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

项目总结 认知缺陷是精神分裂症患者残疾的主要原因，但对所有现有的 治疗。伽马频率范围内的脑电振荡被许多认知任务所吸收，而任务- 精神分裂症患者诱发的伽马振荡是缺陷的。此外，伽马振荡通过以下方式产生 精神分裂症中异常的小白蛋白中间神经元。这表明伽马振荡可能是 精神分裂症患者认知缺陷和小白蛋白中间神经元功能障碍的生物标志物。事实上，许多人 研究表明，伽马振荡可能积极地促进了必要的皮质回路功能。 用于认知。事实上，我们之前的工作已经表明，光遗传恢复中间神经元产生 前额叶皮质的伽马振荡可以挽救突变小鼠的认知缺陷。然而，有一些 测量伽马振荡的方法有很多种，其中一些方法捕捉到了伽马振荡的强度 单个站点，而其他站点则反映跨站点的同步。我们最近的研究表明，长期的 PV中间神经元中伽马频率活动的同步化，而不仅仅是 单部位，可能是前额叶皮质依赖认知灵活性所必需的。此外，我们还拥有 开发了测量来自遗传编码电压指示器的信号的新方法，以便测量 在不同位置的特定细胞类型之间的伽马频率同步。我们现在将利用 这些进展包括：(1)使用我们的新型分析和GEVI直接测量细胞类型的比伽马- 行为啮齿动物的频率同步；(2)确定量化脑电的特定方法 伽马振荡最好地捕捉到这种同步；(3)评估这些脑电测量的相关性如何 在PV神经元间同步性和行为表现方面的变化由几个 药理操作，包括一些已知的挽救伽马振荡和 突变小鼠的前额叶依赖认知，以及(4)通过光遗传学验证这些脑电测量 是反映PV中间神经元功能变化的敏感而特异的指标。该项目将定义特定的 脑电测量反映了特定方面下的远程同步的细胞类型特定模式 认知力。

PROJECT SUMMARY 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.