# Dependence of memory on precisely coordinated oscillations

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $308,454

## Abstract

Project Summary
Healthy cognitive processing is associated with well-defined brain oscillations, which are not only an indication
of accurate timing of neuronal activity within brain regions, but also of the coordination of neural activity
patterns between brain regions. Consistent with this notion, some aspects of oscillatory activity in at least a
subset of brain regions are disrupted in any of the major psychiatric and neurological diseases. However,
evidence for a causal link between disrupted oscillations and impaired behavior has remained
sparse. In particular, it has been challenging to manipulate timing within brain circuits without
simultaneously disrupting other firing statistics of neuronal populations, such as their firing
sparsity or firing rate. Preliminary data are presented which indicate that optogenetic rhythmic stimulation
of medial septal PV neurons at frequencies that are higher than the endogenous theta frequency (≥ 10 Hz)
alters hippocampal spike timing, but without changing other firing statistics, such as spatial firing patterns,
firing rate, and theta phase precession. Furthermore, we found that stimulation at 8 Hz was without effect on
memory performance while stimulation at ≥10 Hz resulted in a memory impairment that was comparable in its
severity to a complete hippocampal lesion. We therefore hypothesize that minor shifts in the timing
of neuronal activity result in a loss of coordination between neuronal networks in the
hippocampus, medial entorhinal cortex, and medial prefrontal cortex, such that these brain
regions can no longer support spatial working memory. We will perform three aims to address this
hypothesis. (1) Determine the minimal time shift at which memory deficits emerge and measure the
coordination of hippocampal neural activity while stimulating at frequencies with and without memory deficits.
(2) Determine whether manipulations of theta frequency critically alter firing patterns in
medial entorhinal cortex (mEC). (3) Determine whether oscillations within the endogenous
theta frequency range are necessary for the coordination between hippocampus and medial
prefrontal cortex (mPFC). In each of the three aims, we will perform LFP and single unit recordings while
mice perform a spatial alternation task. Two versions of the task will be compared, a delayed version which is
dependent on hippocampal and prefrontal function, and a continuous version, which is included as a control.
While mice are performing the task, the medial septal area will be stimulated at frequencies that do not result
in memory deficits or stimulated at frequencies that result in memory deficits. These conditions will be
compared to identify the critical changes in neural activity in hippocampus, mEC, and mPFC at the transition
to the memory impairment. Taken together, the combined manipulations and recordings in the behavioral task
will provide evidence for a causal relation between precise timing and memory function and for a role of...

## Key facts

- **NIH application ID:** 10187666
- **Project number:** 5R01NS102915-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Stefan Leutgeb
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $308,454
- **Award type:** 5
- **Project period:** 2017-07-01 → 2023-05-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10187666

## Citation

> US National Institutes of Health, RePORTER application 10187666, Dependence of memory on precisely coordinated oscillations (5R01NS102915-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10187666. Licensed CC0.

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