Daily Regulation of Ionic Currents

描述（由申请人提供）：昼夜节律是人体生理学的一个基本方面。例如，心血管输出、代谢和睡眠中的适当昼夜节律对身体和精神健康至关重要，中风、哮喘、心脏病发作和睡眠障碍的发生率都与一天中的时间密切相关。然而，了解身体生理的昼夜节律调节如何有助于人类健康和疾病将需要基本了解昼夜节律是如何产生和表达的。这个提议的目的是确定驱动视交叉上核（SCN）（大脑的时钟）昼夜节律输出的基本机制。SCN神经元在自发动作电位放电中表现出昼夜节律，并且这种节律输出对于定时昼夜行为和生理是必不可少的。因此，兴奋性的日常调节是SCN中神经元活动中产生昼夜节律的关键基础。由Kcnma 1基因编码的大电导Ca ~（2+）激活的K ~+通道（BK）是小鼠和果蝇生理和行为节律的重要调节因子。在SCN中，BK电流通过调节放电频率的昼夜差异来塑造神经元放电的昼夜节律，但BK作用的基本机制尚不清楚。在拟议的研究中，我们测试的中心假设，每天调制的BK电流特性驱动SCN神经元放电的昼夜节律。本研究将利用电生理学和分子生物学的方法，通过以下几个具体的目的来研究这一假说：1。为了确定BK通道复合体的成分是否随昼夜节律周期而变化，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。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。这项研究的意义在于，它提供了一种独特的方法，将离子电流的生物物理特性的变化与神经编码的变化直接联系起来。这些研究的结果是对控制昼夜节律输出的详细机制的理解。了解大脑主时钟的输出是开发新方法来操纵人类生理学和病理生理学昼夜节律方面的关键一步。 公共卫生相关性：有强有力的证据表明，例如，心血管输出、代谢和睡眠中的适当昼夜节律对身体和精神健康至关重要。中风、哮喘、心脏病发作和睡眠障碍的发生率都与一天中的时间密切相关。了解身体生理的昼夜节律调节如何有助于人类健康和疾病，需要对昼夜节律如何产生和表达有基本的了解。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: There is strong evidence that proper circadian rhythms in cardiovascular output, metabolism, and sleep, for example, are essential to physical and psychiatric health. The incidence of stroke, asthma, heart attack, and sleep disturbances all correlate strongly with time of day. Understanding how circadian modulation of the body's physiology contributes to human health and disease requires a basic understanding of how circadian rhythms are generated and expressed.