# Real-time manipulations to understand and improve memory processes

> **NIH NIH K99** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $87,870

## Abstract

PROJECT SUMMARY/ABSTRACT
The hippocampus is critical for capturing rich, multimodal representations of experience and facilitating
the long-term storage and later recall of these experiences. During sleep and pauses in
behavior, the hippocampus can “replay” prior experience – reactivating the neural ensemble
corresponding to the original experience in a time-compressed manner. During sleep, such replay is
thought to underlie memory consolidation, while during behavior, replay is thought to additionally
serve a more prospective role: contributing to planning or deliberation by retrieving stored memories in
order to inform upcoming decisions. However, the content of replay neither solely reflects recent
experience nor reliably predicts future behavior, leaving it unclear how exactly the representations of
experience that are replayed relate to upcoming choices. Understanding the relationship between replay
and behavior is particularly critical because abnormalities in replay and sharp wave ripples (SWRs; the
network activity signature of replay) have been observed concurrent with impaired memory-dependent
behavior in aging and diseases of aging. Establishing how replay content changes with aging, and
whether these changes cause deficits in memory-guided behavior, has the potential to generate new
therapeutic strategies to prevent or reverse memory impairment. In order to define how replay contributes to
memory-guided decision-making in normal cognition and in the context of age-related memory impairment,
we have developed a neurofeedback-based operant conditioning paradigm that targets SWRs. This
paradigm provides rapid feedback contingent upon real-time detection of SWRs at a specific point during
each trial of a spatial memory task, and results in substantially increased occurrence of SWRs in a trial
phase-specific manner. Consequently, subjects experience more replay at the required trial phase,
which occurs immediately prior to the choice point of a memory-dependent task. In addition to demonstrating
that replay can be enhanced by neurofeedback, this behavioral paradigm provides an increased opportunity
to link the content of replay with subsequent behavior. This paradigm lays the foundation for the three
aims of this proposal: to define the relationship between replay and memory-guided behavior, to assess
how this relationship changes with age, and to adapt the operant conditioning strategy to directly counter
age-related replay dysfunction. I will complete these aims with the guidance of an exceptional mentoring
team led by Loren Frank and including Carol Barnes, Uri Eden, and Karunesh Ganguly. During the
mentored phase of the award at UCSF, I will conduct the proposed real-time feedback studies, gain
expertise in using state-space models to capture and quantify replay content, scale experiments to
efficiently examine larger cohorts of young and aged animals, and focus on professional development in
order to facilitate a successful transition...

## Key facts

- **NIH application ID:** 10600595
- **Project number:** 3K99AG068425-02S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Anna Kathleen Gillespie
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $87,870
- **Award type:** 3
- **Project period:** 2020-05-15 → 2022-12-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10600595

## Citation

> US National Institutes of Health, RePORTER application 10600595, Real-time manipulations to understand and improve memory processes (3K99AG068425-02S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10600595. Licensed CC0.

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