GIRK channel modulation of SCN excitability and circadian rhythms

描述(申请人提供)：昼夜节律是生物和行为过程中24小时重复发生的变化，由大脑的时钟中心，下丘脑的视交叉上核(SCN)控制。昼夜节律紊乱是许多神经系统疾病的常见症状，包括亨廷顿病、帕金森病和癫痫。尽管褪黑激素通常被用作治疗睡眠和昼夜节律紊乱的非处方药，但其在膜上的作用机制及其对分子时钟的影响仍不清楚。白天服用褪黑素的方式与神经肽Y(NPY)类似，可以调节运动和压力等非光信号。基于这一观察，NPY和褪黑素可能作用于类似的下游靶点。已有研究表明，NPY可激活其他脑区神经元的G蛋白偶联内向整流钾通道，导致膜超极化。褪黑素和神经肽Y都被证明以钾敏感的方式使SCN神经元超极化。GIRK通道激活是NPY和褪黑素在SCN中非光学效应的理想候选介导物。此外，GIRK通道可能在调节SCN兴奋性的昼夜差异中发挥作用，也影响光(光)携带。三个特定的目标将使用电生理、分子和行为分析来检验GIRK通道在SCN中介导NPY和褪黑素的抑制作用、在神经元放电和运动行为中的相移昼夜节律的总体假设。该项目的结果将填补我们关于GIRK通道如何影响SCN神经元的内在电特性和时间信号整合的知识空白，从而允许携带环境中的光和非光刺激。该项目还将提供信息，以开发针对昼夜节律紊乱的创新治疗方法，涉及非光策略(如褪黑素、运动或针对GIRK的新型药物)，与常用的光疗方法相比，这些策略可能产生更高的依从性和有效性。此外，这笔奖学金将使我能够制定和测试假设，开发分子/生理技术和科学写作，所有这些都将是无价的，因为我努力实现我的目标，发展一个独立的研究计划。

DESCRIPTION (provided by applicant): Circadian rhythms are reoccurring 24-h changes in biological and behavioral processes, controlled by the clock center of the brain, the suprachiasmatic nucleus (SCN) of the hypothalamus. Disruption of circadian rhythms is a common symptom of many neurological disorders including Huntington's disease, Parkinson's disease, and epilepsy. Although melatonin is commonly used as an over-the-counter treatment for sleep and circadian disruption, the mechanism of action at the membrane and its effects on the molecular clock remains unknown. Day-time melatonin administration advances the circadian clock in a manner similar to neuropeptide Y (NPY), known to mediate nonphotic signals such as exercise and stress. Based on this observation, NPY and melatonin may be acting on similar downstream targets. It has been shown that NPY can activate G protein- coupled inwardly-rectifying potassium (GIRK) channels in neurons of other brain areas, leading to membrane hyperpolarization. Both melatonin and NPY have been shown to hyperpolarize SCN neurons in a potassium- sensitive manner. GIRK channel activation is an ideal candidate mediator of the nonphotic effects of NPY and melatonin in the SCN. Additionally, GIRK channels may play a role in modulating day-night differences in SCN excitability, influencing photic (light) entrainment as well. Three specific aims will use electrophysiological, molecular, and behavioral assays to test the overall hypothesis that GIRK channels mediate the inhibitory effect of NPY and melatonin in the SCN, phase shifting circadian rhythms in neuronal firing and locomotor behavior. The results of this project will fill a gap in our knowledge of how GIRK channels influence intrinsic electrical properties and time-of-day signal integration of SCN neurons, allowing entrainment to both light and nonphotic stimuli in the environment. This project will also provide information to develop innovative treatments for circadian disruption involving nonphotic strategies (such as melatonin, exercise or novel pharmaceutics aimed at GIRK) that are likely to yield enhanced compliance and efficacy compared to the commonly used light-therapy approach. Furthermore, this fellowship will enable me to formulate and test hypotheses, develop molecular/physiological techniques and scientific writing, all of which will be invaluable as I work toward my goal of developing an independent research program.