# Investigating spatial representation in hippocampal entorhinal circuit of knock in Alzheimer's model

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA-IRVINE · 2020 · $40,278

## Abstract

Project Summary (Abstract)
Alzheimer’s disease (AD) is a progressive neurological disorder that debilitates our mind and memory. The very
sense of self is lost and ability to distinguish between different environments and remember are also impaired in
these patients. Currently, AD affects 5 million people in the US and it is creating significant burden on the health
care system (> $100 billion). Despite significant advances made in uncovering molecular and cellular
mechanisms behind AD pathology, we still lack the proper treatment. No clear studies have been performed to
investigate the changes that occur in the brain circuits of AD. By understanding what type of neuronal activities
are lost and demonstrating the relationship between the dysfunctional neural network and cognitive deficits, we
can develop novel therapies targeted to reactivate these activities in AD patients.
Our lab has been investigating the impairment of brain activity in the AD mouse model using electrophysiological
recording methods. We are focusing on a brain region called the entorhinal cortex (EC). Neurons in the EC
receive input from multiple cortical regions and send projections to the hippocampus. CA1 cells in the
hippocampus send their axons back to the EC, thus, forming the EC-hippocampal loop circuit. This connection
between the two brain regions is involved in memory formation and retrieval and damage to this circuit results in
memory impairment. Histological and imaging studies in AD patients and animal models have shown that the
EC is a primary site of atrophy and activity loss in the early phases of AD. However, it is still unclear what type
of activity is lost in the EC of AD patients, or even in AD mouse models.
Using a novel amyloid precursor protein (APP) knock-in mouse model, we found that brain network activity called
gamma oscillations are impaired in the medial part of the EC (MEC). Furthermore, we acquired preliminary data
showing that MEC neurons called grid cells, a cell type harboring spatial memory-related activity, are impaired
in APP knock-in mice. Place cells, another memory-associated neurons in the hippocampus, are also impaired.
By optogenetically manipulating the principal neurons in the medial entorhinal cortex, we will reactivate the
impaired grid cell activity and test if the disrupted spatial memory of APP knock-in mice can be rescued. This will
be the first study to demonstrate whether cell type specific electroceutical approach can be an effective means
of treatment for AD and it will create opportunities for additional studies in a variety of AD mouse models as well
as potential clinical translation to studies in patients.

## Key facts

- **NIH application ID:** 10068081
- **Project number:** 1F31AG069500-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Heechul Jun
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $40,278
- **Award type:** 1
- **Project period:** 2020-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10068081

## Citation

> US National Institutes of Health, RePORTER application 10068081, Investigating spatial representation in hippocampal entorhinal circuit of knock in Alzheimer's model (1F31AG069500-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10068081. Licensed CC0.

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