# Cell Type-specific Anterograde Circuit Mapping and Functional Control by Optimizing YFV-17D Transneuronal Systems

> **NIH NIH RF1** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $1,566,333

## Abstract

Cell Type-specific Anterograde Circuit Mapping and Functional Control by
 Optimizing YFV-17D Transneuronal Systems
Summary
To elucidate the functional organization of brain circuitry we need to delineate neuronal
connectivity and control the activity of neurons with specific connectivity. Both tasks have
increasingly relied on transneuronal viral vectors. Anterograde transneuronal viral vectors, which
spread from presynaptic neurons to the postsynaptic neurons, can reveal the neuronal projections
and selectively target postsynaptic neurons. Due to the lack of ideal anterograde transneuronal
viral vectors, we have spent the last few years developing a new anterograde system based on
yellow fever vaccine—YFV-17D. We have successfully constructed two major anterograde tools:
the packaging defective YFV∆CME for mapping neuronal projectomes, and the replication defective
YFV∆NS1 (or YFV∆CMENS1) for transneuronal control of gene expression in postsynaptic neurons,
which can be used for functional observation or manipulation. Neuronal toxicity can be avoided
in the case of YFV∆NS1 and YFV∆CMENS1, but not in YFV∆CME. These new systems provide benefits
of transneuronal efficacy, diverse applications, and ease of engineering, but they still have
limitations for many experimental scenarios.
Here we propose to further improve these viral systems to make them broadly applicable,
powerful and safe tools for functional dissection of the brain circuits. Firstly, we will construct self-
constrained YFV-17D to further minimize neuronal toxicity incurred by viral replication in neurons,
which will make these vectors more useful for both research and potential clinical applications.
Secondly, we will test multiple strategies to target this system to specific neurons for cell-type
specific tracing or functional control in both local circuits and long-range projections. Some of the
cell type specific tools will not rely on the availability of genetically modified mouse lines and can
be applied to broad species. Thirdly, we will incorporate commonly used tags, sensors or effectors
in the optimized transneuronal viral vectors for versatile applications. We will also apply the
improved versions to delineate a selected neuronal circuit that is of great interest to
neuroscientists. Therefore, this project will yield a set of highly powerful tools widely applicable to
neuroscience research, and will reveal the projectomes of multiple classical neuronal types.

## Key facts

- **NIH application ID:** 10505702
- **Project number:** 1RF1MH130422-01
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Wei Xu
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,566,333
- **Award type:** 1
- **Project period:** 2022-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10505702

## Citation

> US National Institutes of Health, RePORTER application 10505702, Cell Type-specific Anterograde Circuit Mapping and Functional Control by Optimizing YFV-17D Transneuronal Systems (1RF1MH130422-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10505702. Licensed CC0.

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