# Theta Phase-Locked Stimulation of Entorhinal-Hippocampal Inputs in Healthy and Epileptic Mice

> **NIH NIH F31** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $47,374

## Abstract

Project Summary
Epilepsy is a debilitating neurological disorder characterized not only by spontaneous recurrent seizures, but
also severe cognitive deficits that present a significant detriment to quality of life. Changes in synchrony within
and across brain regions have been implicated in temporal lobe epilepsy (TLE), but it is unclear how these
changes contribute to memory deficits. Electrophysiological recordings from the Shuman lab have shown that
coherence between the hippocampus and medial entorhinal cortex (MEC) is disrupted in a mouse model of
TLE. This synchronization between hippocampus and MEC has been theorized to be important for spatial
memory by allowing efficient information transfer at distinct phases of theta. However, there have been few
causal studies on the impact of synchronization due in part to limited technical methods to manipulate the
timing of inputs in behaving mice. Thus, investigating the causal nature of altered synchrony in cognitive
dysfunction requires the application of novel tools to precisely manipulate the timing neural activity. To address
this gap, I have developed a closed-loop optogenetic system that can stimulate neural populations at distinct
phases of endogenous theta oscillations. In this proposal, I will use this system to test the hypothesis that the
timing of MECII and MECIII inputs relative to endogenous theta oscillations controls memory performance in
both healthy and epileptic mice. I will employ a head-fixed virtual reality task to test the effect of altered input
timing on spatial memory performance and will investigate the role of this timing on other measures of
synchrony including interregional coherence. I hypothesize that mistiming MEC inputs in healthy mice will
impair memory performance and disrupt coherence, while restoring proper timing in epileptic mice will improve
performance and increase coherence. Furthermore, I will use a layer specific viral approach to restrict
optogenetic stimulation to afferents arriving to the hippocampus from MEC layer II or layer III and determine
the distinct role of each of these inputs into hippocampus. Together, the results of these experiments will
determine how the timing of inputs into the hippocampus impacts spatial processing in both health and disease
and will pave the way for future therapeutic targets in epilepsy.

## Key facts

- **NIH application ID:** 10902987
- **Project number:** 1F31NS134301-01A1
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Paul Andrew Philipsberg
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $47,374
- **Award type:** 1
- **Project period:** 2024-04-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10902987

## Citation

> US National Institutes of Health, RePORTER application 10902987, Theta Phase-Locked Stimulation of Entorhinal-Hippocampal Inputs in Healthy and Epileptic Mice (1F31NS134301-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10902987. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*