Presentation PET imaging-guided chemogenetic manipulation of primate neural circuits

南本, 敬史

Designer receptors exclusively activated by designer drugs (DREADDs) have proven to be highly effective neuromodulatory tools for the investigation of neural circuits underlying cognition and behavior. These tools should be especially useful in animals with larger brains because the designer drug, clozapine-N-oxide (CNO), can be administered systemically, thus providing a potential to control large and/or discontinuous regions of the brain. To interpret the behavioral outcome of experiments with the DREADD-CNO system in monkeys, it would be very useful to characterize the level and location of DREADD receptor expression, and the relationship of systemic CNO dose with the level of receptor activation while the experiments are ongoing. To measure these characteristics in vivo, we developed a non-invasive method for visualization of DREADDs using PET in rodents, and adapted the technique for the use in monkeys. With the DREADD-selective PET ligand, we can visualize the location and extent of expression, and measure DREADD receptor occupancy by CNO with a blocking protocol. Using this PET imaging-guided procedure, we demonstrated that chemogenetic inactivation of bilateral caudate nucleus produces a significant and reproducible loss of sensitivity to reward value in monkeys. The mechanism by which DREADDs work, and their potential for covering a large and diffuse population of neurons, as well as the capability of verifying DREADD expression by PET imaging before undertaking functional CNO activation experiments, ought to make this system an attractive tool for application to long-term behavioral studies, and potentially to clinical settings in the future.
Seminar at NIDA

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