Using new methods for voltage imaging to assay the engagement of specific cell-types and brain rhythms in prefrontal-dependent cognition.

点击翻译按钮获取中文摘要

PROJECT SUMMARY (PARENT GRANT) Cognitive deficits represent the major cause of disability in schizophrenia but are refractory to all existing treatments. EEG oscillations in the gamma-frequency range are recruited by many cognitive tasks, and task- evoked gamma oscillations are deficient in schizophrenia. Furthermore, gamma oscillations are generated by parvalbumin interneurons, which are abnormal in schizophrenia. This suggests that gamma oscillations may be biomarkers for cognitive deficits and parvalbumin interneuron dysfunction in schizophrenia. In fact, many studies suggest that gamma oscillations may actively contribute to cortical circuit functions that are necessary for cognition. Indeed, our previous work has shown that optogenetically restoring interneuron-generated gamma oscillations in the prefrontal cortex can rescue cognitive deficits in mutant mice. However, there are many ways to measure gamma oscillations – some of these capture the strength of gamma oscillations at a single site whereas others reflect synchronization across sites. Our recent work suggests that long-range synchronization of gamma-frequency activity in PV interneurons, rather than just gamma-frequency activity at a single site, may be required for prefrontal cortex-dependent cognitive flexibility. Furthermore, we have developed new ways of measuring signals from genetically encoded voltage indicators in order to measure gamma-frequency synchronization between specific cell-types at different locations. We will now leverage these advances to: (1) use our novel analyses and GEVIs to directly measure cell-type specific gamma- frequency synchronization in behaving rodents; (2) determine which particular ways of quantifying EEG gamma oscillations best capture this synchronization; (3) evaluate how well these EEG measures correlate with changes in PV interneuron synchronization and behavioral performance elicited by several pharmacological manipulations including some which are known to rescue deficits in gamma oscillations and prefrontal-dependent cognition in mutant mice, and (4) validate, via optogenetics, that these EEG measures are sensitive and specific indicators for changes in PV interneuron function. This project will define particular EEG measures that reflect cell-type specific patterns of long-range synchronization underlying specific aspects of cognition.