GIRK channel modulation of SCN excitability and circadian rhythms

GIRK 通道对 SCN 兴奋性和昼夜节律的调节

• 批准号: 8822141
• 负责人: Lauren M Hablitz
• 金额: $ 1.72万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-05 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8822141
• 关键词: Antiepileptic Agents; Area; Arousal; Behavior; Behavioral; Behavioral Assay; Biological; Biological Clocks; Bioluminescence; Body Temperature; Brain; Cells; Chronotherapy; Circadian Rhythms; Clinical Treatment; Development; Electrophysiology (science); Environment; Epilepsy; Exercise; Fellowship; Frequencies; Future; G protein-coupled inwardly-rectifying potassium channel; GIRK2 subunit, G protein-coupled inwardly-rectifying potassium channel; Goals; Hormonal; Hormones; Human; Huntington Disease; Hypothalamic structure; Knockout Mice; Knowledge; Laboratories; Light; Mediating; Mediator of activation protein; Melatonin; Membrane; Membrane Potentials; Molecular; Motor Activity; Neurons; Neuropeptides; Organism; Parkinson Disease; Pharmaceutical Preparations; Pharmacy (field); Phase; Phenotype; Phototherapy; Physiological; Play; Potassium; Process; Property; Regulation; Reporting; Research; Research Personnel; Resistance; Rest; Rodent; Role; Running; Seizures; Signal Transduction; Signaling Molecule; Sleep; Sleep Disorders; Stimulus; Stress; Symptoms; Techniques; Testing; Time; Western Blotting; Work; Writing; base; circadian pacemaker; comparative efficacy; early onset; electrical property; innovation; insight; light entrainment; nervous system disorder; neuronal excitability; neuropeptide Y; novel; patch clamp; programs; public health relevance; skills; suprachiasmatic nucleus

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.

描述（由申请人提供）：昼夜节律是由大脑的时钟中心，下丘脑的上核（SCN）控制的生物学和行为过程的24小时变化。昼夜节律的破坏是许多神经系统疾病的常见症状，包括亨廷顿氏病，帕金森氏病和癫痫。尽管褪黑激素通常被用作睡眠和昼夜节律破坏的非处方治疗方法，但膜上的作用机理及其对分子钟的影响仍然未知。白天的褪黑激素给药以类似于神经肽Y（NPY）的方式推进昼夜节律时钟，已知可以介导非细胞信号，例如运动和压力。基于此观察，NPY和褪黑激素可能作用于相似的下游靶标。已经表明，NPY可以激活其他大脑区域神经元中的内部切除钾（GIRK）通道的G蛋白，从而导致膜超极化。褪黑激素和NPY均以钾敏感的方式表明SCN神经元超极化。 GIRK通道激活是NPY和褪黑激素在SCN中的非细菌作用的理想候选介体。此外，Girk通道可能在调节SCN兴奋性的昼夜差异方面发挥作用，也影响光（光）（光）夹带。三个具体目的将使用电生理，分子和行为测定法来检验总体假设，即Girk通道介导SCN中NPY和褪黑激素的抑制作用，在神经元放射和运动行为中的相位转移昼夜节律。该项目的结果将填补我们对Girk通道如何影响内在电气特性和SCN神经元的日期信号整合的空白，从而使环境中的光和非细胞刺激都夹住了。该项目还将提供信息，以开发涉及非疾病策略（例如针对Girk的褪黑激素，运动或新型药物）的昼夜节律中断的创新治疗方法，这些策略可能会产生与常用的光治疗方法相比，可能会提高合规性和效率。此外，这项奖学金将使我能够制定和检验假设，发展分子/生理技术和科学写作，所有这些都是无价的，因为我致力于制定独立研究计划。