheres, and they occur during awake rest or sleep. During SWRs, neural ensembles that are activated during awake experiences are reactivated in rest in compressed sequences of short durations, a process called ‘replay’. Because of their large-scale nature, sharp-wave ripples and replay events can potentially shape plasticity within hippocampal ensembles to promote memory. Studies have shown that lengthening the duration of SWRs can improve memory on spatial tasks performed less than 24 hours later, while disrupting SWRs will impair memory on these spatial tasks. Though SWRs can influence memory processes on short timescales, their role in preserving memories across long timescales remains largely unknown. This proposal will explore the hypothesis that SWRs enhance the stability of long-term memories by generating plasticity to form and maintain ensembles. We will investigate how SWRs shape the stability of spatial memories encoded in hippocampal region CA1 during navigation in virtual reality environments. This study will address two aims. In Aim 1, we will measure the effects SWRs have on the stability of the population-wide place code and replay events across weeks. The proposed experiments will leverage in vivo two-photon calcium imaging and electrophysiological recordings to evaluate whether SWRs causally create stable ensembles on the population level across weeks. In Aim 2, we will determine how SWRs and replay events shape microcircuit organization within replay ensembles. These experiments will utilize a high-speed two-photon optogenetic stimulation approach to optically measure causal functional connectivity between cells within the replay ensemble and to determine whether SWRs can generate plasticity to recruit cells into the replay ensemble. We hypothesize that SWRs contribute to establishing temporally stable memory traces by strengthening the causal functional connections within replay ensembles. These results will provide insight on neural mechanisms that stabilize memory ensembles across long timescales, which is critical for understanding how long-term memory processes are implemented. Long-term memory is impaired in patients with memory disorders and conditions such as Alzheimer’s disease, dementia, and amnesia, so findings from this proposal will help provide a foundation for understanding the pathology of these conditions and will help in the development of new therapies for these patients.