Longitudinal neural connection detection using a ferritin-encoding adeno-associated virus vector and in vivo MRI method,Human Brain Mapping

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Longitudinal neural connection detection using a ferritin-encoding adeno-associated virus vector and in vivo MRI method
Human Brain Mapping ( IF 3.5 ) Pub Date : 2021-07-20 , DOI: 10.1002/hbm.25596
Aoling Cai _{1,

2} , Ning Zheng ₂ , Garth J Thompson ₃ , Yang Wu _{2,

4} , Binbin Nie ₅ , Kunzhang Lin ₆ , Peng Su ₆ , Jinfeng Wu ₂ , Anne Manyande ₇ , LingQiang Zhu ₈ , Jie Wang _{2,

4,

9} , Fuqiang Xu _{1,

2,

4,

6,

10}

Affiliation

Wuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology, Wuhan, China.
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, Wuhan Institute of Physics and Mathematics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences-Wuhan National Laboratory for Optoelectronics, Wuhan, China.
iHuman Institute, ShanghaiTech University, Shanghai, China.
University of Chinese Academy of Sciences, Beijing, China.
Key Laboratory of Nuclear Radiation and Nuclear Energy Technology, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, China.
Shenzhen Key Lab of Neuropsychiatric Modulation, Guangdong Provincial Key Laboratory of Brain Connectome and Behavior, CAS Key Laboratory of Brain Connectome and Manipulation, the Brain Cognition and Brain Disease Institute (BCBDI), Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences; Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, China.
School of Human and Social Sciences, University of West London, London, UK.
Department of Pathophysiology, Key Lab of Neurological Disorder of Education Ministry, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Hebei Provincial Key Laboratory of Basic Medicine for Diabetes, 2nd Hospital of Shijiazhuang, Shijiazhuang, Hebei, China.
Center for Excellence in Brain Science and Intelligent Technology, Chinese Academy of Sciences, Shanghai, China.

The investigation of neural circuits is important for interpreting both healthy brain function and psychiatric disorders. Currently, the architecture of neural circuits is always investigated with fluorescent protein encoding neurotropic virus and ex vivo fluorescent imaging technology. However, it is difficult to obtain a whole-brain neural circuit connection in living animals, due to the limited fluorescent imaging depth. Herein, the noninvasive, whole-brain imaging technique of MRI and the hypotoxicity virus vector AAV (adeno-associated virus) were combined to investigate the whole-brain neural circuits in vivo. AAV2-retro are an artificially-evolved virus vector that permits access to the terminal of neurons and retrograde transport to their cell bodies. By expressing the ferritin protein which could accumulate iron ions and influence the MRI contrast, the neurotropic virus can cause MRI signal changes in the infected regions. For mice injected with the ferritin-encoding virus vector (rAAV2-retro-CAG-Ferritin) in the caudate putamen (CPu), several regions showed significant changes in MRI contrasts, such as PFC (prefrontal cortex), HIP (hippocampus), Ins (insular cortex) and BLA (basolateral amygdala). The expression of ferritin in those regions was also verified with ex vivo fluorescence imaging. In addition, we demonstrated that changes in T2 relaxation time could be used to identify the spread area of the virus in the brain over time. Thus, the neural connections could be longitudinally detected with the in vivo MRI method. This novel technique could be utilized to observe the viral infection process and detect the neural circuits in a living animal.

中文翻译：

使用编码铁蛋白的腺相关病毒载体和体内 MRI 方法进行纵向神经连接检测

神经回路的研究对于解释健康的大脑功能和精神疾病都很重要。目前，神经回路的结构一直是用编码嗜神经病毒的荧光蛋白和离体荧光成像技术来研究的。然而，由于荧光成像深度有限，很难在活体动物中获得全脑神经回路连接。在此，将MRI的无创全脑成像技术与低毒性病毒载体AAV（腺相关病毒）相结合，研究体内全脑神经回路。AAV2-retro 是一种人工进化的病毒载体，允许进入神经元的末端并逆行运输到它们的细胞体。通过表达可积累铁离子并影响MRI对比度的铁蛋白，嗜神经病毒可引起感染区域的MRI信号变化。对于在尾状壳核 (CPu) 中注射铁蛋白编码病毒载体 (rAAV2-retro-CAG-Ferritin) 的小鼠，几个区域的 MRI 对比显示出显着变化，例如 PFC（前额叶皮层）、HIP（海马）、Ins （岛叶皮质）和 BLA（基底外侧杏仁核）。还通过离体荧光成像验证了这些区域中铁蛋白的表达。此外，我们证明了 T2 弛豫时间的变化可用于识别病毒随时间在大脑中的传播区域。因此，可以使用体内 MRI 方法纵向检测神经连接。

更新日期：2021-09-19

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