# Molecular mechanisms of exercise-induced synaptic plasticity in the hippocampus

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $361,900

## Abstract

Neurons have the remarkable ability to process and respond to complex stimuli such as physical exercise and
changes in an organism’s external environment. The value of exercise for brain health cannot be
underestimated as its effects impact mood, learning and memory as well as prevention and rehabilitation and
recovery from neurological illness. However, experimental effort largely has been focused on the effects of
sustained exercise over periods of weeks or months (1-3), which can involve direct effects on the CNS as well
as indirect effects through alterations in multiple organ systems. Likewise, most attention in exercise-induced
hippocampal plasticity has been directed at newborn granule cells (1, 3-7), but plasticity occurs in the far more
numerous mature granule cells as well (8). Aside from its sustained benefits, acute exercise has also been
linked to short term increases in learning and memory (9, 10) that are likely mediated by the hippocampus (11-13). How this occurs at the molecular level is not clear. Thus we decided to examine how a single episode of
exercise affects neural activity and impacts brain function. We developed a novel approach for in vivo analysis
of dentate granule cells activated by a single episode of voluntary exercise. Our approach, akin to an "impulse"
function in engineering terms, allowed us to examine exercise-induced synaptic and molecular changes over a
period of days post-exercise. Mature dentate granule cells, activated by voluntary exercise during a two-hour
window, were permanently marked using Fos-TRAP mice (14, 15), in which the immediate early gene
promoter linked to a fluorescent reporter, permanently marks activated granule cells. The single episode of
exercise resulted in selective increases in synaptic function and dendritic spine density in the outer molecular
layer of the dentate gyrus, the lamina receiving contextual information from entorhinal cortex. The top
upregulated gene in RNAseq of exercised-activated cells was Mtss1L, a previously understudied gene coding
for an I-BAR-domain protein. As BAR domains sense and induce membrane curvature, we hypothesize
that Mtss1L is an early effector of dendritic spine and synapse formation following stimuli such as
exercise. Our preliminary data lead to a number of interesting questions that will be addressed in this
proposal. Namely: 1. Where is Mtss1L localized and why are the effects on synapses limited to a specific
lamina in the dentate gyrus?; What are the effects of other I-BAR family members as several are expressed at
synapses but only Mtss1L is activity-dependent?; and 3. Do exercise-induced synaptic changes prime specific
synapses for learning and memory by salient stimuli? Our approach provides the cellular- and temporal-specificity to link physiologically- and clinically-relevant stimuli in vivo (exercise) to individual synapses and
expression of specific genes contributing to structural plasticity in the hippocampus.

## Key facts

- **NIH application ID:** 10023918
- **Project number:** 1R01NS117371-01
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** GARY L WESTBROOK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $361,900
- **Award type:** 1
- **Project period:** 2020-07-15 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10023918

## Citation

> US National Institutes of Health, RePORTER application 10023918, Molecular mechanisms of exercise-induced synaptic plasticity in the hippocampus (1R01NS117371-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10023918. Licensed CC0.

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