Connectivity and function of inhibitory neurons in the visual cortex

Grant: 1R01EY031959-01
PI: A. Angelucci

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 higher species 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 higher species.

The lack of viral tools to selectively access IN subtypes, and the difficulty of performing genetic manipulations in genetically-intractable species have been major impediments to studying INs in species other than mouse.

The goal of this grant applicationis 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 primary visual cortex (V1) of species with large brains.

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.

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.

Finally, we will useoptogenetic inactivation of distinct IN-typesexpressing inhibitory opsins, to understand the relative roles of IN classes in V1 computations. Impact.

The proposed studies will provide the first account of the connectivity, visual properties and computational function of PV and SOM INs in visual cortex of non-rodent mammalian species.

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.