# Behavioral pattern separation: orchestration by lateral entorhinal cortex-hippocampal circuitry

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2024 · $658,928

## Abstract

PROJECT SUMMARY/ABSTRACT
The discrimination of highly similar episodes is termed behavioral pattern separation. This episodic memory
process is altered by stress and decreased in humans with and rodent models for a range of brain disorders,
including post-traumatic stress disorder (PTSD). Behavioral pattern separation is also susceptible to “load”; it
is harder to discriminate episodes that are very similar (high load) vs. different (low load). Defining the
underlying circuitry in memory stages and load-sensitivity is a key step to a future where poor behavioral
pattern separation might be treated via circuit-based manipulations.
The focus of this application is the role of the lateral entorhinal cortex (LEC) in behavioral pattern separation.
The anatomical connections of the LEC suggest it is central to this stress-sensitive process. The LEC is
innervated by polymodal-, emotion, and stress-linked brain regions. The LEC innervates downstream
hippocampal regions critical for behavioral pattern separation, including the dentate gyrus (DG). In fact LEC
layer IIa stellate fan cells (LECIIa fan cells) send glutamate directly to two key DG cells, DG granule cells and
adult-generated neurons, which are both critical for “high load” pattern separation and are very sensitive to
stress. Excellent human imaging and rodent lesion and neural recording studies also suggest the LEC has a
role in behavioral pattern separation. However, the LEC’s causal role in orchestrating behavioral pattern
separation and its memory stages is untested. The lack of data on LEC’s role is striking given that the LEC is
vulnerable to stress, aging, and disease. A link between LEC and the poor pattern separation seen in age and
disease — including in stress-induced cognitive disorders like PTSD — remains correlative. Direct evidence of
the LEC’s role in behavioral pattern separation is paramount to clear understanding of cortical-hippocampal
circuitry and its function in nonpathological and pathological states.
In this revised R01 application, we propose three aims to provide fundamental understanding of how LECIIa
fan cells are involved in behavioral pattern separation, during what memory stage and which memory load, and
how the LEC-DG circuit activity could be manipulated to overcome stress-induced disruption of pattern
separation. Aim 1. Test if the encoding and consolidation of behavioral pattern separation rely on the activity of
LECIIa fan cell terminals in the DG. Aim 2. Test if behavioral pattern separation performance/retrieval is
modulated by the activity of the LEC fan cell-DG circuit. Aim 3. Test if repeated stress disrupts behavioral
pattern separation performance/retrieval in a way that can be reversed by LEC-DG circuit stimulation.
The data from these Aims will fill major knowledge gaps in the existing models of the neural circuitry that
supports behavioral pattern separation. They will provide essential behavioral and mechanistic insight to
understand poor pattern s...

## Key facts

- **NIH application ID:** 10863994
- **Project number:** 5R01MH129970-02
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** AMELIA J EISCH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $658,928
- **Award type:** 5
- **Project period:** 2023-06-15 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10863994

## Citation

> US National Institutes of Health, RePORTER application 10863994, Behavioral pattern separation: orchestration by lateral entorhinal cortex-hippocampal circuitry (5R01MH129970-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10863994. Licensed CC0.

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