Improving cognition by understanding and harnessing the plasticity of gamma-generating circuits in prefrontal cortex

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PROJECT SUMMARY / ABSTRACT We recently published a study that used genetic encoded voltage indicators to show that gamma-frequency (specifically ~40 Hz) synchronization between parvalbumin (PV) interneurons in the left and right mPFC normally increases during specific cognitive tasks. Furthermore, specifically disrupting this synchrony was sufficient to produce cognitive deficits similar to those observed in schizophrenia. Finally, we have found that transiently increasing or decreasing gamma synchrony using optogenetic manipulations leads to long-lasting changes in both gamma synchrony and cognition. Thus, gamma synchrony is a key mediator of cognition that can undergo bi-directional plasticity thereby correcting or inducing cognitive deficits. This project will now use genetically encoded voltage indicators, optogenetics, chemogenetics, slice electrophysiology and calcium imaging, to identify interventions and cellular/synaptic mechanisms that produce therapeutic increases and deleterious decreases in gamma synchrony, and elucidate exactly how changes in gamma synchrony affect information processing by prefrontal circuits. This will lead to a greater understanding of how gamma synchrony contributes to normal cognition, and reveal specific targets for restoring cognition in conditions such as schizophrenia.