# The role of extracellular matrix in estradiol regulation of hippocampal memory consolidation

> **NIH NIH F32** · UNIVERSITY OF WISCONSIN MILWAUKEE · 2020 · $65,310

## Abstract

PROJECT SUMMARY
Memory impairment is a defining characteristic of many neuropsychiatric disorders, however our understanding
of the neurobiological mechanisms of memory dysfunction and ability to therapeutically address these
symptoms remain inadequate. The sex steroid hormone 17β-estradiol (E2) is a powerful regulator of learning
and memory and has profound effects in the hippocampus, a region critical to memory formation. E2-induced
signaling within the hippocampus is necessary for memory consolidation, but the molecular mechanisms
producing this effect are still not fully defined. Therefore, the long-term goal of our research is to determine the
molecular mechanisms through which E2 regulates hippocampal memory formation. The overall objective of
this application is to determine the extent to which the ECM molecules MMP-9 and β1-integrin are necessary
for E2 to enhance hippocampal memory in both male and female mice. Based on previous data showing that
MMP-9 and β1-integrin work together as critical regulators of hippocampal plasticity, our central hypothesis is
that E2 enhances hippocampal memory consolidation through modification of the ECM via increased MMP-9
enzymatic activity and subsequent activation of cell-surface β1-integrin receptors. The rationale for this work is
that by uncovering novel mechanisms of E2 action in regulating hippocampal plasticity and memory, we will
improve our understanding, and ability to therapeutically target, estrogenic regulation of hippocampal
dysfunction. Our central hypothesis will be tested in two specific aims: 1) determine the extent to which
estrogenic regulation of MMP-9 contributes to hippocampal memory enhancement, and 2) determine the
extent to which estradiol and β1-integrin receptors interact to produce hippocampal memory enhancement.
Both aims will use a combination of biochemical and behavioral methods to characterize the mechanisms and
outcomes of E2 regulation of the hippocampal ECM. First, E2 will be directly infused into the dorsal
hippocampus of male and female mice and the effects on MMP-9 or β1-integrin expression and activity will be
assessed. Then, using one-trial learning tasks and intracranial infusion of pharmacological inhibitors, we will
determine the extent to which MMP-9 and β1-integrin influence estrogenic regulation of memory consolidation.
This work is innovative in that it represents a fundamental shift from the conventional focus on intracellular
signaling mechanisms to consider the potentially important contribution of the ECM in estrogenic regulation of
memory consolidation. By directly assessing the contributions of the ECM to estrogenic memory regulation, we
will advance the existing model of E2 signaling in the hippocampus to integrate extracellular and intracellular
signaling processes. This contribution is significant because it will provide essential foundational knowledge
about the mechanisms through which estradiol regulates memory formation in the male and femal...

## Key facts

- **NIH application ID:** 10069996
- **Project number:** 5F32MH118782-02
- **Recipient organization:** UNIVERSITY OF WISCONSIN MILWAUKEE
- **Principal Investigator:** Kellie Gross
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $65,310
- **Award type:** 5
- **Project period:** 2019-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10069996

## Citation

> US National Institutes of Health, RePORTER application 10069996, The role of extracellular matrix in estradiol regulation of hippocampal memory consolidation (5F32MH118782-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10069996. Licensed CC0.

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