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To enable selective anatomical and functional interrogation of D1\u2010MSNs, we developed an adeno\u2010associated virus (AAV) toolkit that achieved robust and selective transgene expression in D1\u2010MSNs through retrograde transduction of their substantia nigra axons. We first screened an AAV9 capsid insertion library and identified variants with markedly enhanced retrograde access to D1\u2010MSNs. Next, we engineered a series of enhancers and demonstrate that they drive strong and specific gene expression in D1\u2010MSNs after retrograde transduction in both mice and a macaque. Importantly, we demonstrate that our toolkit enables targeted modulation of the direct pathway, eliciting pathway\u2010specific behaviors and rescuing motor deficits in a murine model of Parkinson's disease. These findings highlight the utility of our D1\u2010MSN\u2010targeting tools for basic and translational research.<\/jats:p>","DOI":"10.1002\/advs.202519665","type":"journal-article","created":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T09:59:05Z","timestamp":1782122345000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Toolkit for Targeted Neuromodulation of Striatal Direct Pathway Neurons Rescues Parkinsonian Motor Deficits in Mice"],"prefix":"10.1002","volume":"13","author":[{"given":"Zexuan","family":"Hong","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Women and Children's Medical Center, Shenzhen Maternity and Child Healthcare Hospital Southern Medical University  Shenzhen China"},{"name":"Research Center for Primate Neuromodulation and Neuroimaging, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology Chinese Academy of Sciences  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