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
基本信息
- 批准号:8297426
- 负责人:
- 金额:$ 36.57万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:Adrenal CortexAdrenal GlandsAffectAnimalsArchitectureBehaviorBehavioralBloodBrainBrain regionCircadian RhythmsComplexCorticosteroneCuesDataDiseaseDissectionEndocrine PhysiologyEnvironmentExcretory functionFeedbackGene ExpressionGenesGenetic TranscriptionGenotypeGlucocorticoidsHomeostasisHormonalHormonesHouse miceHumanHypothalamic structureLabelLeadLesionLightMeasuresMetabolicMetabolismModelingMolecularMusNervous System PhysiologyNeuraxisNeuronsOrganPathway interactionsPeriodicityPeripheralPhasePhotoperiodPhysiologicalProsencephalonPseudorabiesRegulationRelative (related person)RetinalRetinal Ganglion CellsRoleRunningSerotonin Receptor 5-HT1BSignal TransductionSuid Herpesvirus 1SystemTechniquesTemperatureTestingTimeTissuesTransplantationTryptophan 5-monooxygenaseViralWild Type Mouseadrenal transplantationbasebody-mindcircadian pacemakerhormone metabolismneural circuitneurodegenerative dementianeuronal cell bodyneurotoxicraphe nucleirelating to nervous systemresearch studysuprachiasmatic nucleus
项目摘要
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引导昼/夜周期。昼夜节律计时系统具有复杂的架构。除了 SCN 之外,辅助时钟还存在于身体的大多数(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。外周时钟直接调节局部节律
细胞代谢和激素分泌,需要每日来自视交叉上核的引导信号来协调行为、生理和代谢昼夜节律的时间,这是健康身心的首要条件。 SCN 通过与支配外周器官的自主神经回路的连接以及对节律性激素分泌(如肾上腺糖皮质激素)的调节来维持全球昼夜节律同步。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。时间稳态是中枢和自主神经回路与肾上腺激素反馈之间复杂的相互作用。昼夜节律功能的变化以及随之而来的相位变化与多种人类疾病有关。 CORT 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 与昼夜周期的夹带变化会导致昼夜 CORT 节律发生变化;随着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减小,最多可达 50%。具体目标 1 使用时钟基因的转录谱来扩展初步发现,并检查改变昼/夜周期的夹带减少昼夜 CORT 节律幅度的潜在机制。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)。通过顺行追踪到下丘脑的视网膜传出神经元,并使用注入肾上腺的伪狂犬病病毒,通过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。功能实验的目标是识别出用于神经毒性损伤的自主神经前下丘脑神经元,以确定对肾上腺功能的影响。具体目标 3 利用将患有心律失常肾上腺振荡器的小鼠(Per2/Cry1 dKO 小鼠)的肾上腺移植到夹带改变的肾上腺切除的野生型小鼠中,以剖析 SCN 和肾上腺振荡器的功能作用,以及 L:D 循环对肾上腺振荡器调节的作用。 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外周振荡器将有助于我们更好地理解和治疗昼夜节律的改变。
公共卫生相关性:人们越来越认识到,健康的身心需要协调行为、生理和代谢昼夜节律的时间安排。昼夜节律计时系统很复杂,主时钟位于大脑中,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。大脑和外周时钟之间的长期破坏或失调可能导致激素分泌和代谢的变化,这与疾病状态以及某些痴呆和神经退行性疾病相关。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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GARY Edward PICKARD其他文献
GARY Edward PICKARD的其他文献
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{{ truncateString('GARY Edward PICKARD', 18)}}的其他基金
Virus-host interactions governing alpha-herpesvirus genome delivery and neuroinvasion
控制α-疱疹病毒基因组传递和神经侵袭的病毒-宿主相互作用
- 批准号:
10569016 - 财政年份:2020
- 资助金额:
$ 36.57万 - 项目类别:
Virus-host interactions governing alpha-herpesvirus genome delivery and neuroinvasion
控制α-疱疹病毒基因组传递和神经侵袭的病毒-宿主相互作用
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10328227 - 财政年份:2020
- 资助金额:
$ 36.57万 - 项目类别:
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:
8975244 - 财政年份:2012
- 资助金额:
$ 36.57万 - 项目类别:
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 - 财政年份:2012
- 资助金额:
$ 36.57万 - 项目类别:
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
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8774933 - 财政年份:2012
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$ 36.57万 - 项目类别:
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
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