Connectivity and function of inhibitory neurons in the primate visual cortex

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PROJECT SUMMARY In the mammalian neocortex, inhibitory neurons (INs) profoundly influence cortical computations and dynamics, and their various functions are thought to be mediated by different IN types. While a large diversity of INs exists, molecular markers in mouse cortex identify three major non-overlapping classes: parvalbumin- (PV), somatostatin- (SOM), and vasoactive intestinal peptide- (VIP) INs. Studies in mouse lines expressing Cre-recombinase in each of these IN classes are rapidly revealing distinct patterns of connectivity, response properties and in vivo function for each class. However, it remains unknown whether insights gained from mouse cortex apply to cortical INs in primates and humans. IN dysfunction in humans has been implicated in several disorders, such as epilepsy, schizophrenia, anxiety and autism, therefore it is important to understand normal cortical IN connectivity and function in primates. The lack of viral tools to selectively access IN subtypes, and the difficulty of performing genetic manipulations in primates have been major impediments to studying INs in this animal model. Our goal is to leverage recent advances in the development of viral tools to express transgenes in specific INs subtypes to investigate the connectivity, response properties, and computational function of two major classes of INs, PV and SOM, in the superficial layers of the primate primary visual cortex (V1). Using IN-type specific expression of Cre-recombinase combined with rabies-virus monosynaptic circuit tracing, we will map local and brain-wide inputs to specific V1 IN classes (Aim1). Using two-photon imaging of IN-type specific targeted calcium indicators, or optogenetic identification of channelrhodopsin-tagged IN types, we will characterize the visual response properties of distinct V1 IN classes (Aim2). Finally, we will use optogenetic inactivation of distinct IN-types expressing inhibitory opsins, to understand the relative roles of IN classes in V1 computations (Aim3). We will test specific hypotheses derived from available data in mouse, the specific geometry of PV and SOM cells in primate cortex, published computational models of feature tuning and surround suppression in visual cortex, and our preliminary results. Impact. The proposed studies will provide the first account of the connectivity, visual properties and computational function of PV and SOM INs in primate cortex, paving the way for studies of IN function in this order. They will also reveal conserved principles of IN function across species, as well as fundamental inter- species differences, stressing the importance of studying cortical function in species that are evolutionarily closer to humans.