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）：上核（SCN）是中枢神经系统中的主要昼夜节律振荡器，在白天/夜间周期中通过视网膜型丘脑区夹带。昼夜节律系统具有复杂的体系结构。除SCN外，辅助时钟还位于大多数（如果不是全部）的组织，器官和人体细胞，包括与SCN不同的大脑区域。外围钟直接调节局部节奏 细胞代谢和激素分泌，需要每天从SCN中提示提示行为，生理和代谢昼夜节律的协调时间，这是健康身心的主要必要条件。 SCN通过与支配外围器官的自主电路的连接以及通过其调节节奏激素分泌（如肾上腺糖皮质激素）来维持全球昼夜节律同步。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的节奏表达。颞稳态是中央和自主神经回路与肾上腺的激素反馈之间的复杂相互作用。昼夜节律功能的变化和随附的阶段变化与几种人类疾病有关。 Cort昼夜节奏振幅的幅度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，SCN夹带到白天/夜间周期的变化会导致昼夜的Cort节奏变化。由于夹带相位角逐渐延迟相对于光偏移，因此昼夜皮质酮节奏的幅度逐渐降低，可降低多达50％。特定的目标1使用时钟基因的转录曲线来扩展初步发现并检查潜在的机制，通过这些机制将夹带改变到白天/夜间周期会降低昼夜Cort节律的幅度。特定目标2描述了向肾上腺发送信号的神经回路（可能绕过SCN）。通过对下丘脑的视网膜传出对下丘脑的前进痕迹以及通过跨丘脑中的自主神经元的标记通过跨索神经元逆行跟踪，使用pseudorabies病毒在下丘脑中标记，通过对下丘脑的下丘脑进行了视网膜前痕迹，可以确定对自节腔前神经元的视网膜输入的视网膜输入。功能实验靶标确定了自治前下丘脑神经元的神经毒性病变，以确定对肾上腺功能的影响。 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.了解视网膜电路和中央时钟如何通过自主电路调节外围振荡器将有助于我们的能力理解和治疗改变的昼夜节律。 公共卫生相关性：越来越认识到，健康的身心需要行为，生理和代谢昼夜节律的协调时间。昼夜节律定时系统很复杂，主要时钟位于大脑中，下属时钟位于人体的组织，器官和细胞中，大多数（如果不是全部）。大脑和外围时钟之间的长期破坏或失调会导致激素分泌和代谢的变化与疾病状态以及某些痴呆症和神经退行性疾病相关。