Multimodal Imaging for Validation and Optimization of Ion Channel-Based Chemogenetics in Nonhuman Primates

Abstract

Chemogenetic tools provide an opportunity to manipulate neuronal activity and behavior selectively and repeatedly in nonhuman primates (NHPs) with minimal invasiveness. Designer Receptors Exclusively Activated by Designer Drugs are one example that is based on mutated muscarinic acetylcholine receptors. Another channel-based chemogenetic system available for neuronal modulation in NHPs uses Pharmacologically Selective Actuator Modules (PSAMs), which are selectively activated by Pharmacologically Selective Effector Molecules (PSEMs). To facilitate the use of the PSAM/PSEM system, the selection and dosage of PSEMs should be validated and optimized for NHPs. To this end, we used a multimodal imaging approach. We virally expressed excitatory PSAM (PSAM4-5HT3) in the striatum and the primary motor cortex of two male macaque monkeys, and visualized its location through positron emission tomography (PET) with the reporter ligand [18F]ASEM. Chemogenetic excitability of neurons triggered by two PSEMs (uPSEM817 and uPSEM792) was evaluated using [18F]fluorodeoxyglucose-PET imaging, with uPSEM817 being more efficient than uPSEM792. Pharmacological magnetic resonance imaging showed that increased brain activity in the PSAM4-expressing region began approximately 13 min after uPSEM817 administration and continued for at least 60 min. Our multimodal imaging data provide valuable information regarding the manipulation of neuronal activity using the PSAM/PSEM system in NHPs, facilitating future applications.Significance statementLike other chemogenetic tools, the ion channel-based system called Pharmacologically Selective Actuator Module/Pharmacologically Selective Effector Molecule (PSAM/PSEM) allows remote manipulation of neuronal activity and behavior in living animals. Nevertheless, its application in non-human primates (NHPs) is still limited. Here, we used multi-tracer positron emission tomography (PET) imaging and pharmacological magnetic resonance imaging (MRI) to visualize an excitatory chemogenetic ion channel (PSAM4-5HT3) and validate its chemometric function in macaque monkeys. Our results provide the optimal agonist, dose, and timing for chemogenetic neuronal manipulation, facilitating the use of the PSAM/PSEM system and expanding the flexibility and reliability of circuit manipulation in NHPs in a variety of situations.

Strength of Activation and Temporal Dynamics of BioLuminescent-Optogenetics in Response to Systemic Injections of the Luciferin

“…However, similar to ICMS, optogenetics requires an invasive surgical procedure to generate neuromodulation effects in the brain. In contrast, chemogenetic methods are minimally invasive (Berglund et al, 2016; Dimidschstein et al, 2016; Gomez-Ramirez et al, 2020; Hori et al, 2023; Song et al, 2022; Urban and Roth, 2015; Vlasov et al, 2018; Zhang et al, 2022), and provide broad coverage of activation that is particularly useful for modulating activity in large-brain animals such as non-human primates (Cushnie et al, 2023; Hori et al, 2023; Raper and Galvan, 2022). However, chemogenetics has less temporal precision, in comparison to optogenetics and ICMS, with some methods producing effects that last hours (and sometimes days) as in the case of designer receptors exclusively activated by designer drugs (DREADDs).…”