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

项目摘要 认知缺陷是精神分裂症残疾的主要原因，但对所有现有的 治疗。在伽马频率范围内的EEG振荡被许多认知任务招募，并且任务- 诱发的伽马振荡在精神分裂症中是缺乏的。此外，伽马振荡是由 小清蛋白中间神经元，这在精神分裂症中异常。这表明伽马振荡可能是 精神分裂症中认知缺陷和小白蛋白中间神经元功能障碍的生物标志物。其实很多 研究表明，伽马振荡可能积极促进皮质回路功能， for cognition认知.事实上，我们以前的工作已经表明，光遗传学恢复中间神经元产生的 前额叶皮层的伽马振荡可以挽救突变小鼠的认知缺陷。但有 测量伽马振荡的许多方法-其中一些捕获伽马振荡的强度， 单个站点，而其他站点反映了跨站点的同步。我们最近的研究表明， PV中间神经元中的γ频率活动的同步，而不仅仅是 单个位点，可能需要前额叶皮层依赖的认知灵活性。此外，我们有 开发了新的方法来测量信号从基因编码的电压指示器，以测量 在不同位置的特定小区类型之间的伽马频率同步。我们现在要利用 这些进展：（1）使用我们的新分析和GEVI直接测量细胞类型特异性γ- 行为啮齿动物的频率同步;（2）确定量化EEG的特定方法 伽马振荡最好地捕捉这种同步;（3）评估这些EEG测量的相关性 与PV中间神经元同步化和行为表现的变化引起的几个 药理学操作，包括一些已知的挽救γ振荡缺陷的方法， 前额叶依赖的认知突变小鼠，和（4）验证，通过光遗传学，这些脑电图测量 是PV中间神经元功能变化的敏感和特异性指标。该项目将定义特定的 反映特定方面的细胞类型特定模式的长程同步的EEG测量 的认知。

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.