Expression of the excitatory opsin ChRERα can be traced longitudinally in rat and nonhuman primate brains with PET imaging

• Published in: Science translational medicine 2023-07, Vol.15 (706), p.eadd1014-eadd1014
• Main Authors: Bonaventura, Jordi, Boehm, Matthew A, Jedema, Hank P, Solis, Oscar, Pignatelli, Marco, Song, Xiaowei, Lu, Hanbing, Richie, Christopher T, Zhang, Shiliang, Gomez, Juan L, Lam, Sherry, Morales, Marisela, Gharbawie, Omar A, Pomper, Martin G, Stein, Elliot A, Bradberry, Charles W, Michaelides, Michael
• Format: Article
• Language: English
• Subjects: Animals; Brain - diagnostic imaging; Brain - metabolism; Brain mapping; Breast Neoplasms - metabolism; Cortex (motor); Estradiol - metabolism; Estrogen Receptor alpha - metabolism; Estrogen receptors; Female; Functional magnetic resonance imaging; Genetics; Humans; Information processing; Mammals - metabolism; Neural networks; Neuroimaging; Opsins - metabolism; Optics; Pharmaceuticals; Positron emission tomography; Primates; Radioisotopes; Rats
• ISSN: 1946-6234; 1946-6242; 1946-6242; 1946-3242
• DOI: 10.1126/scitranslmed.add1014

Optogenetics is a widely used technology with potential for translational research. A critical component of such applications is the ability to track the location of the transduced opsin in vivo. To address this problem, we engineered an excitatory opsin, ChRERα (hChR2(134R)-V5-ERα-LBD), that could be visualized using positron emission tomography (PET) imaging in a noninvasive, longitudinal, and quantitative manner. ChRERα consists of the prototypical excitatory opsin channelrhodopsin-2 (ChR2) and the ligand-binding domain (LBD) of the human estrogen receptor α (ERα). ChRERα showed conserved ChR2 functionality and high affinity for [ F]16α-fluoroestradiol (FES), an FDA-approved PET radiopharmaceutical. Experiments in rats demonstrated that adeno-associated virus (AAV)-mediated expression of ChRERα enables neural circuit manipulation in vivo and that ChRERα expression could be monitored using FES-PET imaging. In vivo experiments in nonhuman primates (NHPs) confirmed that ChRERα expression could be monitored at the site of AAV injection in the primary motor cortex and in long-range neuronal terminals for up to 80 weeks. The anatomical connectivity map of the primary motor cortex identified by FES-PET imaging of ChRERα expression overlapped with a functional connectivity map identified using resting state fMRI in a separate cohort of NHPs. Overall, our results demonstrate that ChRERα expression can be mapped longitudinally in the mammalian brain using FES-PET imaging and can be used for neural circuit modulation in vivo.