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: 8410094
• 负责人: GARY Edward PICKARD
• 金额: $ 34.06万
• 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/8410094
• 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

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.

项目摘要 肌发作核（SCN）是中枢神经系统中的主要昼夜节律振荡器， 通过视网膜丘脑植物束缚于白天/夜间周期。昼夜节律系统有一个 复杂的体系结构。除SCN外，辅助时钟还位于大多数（如果不是全部）， 器官和人体细胞，包括与SCN不同的大脑区域。外围时间直接 调节细胞代谢和激素分泌中的局部节奏，并需要每天纳入线索 从SCN进行行为，生理和代谢昼夜节律的协调时间， 健康身心的主要必要条件。 SCN通过其维护全球昼夜节律同步 与自主电路的连接支配外围器官以及其节奏的调节 激素分泌，例如肾上腺糖皮质激素。有节奏的皮质酮（Cort）信号诱导 包括时钟基因在内的各种基因阵列的节奏表达。颞稳态是 中央和自主神经回路之间的复杂相互作用以及来自 肾上腺。昼夜节律的变化和随附的相变已关联 有几种人类疾病。 Cort昼夜节奏的振幅降低可能会发挥A 对代谢和中枢神经系统功能的广泛影响。初步数据 证明SCN夹带到白天/夜间周期的改变会导致变化 昼夜的cort节奏；由于夹带相位角相对于光偏移而逐渐延迟 昼夜皮质酮节奏的幅度逐渐降低，高达50％。 特定目标1使用时钟基因的转录曲线来扩展初步发现并检查 通过将夹带改变为白天/夜间周期的潜在机制降低了 昼夜节奏。特定目标2描述了神经回路（可能绕过SCN） 向肾上腺发送信号。自主神经元的视网膜输入通过顺行迹鉴定 在下丘脑的视网膜传播与自主神经元的标记 下丘脑通过跨神经元逆行追踪，使用伪标的病毒注射到肾上腺。 功能实验靶标鉴定出自治前下丘脑神经元用于神经毒性病变 确定对肾上腺功能的影响。特定目标3利用小鼠的肾上腺移植 与心律不齐的肾上腺振荡器（PER2/CRY1 DKO小鼠）一起进入肾上腺切除型野生型小鼠， 改变夹带以剖定SCN和肾上腺振荡器的功能作用，L：D周期 关于Cort分泌的昼夜节奏的调节。了解视网膜电路和 中央时钟通过自主电路调节外围振荡器将有助于我们改善 了解并治疗改变的昼夜节律。