Homeostatic regulation of peripheral oscillators via autonomic circuitry

描述(申请人提供)：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。生物钟计时系统有一个复杂的体系结构。除了SCN，辅钟还存在于身体的大部分组织、器官和细胞中，包括与SCN不同的大脑区域。外周时钟直接调节心脏的局部节律 细胞新陈代谢和激素分泌需要来自SCN的日常引导信号，以协调行为、生理和代谢昼夜节律的时间，这是健康身心健康的主要必要条件。SCN通过与支配外周器官的自主神经回路的连接以及对肾上腺糖皮质激素等有节奏的激素分泌的调节，维持全球昼夜节律的同步性。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性表达。时间动态平衡是中枢和自主神经回路以及来自肾上腺的激素反馈之间的复杂相互作用。昼夜节律功能的改变和随之而来的相变与几种人类疾病有关。皮质醇昼夜节律幅度的降低可能对新陈代谢和中枢神经系统功能产生广泛的影响。初步数据表明，SCN对昼夜周期的夹带改变会导致皮质酮昼夜节律的变化；随着夹带相角相对于光抵消逐渐延迟，皮质酮昼夜节律的幅度逐渐减小，最高可达50%。具体目标1使用时钟基因的转录图谱来扩展初步发现，并检查改变昼夜周期的夹带降低皮质醇昼夜节律幅度的潜在机制。特定目的2描述了向肾上腺发送信号的神经回路(可能绕过SCN)。视网膜对自主神经前神经元的输入是通过顺行追踪视网膜传出到下丘脑，结合使用伪狂犬病病毒注射到肾上腺的跨神经元逆行追踪标记下丘脑自主神经前神经元来识别的。功能实验的目标是确定下丘脑自主神经前神经元的神经毒性损害，以确定对肾上腺功能的影响。特定目的3通过将心律失常肾上腺振荡器小鼠(PER2/Cry1dKO小鼠)的肾上腺移植到摘除肾上腺的野生型小鼠的夹带改变后，分析SCN和肾上腺振荡器的功能作用，以及L：D周期对皮质醇分泌昼夜节律的调节。了解视网膜电路和中央时钟如何通过自主电路调节外周振荡器，将有助于我们更好地理解和治疗改变的昼夜节律。 与公共健康相关：越来越多的人认识到，行为、生理和代谢昼夜节律的协调时间对于健康的身心健康是必要的。昼夜节律系统是复杂的，主时钟位于大脑，而从属时钟位于大部分(如果不是全部)组织、器官和身体细胞。大脑和外周生物钟之间的长期干扰或失调可能会导致激素分泌和代谢的变化，这与疾病状态、某些痴呆和神经退行性疾病有关。

DESCRIPTION (provided by applicant): 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 beter understand and treat altered circadian rhythms. PUBLIC HEALTH RELEVANCE: There is growing recognition that coordinated timing of behavioral, physiologic and metabolic circadian rhythms is required for a healthy body and mind. The circadian timing system is complex, with the primary clock located in the brain and subordinate clocks located in most, if not all, tissues, organs, and cells of the body. Long term disruption or dysregulation between brain and peripheral clocks can lead to changes in hormone secretion and metabolism that correlate with disease states and certain dementias and neurodegenerative conditions.