Homeostatic regulation of peripheral oscillators via autonomic circuitry

项目摘要 视交叉上核(SCN)是中枢神经系统的主要昼夜节律振荡器， 通过视黄神经下丘脑束进入昼夜循环。生物钟计时系统有一个 复杂的建筑。除了SCN，辅钟还位于大多数组织中，如果不是全部的话， 器官和身体细胞，包括与SCN不同的大脑区域。外设时钟直接 调节细胞新陈代谢和荷尔蒙分泌的局部节律，并需要每日的诱导性提示 来自行为、生理和代谢昼夜节律的协调计时的SCN， 健康的身心健康的首要条件。SCN通过其以下方式维持全球昼夜节律同步 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一系列不同基因的节律性表达。时间动态平衡是一个 中枢和自主神经回路与激素反馈之间的复杂相互作用 肾上腺。昼夜节律功能的变化和随之而来的位相变化是相关的 患有几种人类疾病。CORT昼夜节律幅度的降低可能会对 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对昼夜循环的夹带的改变会在 昼夜CORT节律；由于卷吸相位角相对于光偏移逐渐延迟 皮质酮昼夜节律的幅度逐渐降低，最高可达50%。 特定目标1使用时钟基因的转录图谱来扩展初步发现并检查 改变对昼夜循环的夹带的潜在机制降低了 白天的Cort节律。特定目标2描述了(可能绕过SCN的)神经回路 向肾上腺发送信号。视网膜对自主神经前神经元的输入通过顺行追踪来识别 视网膜传出至下丘脑的标记与下丘脑自主神经前神经元的标记 利用伪狂犬病病毒注射到肾上腺的跨神经元逆行追踪下丘脑。 功能实验靶向神经毒性损害的下丘脑自主神经前神经元 以确定对肾上腺功能的影响。特殊目的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)注入去肾上腺的野生型小鼠 改变夹带以剖析SCN和肾上腺振荡器的功能作用以及L：D周期 皮质醇分泌昼夜节律的调节。了解视网膜回路和视网膜如何 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。

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.