CELL-TYPE-SPECIFIC OPTOGENETIC ACCESS TO INHIBITORY INTERNEURONS IN PRIMATE VISUAL CORTEX

Despite major advances in defining cortical cell types across mammalian species, the ability to selectively manipulate specific neuronal populations in non-human primates has remained extremely limited, constraining causal tests of circuit function beyond rodents. In particular, whether and how inhibitory interneuron subclasses can be selectively controlled in the primate cortex has remained an open technical and conceptual challenge. Here, we establish enhancer-driven viral strategies that enable cell-type-specific optogenetic manipulation of inhibitory interneurons in primary visual cortex (V1) of Macaca monkeys. We extend previously validated interneuron subclass–enriched enhancer strategies beyond labeling to achieve functional, cell-type-specific optogenetic control in the primate cortex. Using subclass-enriched genetic enhancers combined with adeno-associated viral delivery, we achieved selective expression of optogenetic actuators in parvalbumin (PV) and somatostatin (SST) interneuron populations without reliance on transgenic models. We combined a cranial recording chamber providing access to V1 with high-density laminar Neuropixels electrophysiology to demonstrate robust and reproducible optogenetic control of targeted inhibitory populations in vivo across cortical layers, with post hoc histological analyses used to assess targeting specificity relative to endogenous interneuron markers. Building on extensive work in rodents linking PV and SST interneurons to distinct computational regimes of sensory processing, including gain control, orientation tuning, and contextual modulation, we use homologous visual stimulus paradigms to interrogate how these core dimensions of visual computation are shaped by defined inhibitory cell types in the primate cortex. More broadly, this work establishes a foundation for directly testing cell-type-specific circuit mechanisms and their relevance to primate sensory processing and cognition.