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

• 批准号: 8297426
• 负责人: GARY Edward PICKARD
• 金额: $ 36.57万
• 依托单位: UNIVERSITY OF NEBRASKA LINCOLN
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-15 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8297426
• 关键词: Adrenal Cortex; Adrenal Glands; Affect; Animals; Architecture; Behavior; Behavioral; Blood; Brain; Brain region; Circadian Rhythms; Complex; Corticosterone; Cues; Data; Disease; Dissection; Endocrine Physiology; Environment; Excretory function; Feedback; Gene Expression; Genes; Genetic Transcription; Genotype; Glucocorticoids; Homeostasis; Hormonal; Hormones; House mice; Human; Hypothalamic structure; 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; Relative (related person); Retinal; Retinal Ganglion Cells; Role; Running; Serotonin Receptor 5-HT1B; Signal Transduction; Suid Herpesvirus 1; System; Techniques; Temperature; Testing; Time; Tissues; Transplantation; Tryptophan 5-monooxygenase; Viral; Wild Type Mouse; adrenal transplantation; base; body-mind; circadian pacemaker; hormone metabolism; neural circuit; neurodegenerative dementia; neuronal cell body; neurotoxic; raphe nuclei; relating to nervous system; research study; suprachiasmatic nucleus

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.

描述（由申请人提供）：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参与昼夜循环。昼夜节律计时系统具有复杂的体系结构。除了SCN之外，辅助时钟位于身体的大多数（如果不是全部）组织，器官和细胞中，包括与SCN不同的大脑区域。外围生物钟直接调节局部节律， 细胞代谢和激素分泌，并需要每天从SCN中提取线索，以协调行为、生理和代谢昼夜节律的时间，这是健康身心的基本要求。SCN通过其与支配外周器官的自主神经回路的连接以及通过其对节律性激素分泌（诸如肾上腺糖皮质激素）的调节来维持全球昼夜同步。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。时间内稳态是中枢和自主神经回路与肾上腺激素反馈之间的复杂相互作用。昼夜节律功能的变化和伴随的相位变化与几种人类疾病有关。CORT昼夜节律幅度的降低可能对代谢和中枢神经系统功能产生广泛的影响。初步数据表明，在夹带的SCN的日/夜周期的变化产生的昼夜CORT节律的变化，作为夹带相位角是逐渐更多的延迟相对于光偏移的昼夜皮质酮节律的幅度逐渐减少，高达50%。具体目标1使用时钟基因的转录谱来扩展初步的发现，并检查潜在的机制，改变夹带到白天/黑夜周期降低昼夜CORT节律的幅度。具体目标2描述了向肾上腺发送信号的神经回路（可能绕过SCN）。通过顺行追踪视网膜传出神经到下丘脑，并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标记下丘脑中的前自主神经元，来识别对前自主神经元的视网膜输入。功能实验的目标确定前自主下丘脑神经元神经毒性损伤，以确定对肾上腺功能的影响。具体目标3利用移植肾上腺从小鼠肾上腺振荡器（Per 2/Cry 1 dKO小鼠）到肾上腺切除的野生型小鼠与改变夹带解剖SCN和肾上腺振荡器的功能作用，和L：D周期的调节CORT分泌的昼夜节律。了解视网膜回路和中央时钟如何通过自主回路调节周边振荡器将有助于我们更好地理解和治疗昼夜节律改变的能力。 公共卫生相关性：越来越多的人认识到，行为、生理和代谢昼夜节律的协调定时是健康的身心所必需的。昼夜节律计时系统是复杂的，主要时钟位于大脑中，次要时钟位于身体的大多数（如果不是全部）组织，器官和细胞中。大脑和外周生物钟之间的长期中断或失调可导致与疾病状态和某些痴呆症和神经退行性疾病相关的激素分泌和代谢的变化。