Enhancer AAV toolbox for accessing and perturbing striatal cell types and circuits
Authors: Avery C Hunker, Morgan E Wirthlin, Gursajan Gill, Nelson J Johansen, Marcus Hooper, Victoria Omstead, Sara Vargas, M Nathaly Lerma, Naz Taskin, Natalie Weed, William D Laird, Yemeserach M Bishaw, Jacqueline L Bendrick, Bryan B Gore, Yoav Ben-Simon, Ximena Opitz-Araya, Refugio A Martinez, Sharon W Way, Bargavi Thyagarajan, Sven Otto, Raymond E A Sanchez, Jason R Alexander, Avalon Amaya, Adam Amster, Joel Arbuckle, Angela Ayala, Pam M Baker, Tyler Barcelli, Stuard Barta, Darren Bertagnolli, Cameron Bielstein, Prajal Bishwakarma, Jessica Bowlus, Gabriella Boyer, Krissy Brouner, Brittny Casian, Tamara Casper, Anish Bhaswanth Chakka, Rushil Chakrabarty, Peter Chong, Michael Clark, Kaity Colbert, Scott Daniel, Tim Dawe, Maxwell Departee, Peter DiValentin, Nicholas P Donadio, Nadezhda I Dotson, Deepanjali Dwivedi, Tom Egdorf, Tim Fliss, Amanda Gary, Jeff Goldy, Conor Grasso, Erin L Groce, Kathryn Gudsnuk, Warren Han, Zeb Haradon, Sam Hastings, Olivia Helback, Windy V Ho, Cindy Huang, Tye Johnson, Danielle L Jones, Zoe Juneau, Jaimie Kenney, Madison Leibly, Su Li, Elizabeth Liang, Henry Loeffler, Nicholas A Lusk, Zachary Madigan, Jessica Malloy, Jocelin Malone, Rachel McCue, Jose Melchor, John K Mich, Skyler Moosman, Elyse Morin, Robyn Naidoo, Dakota Newman, Kiet Ngo, Katrina Nguyen, Aaron L Oster, Ben Ouellette, Alana A Oyama, Nick Pena, Trangthanh Pham, Elliot Phillips, Christina Pom, Lydia Potekhina, Shea Ransford, Patrick L Ray, Melissa Reding, Dean F Rette, Cade Reynoldson, Christine Rimorin, Ana Rios Sigler, Dana B Rocha, Kara Ronellenfitch, Augustin Ruiz, Lane Sawyer, Josh P Sevigny, Nadiya V Shapovalova, Noah Shepard, Lyudmila Shulga, Sherif Soliman, Brian Staats, Michael J Taormina, Michael Tieu, Yimin Wang, Josh Wilkes, Toren Wood, Thomas Zhou, Ali Williford, Nick Dee, Tyler Mollenkopf, Lydia Ng, Luke Esposito, Brian E Kalmbach, Shenqin Yao, Jeanelle Ariza, Forrest Collman, Shoaib Mufti, Kimberly Smith, Jack Waters, Ina Ersing, Marcella Patrick, Hongkui Zeng, Ed S Lein, Yoshiko Kojima, Greg Horwitz, Scott F Owen, Boaz P Levi, Tanya L Daigle, Bosiljka Tasic, Trygve E Bakken, Jonathan T Ting
Journal: Neuron (2025)

We present an enhancer-AAV toolbox for accessing and perturbing striatal cell types and circuits. Best-in-class vectors were curated for accessing major striatal neuron populations including medium spiny neurons (MSNs), direct- and indirect-pathway MSNs, Sst-Chodl, Pvalb-Pthlh, and cholinergic interneurons. Specificity was evaluated by multiple modes of molecular validation, by three different routes of virus delivery, and with diverse transgene cargos. Importantly, we provide detailed information necessary to achieve reliable cell-type-specific labeling under different experimental contexts. We demonstrate direct pathway circuit-selective optogenetic perturbation of behavior and multiplex labeling of striatal interneuron types for targeted analysis of cellular features. Lastly, we show conserved in vivo activity for exemplary MSN enhancers in rats and macaques. This collection of striatal enhancer AAVs offers greater versatility compared to available transgenic lines and can readily be applied for cell type and circuit studies in diverse mammalian species beyond the mouse model.