Enhancer-AAVs allow genetic access to oligodendrocytes and diverse populations of astrocytes across species

Abstract Proper brain function requires the assembly and function of diverse populations of neurons and glia. Single cell gene expression studies have mostly focused on characterization of neuronal cell diversity; however, recent studies have also revealed substantial diversity of glial cells, particularly astrocytes. To better understand glial cell types and their roles in neurobiology, we built a new suite of adeno-associated viral (AAV)-based genetic tools to enable genetic access to astrocytes and oligodendrocytes. These oligodendrocyte and astrocyte enhancer-AAVs are highly specific (usually > 95% cell type specificity) with variable expression levels, and the astrocyte enhancer-AAVs show multiple distinct expression patterns reflecting the spatial distribution of astrocyte cell types. To provide the best glial-specific functional tools, several enhancer-AAVs were: optimized for higher expression levels, shown to be functional and specific in rat and macaque, shown to maintain specific activity across transgenes and in epilepsy where traditional promoters changed activity, and used to drive functional transgenes in astrocytes including Cre recombinase and acetylcholine-responsive sensor iAChSnFR. The astrocyte-specific iAChSnFR revealed a clear reward-dependent acetylcholine response in astrocytes of the nucleus accumbens during reinforcement learning. Together, this collection of glial enhancer-AAVs will enable characterization of astrocyte and oligodendrocyte populations and their roles across species, disease states, and behavioral epochs.

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Publication Details

Journal
eLife
Published
2025-10-10
DOI
https://doi.org/10.7554/elife.108640.1
Primary Topic
Neurogenesis and neuroplasticity mechanisms
Type
article
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article

Enhancer-AAVs allow genetic access to oligodendrocytes and diverse populations of astrocytes across species

Adriana E. Sedeño-Cortés, Delissa McMillen, Jiatai Liu, Michael Kunst et al.
eLife
Neurogenesis and neuroplasticity mechanisms
article

Enhancer-AAVs allow genetic access to oligodendrocytes and diverse populations of astrocytes across species

Adriana E. Sedeño-Cortés, Delissa McMillen, Jiatai Liu, Michael Kunst, Amanda Gary, Nicholas A. Lusk, Mckaila Leytze, Yoav Ben‐Simon, Naz Taskin, Mary McGraw, Tamara Casper, Natalie Weed, Hongkui Zeng, Naomi Martin, Bosiljka Tasic, Nasmil Valera Cuevas, Michael J. Taormina, Jonathan T. Ting, Trygve E. Bakken, Ximena Opitz-Araya, Nicholas Donadio, Kiet Ngo, Nelson Johansen, Jazmin Campos, Joseph T. Mahoney, Christine Rimorin, Tanya L. Daigle, Luke V. Loftus, Tingfa Zhou, Sharon W. Way, Smrithi Sunil, Shane Gibson, Deja Monet, Gregory D. Horwitz, Jeff Goldy, Will Laird, Krissy Brouner, Ryan A. Canfield, Michael Tieu, Lydia Potekhina, Daniel Hirschstein, Zizhen Yao, Boaz P. Levi, Jack Waters, Kaspar Podgorski, Christina Alice Pom, John K. Mich, Nadiya V. Shapovalova, Nick Dee, Jocelin Malone, Bryan B. Gore, Elizabeth Liang, Kimberly A. Smith, Han Hou, Augustin Ruiz, Paul Olsen, Ravi Bhowmik, Refugio A. Martinez, Yemeserach Bishaw, Kenta M. Hagihara, Victoria Omstead, Melissa Reding, Shenqin Yao, Ed S. Lein, Bargavi Thyagarajan, Tom Egdorf, Dakota Newman, Karel Svoboda, Darren Bertagnolli, Erin L Groce, Aaron Oster, Josh Nagra, Yoshiko Kojima, Nadezhda Dotson, Vonn Wright
article en

Abstract

Abstract Proper brain function requires the assembly and function of diverse populations of neurons and glia. Single cell gene expression studies have mostly focused on characterization of neuronal cell diversity; however, recent studies have also revealed substantial diversity of glial cells, particularly astrocytes. To better understand glial cell types and their roles in neurobiology, we built a new suite of adeno-associated viral (AAV)-based genetic tools to enable genetic access to astrocytes and oligodendrocytes. These oligodendrocyte and astrocyte enhancer-AAVs are highly specific (usually > 95% cell type specificity) with variable expression levels, and the astrocyte enhancer-AAVs show multiple distinct expression patterns reflecting the spatial distribution of astrocyte cell types. To provide the best glial-specific functional tools, several enhancer-AAVs were: optimized for higher expression levels, shown to be functional and specific in rat and macaque, shown to maintain specific activity across transgenes and in epilepsy where traditional promoters changed activity, and used to drive functional transgenes in astrocytes including Cre recombinase and acetylcholine-responsive sensor iAChSnFR. The astrocyte-specific iAChSnFR revealed a clear reward-dependent acetylcholine response in astrocytes of the nucleus accumbens during reinforcement learning. Together, this collection of glial enhancer-AAVs will enable characterization of astrocyte and oligodendrocyte populations and their roles across species, disease states, and behavioral epochs.

eLife
Allen Institute for Brain Science (US), University of Washington (US), University of Washington Medical Center (US), Allen Institute (US), Neurological Surgery (US), Allen Institute for Neural Dynamics (US)
Openalex Percentile: Top 68%
Neurogenesis and neuroplasticity mechanisms
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