Uncovering the dynamics of hippocampal-neocortical coupling in humans and mice

The National Institute of Mental Health awarded New York University $110,228 on October 6, 2026, under the Mental Health Research Grants program (CFDA 93.242) to investigate hippocampal-neocortical coupling in memory consolidation.

The funded research examines how hippocampal sharp-wave ripples facilitate communication between the hippocampus and neocortex during non-rapid eye movement sleep and support long-term memory consolidation. The project includes three parallel studies: analysis of stereo-EEG data from epilepsy patients using a novel human sharp-wave ripple detection pipeline combined with current source localization to test whether the timing and spread of ripple activity are conserved between rodents and humans; optogenetic silencing of the entorhinal cortex in rodent models to assess bidirectional hippocampal-neocortical coupling and changes in ripple timing relative to cortical state transitions; and selective suppression of distinct sharp-wave ripple types in mice using optogenetics to measure their functional significance for memory retention in a cheeseboard maze task.

The recipient, New York University School of Medicine, operates as a major academic medical center and NIH-focused research institution. Work is performed in New York, New York. The period of performance runs through April 8, 2030. The assistance type is a Project Grant.

Abstract

Hippocampal sharp-wave ripples (swrs) are high-frequency bursts of pyramidal cell activity that facilitate communication between the hippocampus and neocortex, primarily during non-rapid eye movement (nrem) sleep. These bursts drive neural representations of experience across the neocortical mantle, supporting long- term memory consolidation through synaptic strengthening. Numerous studies have highlighted the importance of hippocampal-neocortical coupling in memory, implicating swrs in animal models of alzheimer's, epilepsy, autism, schizophrenia, and depression. Recent work from our lab revealed that not all swrs serve the same function. Researchers identified four distinct SWR types based on their timing relative to neocortical up and down state transitions, suggesting that different SWR types play specialized roles in memory processing. Here, i propose a series of studies to clarify the mechanisms underlying SWR-dependent consolidation in both rodents and humans. First, i will test the hypothesis that the timing of SWR-dependent hippocampal-neocortical coupling and the spread of ripple activity across the cortex are conserved between rodents and humans. I will use a novel human SWR detection pipeline, combined with current source localization and time-locked averaging, to analyze stereo- EEG data from epilepsy patients. Second, i will investigate whether hippocampal-neocortical coupling is BI- directional by using optogenetics to silence the entorhinal cortex, a key input to the hippocampus. This will allow me to assess changes in SWR timing and content relative to cortical state transitions during nrem sleep. Finally, i will probe the functional significance of different SWR types in mice by selectively suppressing swrs with optogenetics and testing their impact on memory retention in a cheeseboard maze task. Successful completion of these studies will clarify the conserved role of swrs in memory consolidation across species and provide a framework for targeting SWR-related mechanisms in memory-related disorders such as epilepsy and alzheimer's disease.