Homeostatic regulation of peripheral oscillators via autonomic circuitry

项目摘要 视交叉上核（SCN）是中枢神经系统中的主要昼夜节律振荡器， 通过视网膜下丘脑束进入昼夜循环。昼夜节律计时系统有一个 复杂的架构。除了SCN，辅助时钟位于大多数（如果不是全部）组织中， 器官和身体的细胞，包括与SCN不同的脑区域。外设时钟直接 调节细胞代谢和激素分泌的局部节律，并需要每天的诱导信号 从SCN的协调时间的行为，生理和代谢昼夜节律， 健康的身体和精神的基本条件。SCN通过其自身的生物钟维持全球昼夜节律同步。 与支配外周器官的自主神经回路的联系，以及通过其对节律性 激素分泌如肾上腺糖皮质激素。节律性皮质酮（CORT）信号诱导 包括生物钟基因在内的多种基因的节律性表达。时间内稳态是一种 中枢和自主神经回路之间的复杂相互作用以及来自 肾上腺昼夜节律功能的变化和伴随的相位变化 几种人类疾病CORT昼夜节律振幅的降低可能会产生一种 对新陈代谢和中枢神经系统功能的广泛影响。初步数据 证明SCN夹带到日/夜周期的改变会导致 昼夜CORT节律;由于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，最高达50%。 Specific Aim 1使用时钟基因的转录谱来扩展初步发现， 潜在的机制，改变夹带到白天/黑夜周期降低的幅度， 昼夜CORT节律。具体目标2描述了神经回路（可能绕过SCN）， 向肾上腺发送信号视网膜对前自主神经元的输入通过顺行追踪来识别 视网膜传出神经的下丘脑结合标记前自主神经元在 下丘脑通过使用注射到肾上腺中的伪狂犬病病毒的跨神经元逆行追踪。 下丘脑前自主神经元的功能实验研究 以确定对肾上腺功能的影响。Specific Aim 3利用小鼠肾上腺移植 用肾上腺皮质振荡器（Per 2/Cry 1 dKO小鼠）移植到肾上腺切除的野生型小鼠中， 改变夹带解剖SCN和肾上腺振荡器的功能作用，和L：D周期 调节CORT分泌的昼夜节律。了解视网膜回路和 通过自主电路的中央时钟调节外围振荡器将有助于我们更好地 理解和治疗改变的昼夜节律。

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.