# Circuit mechanisms of hippocampal replay

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA BERKELEY · 2024 · $502,540

## Abstract

We study how neural activity in the hippocampus and connected areas mediates their roles in learning and
memory. We are interested in circuit mechanisms responsible for activation of hippocampal units in precise
sequences that depict past and future behavioral trajectories. These sequences, called "replays", are attracting
increasing attention because of the unique way they allow a subject to re-experience events from another time
and place. Despite these intriguing features, several questions remain. We do not know how replays impact
other brain activity and what role they play in behavior. We also do not know how other circuits outside of the
hippocampus are involved in generating replays. Here, we will find answers to these questions, by recording
and manipulating neural activity, in hippocampus and in a closely connected area called entorhinal cortex, in
awake and freely behaving rats. (Aim 1) Previous attempts to disrupt replay have only revealed relatively
subtle effects on behavior. For example, disruption during a post-training consolidation period has relatively
weak effects on a spatial memory task. Here we present preliminary evidence that disrupting replay while a rat
learns a new goal location in a spatial memory task dramatically affects performance during a probe test
performed immediately afterward. We will use this effect to determine which parts of replays are important. For
example, it could be that replays must join up the goal location and more distant locations in the environment
to enable later navigation to the goal from those distant locations. These and other hypotheses will be tested
systematically to reveal how replay contributes to spatial learning. (Aim 2) The medial entorhinal cortex (MEC)
has been implicated in the representation of spatial goals, and in supporting longer hippocampal replays.
However, this latter result was found with only a partial suppressive effect on MEC activity, and in mice, where
replay is difficult to measure. We use an innovative new optogenetic technique using more penetrative
wavelengths of light, and an innovative form of optical fiber geometry, to shut down activity along the entire
length of the MEC in the rat. We will use this to look for stronger effects on hippocampal replay, and for effects
that are specific to certain types of replay, such as those that travel toward the goal. Further, we can test
whether MEC is necessary for replay-dependent spatial learning as shown in Aim 1. (Aim 3) We also use
advanced silicon probes to measure activity from hundreds of units along the length of the MEC. Therefore we
will look for replay within MEC itself, and how it relates to hippocampal replay. This has been controversial in
the literature, but with our increased cell yield we will be able to resolve this, and also examine sub-types of
MEC cell such as grid cells, border cells, head direction cells etc. Taken together, our results will provide
insight into fundamental mechanisms of learnin...

## Key facts

- **NIH application ID:** 10907005
- **Project number:** 5R01MH103325-10
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** David J Foster
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $502,540
- **Award type:** 5
- **Project period:** 2014-09-15 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10907005

## Citation

> US National Institutes of Health, RePORTER application 10907005, Circuit mechanisms of hippocampal replay (5R01MH103325-10). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10907005. Licensed CC0.

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