Metabolic and KATP channel regulation of the cortical slow oscillation

项目摘要/摘要 该项目将研究代谢敏感钾通道(K{ATP})在大脑皮层中的作用。这些通道最近被证明可以调节大脑皮层(1赫兹)的缓慢振荡。在深度睡眠阶段或麻醉期间，大脑皮层神经元在两种状态之间振荡：一种是向上状态，在此期间神经元去极化；另一种是向下状态，在此期间神经元处于超极化状态。钾通道被认为对向DOWN状态的转变和调节两种状态的持续时间具有重要作用。特别是，K{ATP}通道已被证明在调节慢振荡中起重要作用。由于K{ATP}通道将细胞代谢与细胞的电状态相结合，因此代谢很可能可以调节皮层的慢振荡。 我们建议使用慢振荡的体外模型来进一步表征K{ATP}通道在控制皮层网络活动中的作用。在目标1中，我们将使用膜片钳电生理学策略识别表达功能性K{ATP}通道的皮质神经元群体。在目标2中，我们将通过对K{ATP}通道的药理和遗传操作来表征K{ATP}通道调节小鼠脑片上、下状态持续时间的能力。在目标3中，我们将通过提供不同的能量燃料，特别是可能改变K{ATP}通道活性的酮体，来确定细胞代谢对振荡调节的贡献。这些研究旨在利用慢振荡来测试酮体代谢改变K{ATP}通道活性和网络兴奋性的能力。这项工作将对了解K{ATP}通道在脑中的作用具有重要意义，因为它们可能有助于癫痫的营养治疗的抗惊厥特性，如生酮饮食。

Project Summary/Abstract This project will examine the role of metabolically-sensitive potassium channels (K{ATP}) in the cortex. These channels have recently been shown to regulate a cortical (< 1 Hz) slow oscillation. During deep sleep stages or anesthesia, cortical neurons oscillate between two states: an up-state during which neurons are depolarized and a down-state during which neurons are hyperpolarized. Potassium channels are believed to be important for the transition to the down-state and regulating the duration of the two states. In particular, the K{ATP} channel has been shown to be important in regulating the slow oscillation. Since K{ATP} channels couple cellular metabolism to the electrical state of the cell, it is likely that metabolism can regulate the cortical slow oscillation. We propose to further characterize the role of K{ATP} channels in controlling cortical network activity using an in vitro model of the slow oscillation. In aim 1, we will identify populations of cortical neurons that express functional K{ATP} channels using patch-clamp electrophysiology strategies. In aim 2, we will characterize the ability of K{ATP} channels to regulate the duration of up-states and downstates in mouse brain slices using pharmacological and genetic manipulation of K{ATP} channels. In aim 3, we will determine the contribution of cellular metabolism to the regulation of the oscillation by providing different energy fuels, particularly ketone bodies that may alter K{ATP} channel activity. These proposed studies aim to use the slow oscillation to test the ability of ketone body metabolism to alter K{ATP} channel activity and network excitability. This work will have significant importance in understanding the role of K{ATP} channels in the brain where they may contribute to the anticonvulsant properties of nutritional therapies for epilepsy, such as the ketogenic diet.