Restoring cognition by optogenetically rescuing gamma rhythms in PFC interneurons

 描述(申请人提供)：前额叶皮质(PFC)和伽马频率(~30-120赫兹)内的同步节律活动被认为有助于许多认知过程。一类特殊的GABA能中间神经元(FSIN)在这些振荡中起着关键作用，这些FSIN可以根据它们的快峰特性或根据它们对钙结合蛋白小白蛋白(PV)的表达来识别。前额叶FSIN和伽马振荡在精神分裂症中都是异常的，这表明伽马振荡可能是神经元间功能障碍和认知障碍之间的重要联系；类似的机制可能导致其他神经精神障碍，如自闭症。在这里，我们将建立在我们实验室最近的一项研究基础上，该研究发现，以伽马频率刺激中间神经元可以在小鼠的认知灵活性方面产生长期的改善。具体地说，我们研究了突变小鼠，它们模拟了FSIN和伽马振荡的异常，以及与精神分裂症相关的认知灵活性缺陷。我们发现，使用光敏蛋白以伽马频率激活PFC中的中间神经元，使这些小鼠能够在衡量认知灵活性的任务中正常执行。相比之下，在其他频率激活这些中间神经元是无效的。现在，我们建议探索在伽马频率激活PFC中间神经元是否可以在其他背景下增强认知。例如，我们将测试在伽马频率激活PFC中间神经元是否可以挽救其他突变小鼠的认知缺陷，在这些突变小鼠中，中间神经元功能不是唯一或主要的缺陷，或者是否可以在正常小鼠中产生超出正常水平的表现。我们还将探索在伽马频率激活PFC中间神经元是否可以提高在测量认知的其他方面的任务中的表现，例如工作记忆。第二个方向将是测试在伽马频率激活PFC中间神经元可能通过促进PFC与其他大脑结构之间的相互作用来增强认知能力的想法。为了测试这一想法，我们将测量刺激中间神经元如何影响PFC中的活动与其他结构同步的程度。我们还将确定在伽马频率激活PFC中间神经元是否会改变与认知灵活性有关的其他大脑结构的活动。该项目的长期目标是确定增强PFC中神经元间驱动的伽马振荡是否可以改善与精神分裂症和相关障碍相关的认知缺陷，并确定可能发生这种情况的机制。

 DESCRIPTION (provided by applicant): Synchronized, rhythmic activity within the prefrontal cortex (PFC) and at frequencies in the gamma range (~30- 120 Hz) is believed to contribute to many cognitive processes. A specific class of GABAergic interneurons (FSINs) that can be identified based either on their fast-spiking properties, or based on their expression of the calcium-binding protein parvalbumin (PV), play a critical role in these oscillations. Both prefrontal FSINs and gamma oscillations are abnormal in schizophrenia, suggesting that gamma oscillations may represent an important link between interneuron dysfunction and cognitive deficits; similar mechanisms may contribute to other neuropsychiatric disorders such as autism. Here, we will build on a recent study from our laboratory which found that stimulating interneurons at gamma frequencies can produce long-lasting improvements in cognitive flexibility in mice. Specifically, we studied mutant mice which model abnormalities in FSINs and gamma oscillations, as well as deficits in cognitive flexibility that are associated with schizophrenia. We found that using light sensitive proteins to active interneurons in the PFC at gamma frequencies enables these mice to perform normally on a task that measures cognitive flexibility. By contrast, activating these interneurons at other frequencies was ineffective. Now, we propose to explore whether activating PFC interneurons at gamma frequencies can enhance cognition in other contexts. For example, we will test whether activating PFC interneurons at gamma frequencies can rescue cognitive deficits in other mutant mice, in which interneuron function is not the sole or primary defect, or can produce supra-normal levels of performance in normal mice. We will also explore whether activating PFC interneurons at gamma frequencies can improve performance in tasks that measure other aspects of cognition, e.g. working memory. A second direction will be testing the idea that activating PFC interneurons at gamma-frequencies might enhance cognition by facilitating interactions between the PFC and other brain structures. In order to test this idea, we will measure how stimulating interneurons affects the degree to which activity in the PFC is synchronized with other structures. We will also determine whether activating PFC interneurons at gamma frequencies alters activity in other brain structures that are involved in cognitive flexibility. The long-term goal of this project is o determine whether enhancing interneuron-driven gamma oscillations in the PFC can improve cognitive deficits associated with schizophrenia and related disorders, and to identify possible mechanisms through which this might occur.