# Elucidating the Role of Brain Extracellular Matrix in Hippocampal Learning and Memory

> **NIH NIH F30** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $41,324

## Abstract

PROJECT SUMMARY/ABSTRACT
Composed of a latticework of proteoglycans and associated molecules, the brain extracellular matrix (ECM) is
a medium for synaptic plasticity. The expression of chondroitin sulfate proteoglycans (CSPGs), most notably
aggrecan (gene: Acan), has been shown to mediate the closure of critical periods of plasticity through the
formation of perineuronal nets, structures thought to stabilize synaptic connections. Furthermore, enzymatic
digestion of hippocampal ECM results in contextual learning deficits, suggesting that ECM may stabilize
learning-related synaptic changes. The dentate gyrus of the hippocampus, a critical learning structure, has
abundant aggrecan in its molecular layer, and dentate gyrus granule cells (DG GCs) continuously produce
Acan mRNA in adulthood. Thus, aggrecan production by dentate gyrus neurons may underlie the stability of
memory processes.
Preliminary data presented here show that genetic deletion of Acan in dentate gyrus neurons results in remote
contextual discrimination deficits. This proposal will test the hypothesis that activity-dependent aggrecan
expression by DG GCs following learning is essential for DG ensemble separation and memory precision at
retrieval. First, the effect of contextual fear learning on DG GC Acan expression and deposition will be
characterized (Aim 1). Next, DG-specific Acan deletion will be used to test if aggrecan production is necessary
for recent or remote contextual memory precision (Aim 2). Lastly, using microendoscopic calcium imaging, I
will describe how aggrecan deletion changes DG GC ensemble properties (Aim 3). Altogether, this proposal
aims to elucidate the extracellular matrix's role in mammalian learning and memory and the underlying
molecular and network mechanisms. Furthermore, given that alterations to brain ECM are found in
neurodegenerative and psychiatric conditions, understanding the physiologic properties of ECM may yield
insights into disease pathophysiology and potential therapeutic avenues.
These research goals will be realized in conjunction with a comprehensive training plan aimed at developing the
applicant’s career as a physician-scientist. This training will include consistent, rigorous mentorship in conceptual
and technical skills from two highly-qualified mentors, one of whom is a physician-scientist. The research and
training proposed here will be carried out at the University of California, San Francisco, which offers both a world-
class neuroscience research environment and an exceptional medical school for clinical training.

## Key facts

- **NIH application ID:** 10885930
- **Project number:** 5F30MH134458-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Ricardo Guajardo
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $41,324
- **Award type:** 5
- **Project period:** 2023-06-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10885930

## Citation

> US National Institutes of Health, RePORTER application 10885930, Elucidating the Role of Brain Extracellular Matrix in Hippocampal Learning and Memory (5F30MH134458-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10885930. Licensed CC0.

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