Metabolic and KATP channel regulation of the cortical slow oscillation

该项目将研究代谢敏感性钾通道（KATP）在大脑皮层中的作用。这些通道最近被证明可以调节皮质（< 1 Hz）的缓慢振荡。在深度睡眠阶段或麻醉期间，皮质神经元在两种状态之间振荡：在神经元去极化的向上状态和在神经元超极化的向下状态。钾通道被认为是重要的过渡到下降状态和调节两个状态的持续时间。特别是，KATP通道已被证明在调节慢振荡中是重要的。由于KATP通道将细胞代谢耦合到细胞的电状态，因此代谢可能可以调节皮质慢振荡。 我们建议进一步表征的作用，ATP通道在控制皮质网络活动使用体外模型的缓慢振荡。在目标1中，我们将使用膜片钳电生理策略识别表达功能性KATP通道的皮质神经元群体。在目标2中，我们将使用KATP通道的药理学和遗传操作来表征KATP通道调节小鼠脑切片中的上升状态和下降状态的持续时间的能力。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KATP通道活性的酮体，确定细胞代谢对振荡调节的贡献。这些拟定研究旨在使用缓慢振荡来测试酮体代谢改变KATP通道活性和网络兴奋性的能力。这项工作将具有重要意义，在了解KATP通道在大脑中的作用，他们可能有助于抗惊厥特性的营养治疗癫痫，如生酮饮食。

This project will examine the role of metabolically-sensitive potassium channels (KATP) 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 KATP channel has been shown to be important in regulating the slow oscillation. Since KATP 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 KATP 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 KATP channels using patch-clamp electrophysiology strategies. In aim 2, we will characterize the ability of KATP channels to regulate the duration of up-states and down- states in mouse brain slices using pharmacological and genetic manipulation of KATP 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 KATP channel activity. These proposed studies aim to use the slow oscillation to test the ability of ketone body metabolism to alter KATP channel activity and network excitability. This work will have significant importance in understanding the role of KATP channels in the brain where they may contribute to the anticonvulsant properties of nutritional therapies for epilepsy, such as the ketogenic diet.