Homeostatic regulation of peripheral oscillators via autonomic circuitry

通过自主电路对外围振荡器进行稳态调节

基本信息

批准号：
8975244
负责人：
GARY Edward PICKARD
金额：
$ 35.29万
依托单位：
UNIVERSITY OF NEBRASKA LINCOLN
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-01-15 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8975244
关键词：
Adrenal Cortex Adrenal Glands Affect Animals Architecture Behavior Behavioral Blood Brain Brain region Cells Circadian Rhythms Complex Corticosterone Cues Data Disease Dissection Endocrine Physiology Environment Excretory function Feedback Gene Expression Genes Genetic Transcription Genotype Glucocorticoids Homeostasis Hormonal Hormones Housing Human Hypothalamic structure Knockout Mice Label Lead Lesion Light Measures Metabolic Metabolism Modeling Molecular Mus Nervous System Physiology Neuraxis Neurons Organ Pathway interactions Periodicity Peripheral Phase Photoperiod Physiological Prosencephalon Pseudorabies Regulation Retinal Retinal Ganglion Cells Role Running Serotonin Receptor 5-HT1B Signal Transduction Suid Herpesvirus 1 System TPH2 Techniques Temperature Testing Time Tissues Transplantation Viral Wild Type Mouse adrenal transplantation base body-mind circadian pacemaker hormone metabolism neural circuit neurodegenerative dementia neurotoxic raphe nuclei relating to nervous system research study suprachiasmatic nucleus

项目摘要

Project Summary The suprachiasmatic nucleus (SCN) is the primary circadian oscillator in the central nervous system, entrained to the day/night cycle via the retinohypothalamic tract. The circadian-timing system has a complex architecture. In addition to the SCN, subsidiary clocks are located in most, if not all, tissues, organs, and cells of the body including brain regions distinct from the SCN. Peripheral clocks directly regulate local rhythms in cellular metabolism and hormone secretion and require daily entraining cues from the SCN for coordinated timing of behavioral, physiologic and metabolic circadian rhythms, a primary requisite for a healthy body and mind. The SCN maintains global circadian synchrony via its connections with autonomic circuits innervating peripheral organs and by its regulation of rhythmic hormone secretion such as adrenal glucocorticoids. Rhythmic corticosterone (CORT) signals induce the rhythmic expression of a diverse array of genes including clock genes. Temporal homeostasis is a complex interplay between central and autonomic neural circuits and hormonal feedback from the adrenal. Changes in circadian function and the accompanying changes in phase have been associated with several human disorders. A reduction in the amplitude of the CORT diurnal rhythm may exert a wide range of effects on metabolism and central nervous system function. Preliminary data demonstrate that alterations in entrainment of the SCN to the day/night cycle produce changes in the diurnal CORT rhythm; as entrainment phase angle is progressively more delayed relative to light offset the amplitude of the diurnal corticosterone rhythm is progressively reduced, up to as much as 50%. Specific Aim 1 uses transcriptional profiles of clock genes to extend preliminary findings and examines potential mechanisms by which altered entrainment to the day/night cycle reduces the amplitude of the diurnal CORT rhythm. Specific Aim 2 describes the neural circuits (that may circumvent the SCN) that send signals to the adrenal. Retinal input to pre-autonomic neurons is identified by anterograde tracing of retinal efferents to the hypothalamus in conjunction with labeling of pre-autonomic neurons in the hypothalamus via transneuronal retrograde tracing using pseudorabies virus injected into the adrenal. Functional experiments target identified pre-autonomic hypothalamic neurons for neurotoxic lesioning to determine effects on adrenal function. Specific Aim 3 utilizes transplantation of adrenals from mice with arrhythmic adrenal oscillators (Per2/Cry1 dKO mice) into adrenalectomized wild type mice with altered entrainment to dissect the functional roles of the SCN and adrenal oscillators, and the L:D cycle on the regulation of the diurnal rhythm of CORT secretion. Understanding how retinal circuits and the central clock regulate peripheral oscillators via autonomic circuits will aid in our ability to better understand and treat altered circadian rhythms.

项目概要视交叉上核（SCN）是中枢神经系统中主要的昼夜节律振荡器，通过视网膜下丘脑束进入昼夜循环。昼夜节律系统有一个复杂的架构。除了 SCN 之外，辅助时钟还存在于大多数（如果不是全部）组织中，身体的器官和细胞，包括与视交叉上核不同的大脑区域。直接外设时钟调节细胞代谢和激素分泌的局部节律，需要日常引导线索来自 SCN 的协调行为、生理和代谢昼夜节律的计时，健康身心的首要条件。 SCN 通过其维持全球昼夜节律同步与支配周围器官的自主神经回路的联系及其对节律的调节激素分泌，如肾上腺糖皮质激素。节律性皮质酮 (CORT) 信号诱导包括时钟基因在内的多种基因的节律表达。时间稳态是中枢神经回路和自主神经回路以及荷尔蒙反馈之间复杂的相互作用肾上腺。昼夜节律功能的变化和随之而来的相位变化相关患有多种人类疾病。 CORT 昼夜节律幅度的降低可能会产生对新陈代谢和中枢神经系统功能有广泛的影响。初步数据证明 SCN 夹带昼/夜周期的变化会产生昼夜 CORT 节律；因为夹带相位角相对于光偏移逐渐延迟昼夜皮质酮节律的幅度逐渐降低，最多可达 50%。具体目标 1 使用时钟基因的转录谱来扩展初步发现和检查改变昼夜循环的夹带会降低振幅的潜在机制昼夜 CORT 节律。具体目标 2 描述了神经回路（可能绕过 SCN）向肾上腺发送信号。通过顺行追踪识别前自主神经元的视网膜输入视网膜传出到下丘脑的信号与前自主神经元的标记相结合使用注射到肾上腺的伪狂犬病病毒通过跨神经元逆行追踪下丘脑。功能实验针对已识别的前自主神经下丘脑神经元的神经毒性损伤以确定对肾上腺功能的影响。具体目标 3 利用小鼠肾上腺移植将心律失常肾上腺振荡器（Per2/Cry1 dKO 小鼠）注入肾上腺切除的野生型小鼠中改变夹带以剖析 SCN 和肾上腺振荡器以及 L:D 循环的功能作用 CORT 分泌的昼夜节律的调节。了解视网膜回路和中央时钟通过自主电路调节外围振荡器将有助于我们更好地了解并治疗昼夜节律改变。