Abstract

Viral tracers that enable efficient retrograde labeling of projection neurons are powerful vehicles for structural and functional dissections of the neural circuit and for the treatment of brain diseases. Currently, some recombinant adeno-associated viruses (rAAVs) based on capsid engineering are widely used for retrograde tracing, but display undesirable brain area selectivity due to inefficient retrograde transduction in certain neural connections. Here we developed an easily editable toolkit to produce high titer AAV11 and demonstrated that it exhibits potent and stringent retrograde labeling of projection neurons in adult male wild-type or Cre transgenic mice. AAV11 can function as a powerful retrograde viral tracer complementary to AAV2-retro in multiple neural connections. In combination with fiber photometry, AAV11 can be used to monitor neuronal activities in the functional network by retrograde delivering calcium-sensitive indicator under the control of a neuron-specific promoter or the Cre-lox system. Furthermore, we showed that GfaABC1D promoter embedding AAV11 is superior to AAV8 and AAV5 in astrocytic tropism in vivo, combined with bidirectional multi-vector axoastrocytic labeling, AAV11 can be used to study neuron-astrocyte connection. Finally, we showed that AAV11 allows for analyzing circuit connectivity difference in the brains of the Alzheimer’s disease and control mice. These properties make AAV11 a promising tool for mapping and manipulating neural circuits and for gene therapy of some neurological and neurodegenerative disorders.

Viral tracers play a crucial role in studying neural circuits, but current options are limited in areas like retrograde transduction and astrocytic tropism. Here, the authors demonstrate that AAV11 function as a powerful retrograde viral tracer allowing for analyzing circuit connectivity and shows superior astrocytic tropism compared to the commonly used AAV vectors.

Details

Title
AAV11 enables efficient retrograde targeting of projection neurons and enhances astrocyte-directed transduction
Author
Han, Zengpeng 1   VIAFID ORCID Logo  ; Luo, Nengsong 2   VIAFID ORCID Logo  ; Ma, Wenyu 3   VIAFID ORCID Logo  ; Liu, Xiaodong 4 ; Cai, Yuxiang 2 ; Kou, Jiaxin 5   VIAFID ORCID Logo  ; Wang, Jie 3 ; Li, Lei 6 ; Peng, Siqi 7   VIAFID ORCID Logo  ; Xu, Zihong 7   VIAFID ORCID Logo  ; Zhang, Wen 7   VIAFID ORCID Logo  ; Qiu, Yuxiang 8 ; Wu, Yang 3 ; Ye, Chaohui 3 ; Lin, Kunzhang 9   VIAFID ORCID Logo  ; Xu, Fuqiang 10   VIAFID ORCID Logo 

 Chinese Academy of Sciences, Shenzhen Key Laboratory of Viral Vectors for Biomedicine, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institute of Advanced Technology, Shenzhen, PR China (GRID:grid.9227.e) (ISNI:0000000119573309); Chinese Academy of Sciences, Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Innovation Academy for Precision Measurement Science and Technology, Wuhan, PR China (GRID:grid.9227.e) (ISNI:0000000119573309); Chinese Academy of Sciences, Key Laboratory of Quality Control Technology for Virus-Based Therapeutics, Guangdong Provincial Medical Products Administration, NMPA Key Laboratory for Research and Evaluation of Viral Vector Technology in Cell and Gene Therapy Medicinal Products, the Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Shenzhen, PR China (GRID:grid.9227.e) (ISNI:0000000119573309); University of Chinese Academy of Sciences, Beijing, PR China (GRID:grid.410726.6) (ISNI:0000 0004 1797 8419) 
 Huazhong University of Science and Technology, Wuhan National Laboratory for Optoelectronics, Wuhan, PR China (GRID:grid.33199.31) (ISNI:0000 0004 0368 7223) 
 Chinese Academy of Sciences, Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Innovation Academy for Precision Measurement Science and Technology, Wuhan, PR China (GRID:grid.9227.e) (ISNI:0000000119573309); University of Chinese Academy of Sciences, Beijing, PR China (GRID:grid.410726.6) (ISNI:0000 0004 1797 8419) 
 The Chinese University of Hong Kong, Department of Anaesthesia and Intensive Care, Peter Hung Pain Research Institute, Hong Kong SAR, PR China (GRID:grid.10784.3a) (ISNI:0000 0004 1937 0482) 
 Huazhong University of Science and Technology, Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Wuhan, PR China (GRID:grid.33199.31) (ISNI:0000 0004 0368 7223) 
 Chinese Academy of Sciences, Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Innovation Academy for Precision Measurement Science and Technology, Wuhan, PR China (GRID:grid.9227.e) (ISNI:0000000119573309) 
 Wuhan University, College of Life Sciences, Wuhan, PR China (GRID:grid.49470.3e) (ISNI:0000 0001 2331 6153) 
 Chinese Academy of Sciences, Shenzhen Key Laboratory of Viral Vectors for Biomedicine, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institute of Advanced Technology, Shenzhen, PR China (GRID:grid.9227.e) (ISNI:0000000119573309); Chinese Academy of Sciences, Key Laboratory of Quality Control Technology for Virus-Based Therapeutics, Guangdong Provincial Medical Products Administration, NMPA Key Laboratory for Research and Evaluation of Viral Vector Technology in Cell and Gene Therapy Medicinal Products, the Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Shenzhen, PR China (GRID:grid.9227.e) (ISNI:0000000119573309); University of Chinese Academy of Sciences, Beijing, PR China (GRID:grid.410726.6) (ISNI:0000 0004 1797 8419) 
 Chinese Academy of Sciences, Shenzhen Key Laboratory of Viral Vectors for Biomedicine, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institute of Advanced Technology, Shenzhen, PR China (GRID:grid.9227.e) (ISNI:0000000119573309); Chinese Academy of Sciences, Key Laboratory of Quality Control Technology for Virus-Based Therapeutics, Guangdong Provincial Medical Products Administration, NMPA Key Laboratory for Research and Evaluation of Viral Vector Technology in Cell and Gene Therapy Medicinal Products, the Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Shenzhen, PR China (GRID:grid.9227.e) (ISNI:0000000119573309) 
10  Chinese Academy of Sciences, Shenzhen Key Laboratory of Viral Vectors for Biomedicine, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institute of Advanced Technology, Shenzhen, PR China (GRID:grid.9227.e) (ISNI:0000000119573309); Chinese Academy of Sciences, Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Innovation Academy for Precision Measurement Science and Technology, Wuhan, PR China (GRID:grid.9227.e) (ISNI:0000000119573309); Chinese Academy of Sciences, Key Laboratory of Quality Control Technology for Virus-Based Therapeutics, Guangdong Provincial Medical Products Administration, NMPA Key Laboratory for Research and Evaluation of Viral Vector Technology in Cell and Gene Therapy Medicinal Products, the Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Shenzhen, PR China (GRID:grid.9227.e) (ISNI:0000000119573309); University of Chinese Academy of Sciences, Beijing, PR China (GRID:grid.410726.6) (ISNI:0000 0004 1797 8419); Huazhong University of Science and Technology, Wuhan National Laboratory for Optoelectronics, Wuhan, PR China (GRID:grid.33199.31) (ISNI:0000 0004 0368 7223); Chinese Academy of Sciences, Center for Excellence in Brain Science and Intelligence Technology, Shanghai, PR China (GRID:grid.9227.e) (ISNI:0000000119573309) 
Pages
3792
Publication year
2023
Publication date
2023
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2829614382
Copyright
© The Author(s) 2023. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.