# Systematic and functional analysis of alternative mRNA splicing in an in vivo model of learning

> **NIH NIH R21** · HARVARD UNIVERSITY · 2021 · $464,750

## Abstract

PROJECT SUMMARY
Alternative mRNA splicing (AS) is a fundamental process that regulates the expression of more than 90% of
human protein-coding genes. The function of AS in the nervous system is particularly prevalent and has been
implicated in multiple neurological disorders that impair learning. Although AS is implicated in activity-
dependent gene expression underlying neural plasticity, no systematic analysis on AS has been
performed on an in vivo learning model. The complexity of the mammalian brain poses challenges to this
type of studies. Thus, we still do not understand (1) to what extent learning engages AS in the nervous
system, (2) how AS contributes to learning-induced changes in neuronal gene expression, and (3) how
learning modulates AS and splice isoforms of specific genes to generate learned behavior. Here, we propose
to address these fundamental questions in C. elegans. The rationale is that the wiring and genetic make-up
of the C. elegans nervous system are well characterized, dynamic gene expression can be profiled for the
whole brain or individual neurons, functions of genes in learning can be dissected at the cellular resolution
with genetic and imaging tools, and the fundamental properties of the development and function of the
nervous system are well conserved between C. elegans and more complex animals. In addition, many forms
of learning exhibited by C. elegans share similar behavioral characteristics and molecular underpinnings with
those displayed by higher organisms. The overall goal of this project is to characterize how AS regulates
learning and to provide insights into neurological defects in brain function under many disease conditions.
The hypothesis of this project is that AS regulates neuronal gene expression to modulate neural function
and produce learning. Specifically, we will first characterize the global patterns of AS network and splice
isoforms that are regulated by a learning paradigm well-characterized in our laboratory. We plan to
systematically analyze how learning alters splicing or isoform usage of all genes expressed in the C. elegans
nervous system. Next, we will use genetic perturbations to address the causal function of learning-regulated
splice isoforms of conserved molecules in neural activity and behavior. The grant is exploratory, because it
(1) presents the first systematic analysis of AS in an in vivo model of learning and (2) introduces conceptual
and technical advances to address causal links between AS and learning behavior. The proposed work is
significant, because it (1) tests a highly plausible function of AS, a fundamental gene expression process
conserved in eukaryotes, in learning, and (2) characterizes the mechanisms whereby AS of conserved
molecules regulates neuronal gene expression and function to produce learning. Meanwhile, our grant is built
on a substantial amount of preliminary results that support conceptual and technical productivity. The
outcome of this study will provi...

## Key facts

- **NIH application ID:** 10372656
- **Project number:** 1R21NS121825-01A1
- **Recipient organization:** HARVARD UNIVERSITY
- **Principal Investigator:** Yun Zhang
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $464,750
- **Award type:** 1
- **Project period:** 2021-09-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10372656

## Citation

> US National Institutes of Health, RePORTER application 10372656, Systematic and functional analysis of alternative mRNA splicing in an in vivo model of learning (1R21NS121825-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10372656. Licensed CC0.

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