# Towards a Complete Description of the Circuitry Underlying Sharp Wave-Mediated Memory Replay

> **NIH NIH U19** · STANFORD UNIVERSITY · 2020 · $2,670,949

## Abstract

Although neuroscience has provided a great deal of information about how neurons work, the fundamental
question of how neurons function together in a network to produce cognition has been difficult to address.
Our group has been at the forefront of developing methods that allow large scale monitoring of identified
neurons, monitoring of voltage signals by optical means and elucidation of subcellular events in dendrites,
all of which can now be done in awake behaving animals. We propose to use these methods to provide a
deep understanding of how the neurons of the hippocampal region generate the sharp-wave ripple (SPW-
R). This remarkable signal has been shown to depend on prior learning and to produce high-speed replay
of memory sequences (e.g. a path along a track). The function of this signal is memory consolidation;
disruption of SPW-Rs results in strong deficits in memory-guided behavior. Because much is known about
the hippocampal cell types involved and their network connections, understanding the SPW-R is a
tractable target for the first major effort to elucidate the cellular/network mechanism of a mammalian brain
signal at an analytical level comparable to that achieved in the study of simple invertebrate systems.
Project 1 is aimed at understanding the external and intra-hippocampal pathways that control the initiation
of SPW-Rs. Project 2 deals with the events that occur during the SPW-R, including the timing of activity in
identified cell types and understanding the fundamental network architecture by which memory sequences
are produced. Project 3 deals with how the information that is replayed during the SPW-R is encoded. We
will attempt to create an artificial memory and then determine whether the memory is replayed during a
SPW-R; we will also interfere with molecular mechanisms of memory storage to determine whether we can
erase the memories that are replayed during the SPW-R. Project 4 builds upon recent work indicating that
differentially projecting CA1 pyramidal cells have distinct properties and will test the possibility that SPW-
Rs in distinct output channels may carry different information and affect different behaviors. In Project 5 we
will develop the first non-reduced computational model of the hippocampus, incorporating information
about cell types and connections. This will be a major new resource for our group and the research
community that will permit unprecedentedly close interplay between experiment and computation. To the
extent that the model can account for the experimental observations, we can use it to understand
underlying network principles and design interventional experiments to validate this understanding. To the
extent that the model cannot explain results, it will help point us to aspects of network function that require
further elucidation. Taken together, Projects 1-5 provide a tractable path to a major breakthrough in
understanding how a cognitively important brain signal is generated.

## Key facts

- **NIH application ID:** 9993592
- **Project number:** 5U19NS104590-04
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** GYORGY BUZSAKI
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $2,670,949
- **Award type:** 5
- **Project period:** 2017-09-25 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9993592

## Citation

> US National Institutes of Health, RePORTER application 9993592, Towards a Complete Description of the Circuitry Underlying Sharp Wave-Mediated Memory Replay (5U19NS104590-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9993592. Licensed CC0.

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