# Genetic and molecular regulation of experience-dependent structural plasticity

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $384,696

## Abstract

PROJECT SUMMARY
 Structural plasticity of neuronal connections is crucial for the wiring and rewiring of
neuronal circuits in response to experience during development and in adulthood. Defects in
plasticity of neuronal connectivity underlie, exacerbate, or contribute to the pathogenesis of many
neurodevelopmental, neuropsychiatric, and neurological disorders, including age-related decline.
However, our understanding of the molecular control of structural plasticity across the lifespan
and in different neuronal contexts is far from complete, in part due to the lack of an experimentally
tractable system to study this complex process at this resolution. The well-defined nervous system
of the nematode Caenorhabditis elegans is an ideal system to identify the genes and molecular
mechanisms involved with direct comparison of multiple life stages. We propose to exploit a
robust model of structural plasticity we discovered in C. elegans to identify and compare
the genetic and molecular regulation of experience-dependent structural plasticity across
development, adulthood, and aging at single neuron resolution. In Aim #1, we will use the
power of C. elegans genetics to screen 20 conserved cell adhesion, scaffolding, and signaling
molecules for roles in experience-dependent structural plasticity during both development and in
early adulthood. Aim #2 will comprehensively characterize the impact of aging on a neuron,
circuit, and behavior in both sexes, and directly measure any changes in the capacity for structural
plasticity across adulthood and aging by inducing and inhibiting structural plasticity with opto- and
chemo-genetic tools. We will identify the mechanisms that maintain or degrade the capacity for
structural plasticity with age, providing novel characterization and understanding of structural
plasticity across the lifespan. In Aim #3, we will leverage the model of experience-dependent
structural plasticity in C. elegans to gain mechanistic insights into the role of multiple conserved
and disease-associated cell adhesion molecules in the regulation of structural plasticity. Using a
combination of transgenic rescue experiments and insertion of tags/tools into the endogenous
CAM genes, we will define the cellular, molecular, and temporal mechanisms by which CAMs
contribute to plasticity. The proposed experiments will directly contribute to our understanding of
the mechanisms and conserved genes that regulate experience-dependent structural plasticity.
thereby informing its role in brain health, disease, and aging, while potentially identifying novel
molecular targets for therapeutic intervention.

## Key facts

- **NIH application ID:** 10798124
- **Project number:** 5R01NS129736-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Michael P Hart
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $384,696
- **Award type:** 5
- **Project period:** 2023-03-01 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10798124

## Citation

> US National Institutes of Health, RePORTER application 10798124, Genetic and molecular regulation of experience-dependent structural plasticity (5R01NS129736-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10798124. Licensed CC0.

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