Daily Regulation of Ionic Currents

项目摘要 昼夜节律是人体生理学的一个基本方面。适当的昼夜节律 例如，心血管输出量、新陈代谢和睡眠对身体和精神健康是必不可少的， 中风、哮喘、心脏病发作和睡眠障碍的发生率都与睡眠时间密切相关。 天然而，了解人体生理学的昼夜节律调节如何有助于人类健康 和疾病将需要对昼夜节律是如何产生和表达的基本理解。的 这项提议的目的是确定驱动视交叉上核昼夜节律输出的基本机制。 核（SCN），大脑的时钟。SCN神经元自发动作电位的昼夜节律 这种有节奏的输出对于定时昼夜节律的行为和生理是必不可少的。因此，每天 兴奋性的调节是在SCN中神经元活动中产生昼夜节律的关键基础。 由Kcnma1基因编码的大电导Ca 2+激活的K+通道（BK）是一种重要的钙通道， 调节小鼠和苍蝇的昼夜生理和行为节律。在SCN中，BK电流形状 昼夜节律的神经元放电通过调节昼夜差异的放电频率，但基本的 BK的作用机制尚不清楚。在拟议的研究中，我们测试了中心假设 BK电流特性的日常调节驱动SCN神经元放电的昼夜节律。 这一假设将使用电生理学和分子生物学通过以下方式进行研究 具体目标：1.为了确定BK通道复合体的成分是否随昼夜节律而变化， 循环，2.为了确定如何自然BK电流的属性与SCN中的昼夜节律相位变化，3。到 测试BK电流的日常调制是否驱动SCN中神经元放电的昼夜节律。的 这项研究的重要性在于，它提供了一种独特的方法，可以直接将生物物理学的变化联系起来， 离子电流的性质与神经编码的变化有关。这些研究的结果是， 控制昼夜节律输出的详细机制。了解大脑主时钟的输出 是朝着开发新方法来操纵人类生理节律方面迈出的关键一步。 生理学和病理生理学。

Project Summary Circadian rhythmicity is a fundamental aspect of human physiology. Proper circadian rhythms in cardiovascular output, metabolism, and sleep, for example, are essential to physical and psychiatric health, and the incidence of stroke, asthma, heart attack, and sleep disturbances all correlate strongly with time of day. However, understanding how circadian modulation of the body's physiology contributes to human health and disease will require a basic understanding of how circadian rhythms are generated and expressed. The goal of this proposal is to identify the basic mechanisms that drive circadian output from the suprachiasmatic nucleus (SCN), the brain's clock. SCN neurons demonstrate circadian rhythms in spontaneous action potential firing, and this rhythmic output is essential for timing circadian behaviors and physiology. Therefore, daily modulation of excitability is a critical basis for generating the circadian rhythm in neuronal activity in the SCN. The large conductance Ca2+-activated K+ channel (BK), encoded by the Kcnma1 gene, is an essential regulator of circadian physiological and behavioral rhythms in mouse and fly. In the SCN, BK currents shape circadian rhythms in neuronal firing by regulating the day-night difference in firing frequency, but the basic mechanisms underlying BK's actions are unknown. In the proposed research, we test the central hypothesis that the daily modulation of BK current properties drives the circadian rhythm in SCN neuronal firing. This hypothesis will be investigated using electrophysiology and molecular biology through the following specific aims: 1. To determine whether the constituents of the BK channel complex vary over the circadian cycle, 2. To determine how the properties of native BK currents vary with circadian phase in the SCN, 3. To test whether daily modulation of BK currents drives circadian rhythms in neuronal firing in the SCN. The significance of this research is that it provides a unique approach to directly link changes in the biophysical properties of an ionic current to changes in neural coding. The outcome of these studies is an understanding of the detailed mechanisms that govern circadian output. Understanding output from the brain's master clock is a critical step toward the development of novel ways to manipulate the circadian aspects of human physiology and pathophysiology.