# Mechanisms of hippocampal network-targeted stimulation to rescue memory impairment due to Alzheimer's disease

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2021 · $263,333

## Abstract

Supplement Project Summary/Abstract
The purpose of this administrative supplement for our ongoing grant “Cellular mechanisms of hippocampal
network neuroplasticity generated by brain stimulation” (R01-NS11380) is to use the innovative translational
brain stimulation methods developed under the ongoing parent grant to test whether and how they rescue
memory impairments in the next-generation rodent model of Alzheimer’s disease (AD), TgF344-AD. AD
produces memory impairment by affecting the function of the distributed network of the hippocampus. Our
ongoing project investigates the mechanisms whereby electrical brain stimulation targeting the hippocampal
network can improve its function. By performing companion in vivo electrophysiological experiments in healthy
young adult rodents and in human neurosurgical cases with depth electrodes in regions homologous to those
implanted in the rodents, the ongoing project takes a highly translational approach to identify similarities across
species in how the hippocampal network responds to brain stimulation. This approach thereby enhances the
relevance to human function of the mechanistic insights offered by rodent in vivo and in vitro electrophysiology
experiments performed for the ongoing project. This administrative supplement will expand our translational
model of hippocampal network brain stimulation to address memory impairment due to AD. We first will
behaviorally characterize young (5-6 mo.) and aged (20-23 mo.) F344 wild-type and aged TgF344-AD rats (a
rodent model of AD) using the spatial Morris water maze task. Aged F344 rats will be categorized based on
performance of this task into age-unimpaired (AU) and age-impaired (AI) subgroups, such that comparisons
among the four groups (young, AU, and AI F344 rats and aged TgF344-AD rats) will be able to differentiate
variation in stimulation efficacy based on aging, on typical aging-related memory impairment, and on AD
pathology. In each of these groups, we will then compare the effects of locking stimulation to the ongoing
phase of the hippocampal theta rhythm (versus non-phase-locked control conditions) on hippocampal network
in vivo electrophysiology and on performance on the paired associate learning (PAL) touchscreen task, which
is hippocampal dependent in both rodents and humans. Across-group comparisons will be used to determine
whether phase-locked stimulation is maximally beneficial for hippocampal network electrophysiology and PAL
performance in TgF344-AD rats relative to AI rats, with comparisons between AI and AU groups and between
AU and young groups used to differentiate the effects of AD from those of aging with versus without memory
impairment. Notably, although brain stimulation has shown moderate efficacy for memory impairment in aging
and AD, very little data are available regarding mechanisms. These experiments will thus yield important and
highly novel data on how brain stimulation targeting the hippocampal network influences its fu...

## Key facts

- **NIH application ID:** 10294112
- **Project number:** 3R01NS113804-02S1
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** JOHN F DISTERHOFT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $263,333
- **Award type:** 3
- **Project period:** 2021-01-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10294112

## Citation

> US National Institutes of Health, RePORTER application 10294112, Mechanisms of hippocampal network-targeted stimulation to rescue memory impairment due to Alzheimer's disease (3R01NS113804-02S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10294112. Licensed CC0.

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