Optimizing Optogenetics for Cell-type-specific Control in Freely-moving Primates

ABSTRACT Optogenetics is a revolutionary technique in neuroscience. By combining light-sensitive proteins with intracranial light delivery, optogenetics offers unprecedented, cell-type specific control over neuronal activity. The technique has become the dominant approach for studying neural circuits in small animal models such as mice and flies. Unfortunately, optogenetics has so far failed to have a major impact on research using larger animals more similar to humans, such as macaque monkeys, undermining its translational potential for human patients. We conducted a world-wide Open Science initiative to identify the challenges remaining to be solved in primate optogenetics (Tremblay et al. Neuron, 2020). We identified the sheer size of the macaque monkey brain, which is 200 times bigger than the mouse brain, as well as its immune system, as the main challenges for both gene expression and light delivery. Our multidisciplinary team of investigators will overcome these obstacles by developing and optimizing three new technologies: 1) large-scale, safe delivery of ultra-sensitive opsins using gene therapy techniques; 2) chronically-implantable, ultra-thin, flexible, biocompatible LED arrays; and 3) implantable, battery-powered LED drivers for wireless control during unrestrained, naturalistic behavior. This approach will allow precise control of large volumes of the primate brain with cell-type specificity and millisecond resolution in monkeys free of physical restraint, thus permitting causal dissection of the neural circuits mediating natural behavior relevant for understanding and treating human brain disorders. This technology platform could be directly applied as a cell-type-specific optogenetic therapy for humans suffering from neurological disorders that affect specific neural populations, such as focal epilepsy.