Optogenetic modulation of long-range cortical circuits in awake nonhuman primates

Causal control of short- and long-range projections between networks is necessary to study complex cognitive processes and cortical computations. Neural circuits can be studied via optogenetic approaches, which provide excellent genetic and temporal control and electrophysiological recordings. However, in nonhuman primates (NHPs), these approaches are commonly performed at a single location, missing out on the potential to test connections between separate networks. We have recently developed an approach for optogenetic manipulation in NHPs which targets intra- and interareal cortical projections. Here we describe the combination of optogenetic stimulation with standard chamber-based electrophysiological recordings in awake NHPs to monitor and manipulate both short- and long-range feedforward and feedback circuits. We describe the injection of viral constructs, the simultaneous electrophysiological recordings with the optical stimulation of neurons at various cortical distances and the evaluation of gene expression using a focal biopsy technique. We focus on details that are specific to NHP preparations, such as the precise targeting of injection sites, choosing appropriate viral constructs and considerations for behavioral measures. When combined with laminar electrode configurations (to functionally identify cortical layers) and complex cognitive behavioral tasks, our approach can be used to investigate an array of systems neuroscience questions, such as the role of feedback circuits in attention and the role of lateral connections in contrast normalization. The procedure requires 2-3 active days and 45 waiting days to transduce selected neural circuits and several weeks to complete experiments. The procedure is appropriate for users with expertise in in vivo, awake electrophysiology with NHPs.