Effect of fragmented maternal care on the development of the circadian system: implications for stress and metabolic regulation in the offspring

分散的孕产妇护理对昼夜节律系统发育的影响：对后代压力和代谢调节的影响

• 批准号: RGPIN-2018-03871
• 负责人: Walker, ClaireDominique
• 金额: $ 4.81万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=763680
• 关键词: Effect; fragmented; maternal; care; development

Genetic and environmental factors early in life interact to shape normal and aberrant brain development, with major implications for health and disease. The major focus of my research program is to understand some of the mechanisms mediating the effects of early stress on brain development and long term physiological and behavioral outcomes. Using the limited bedding (LB) paradigm as a rodent model of early-life adversity, which produces fragmented maternal care, we identified multiple consequences on the activity of the stress axis and amygdala function in neonatal rats. What remains unclear is how the signal from fragmented maternal care can influence the development of neonatal physiology controlled by circadian oscillating systems in central and peripheral tissues. Our overall hypothesis is that the fragmented maternal care caused by limited bedding will disturb the establishment of rhythmic variations of clock genes in brain regions and peripheral tissues, leading to inappropriate regulation of key neuronal functions and the control of homeostatic systems, in particular those related to stress and metabolic regulation. Clock genes and the proteins they regulate are key elements of the central clock in the suprachiasmatic nucleus (SCN) as well as peripheral oscillators in the brain and periphery. The relationships established between central and peripheral oscillators are essential to control homeostasis and might be critical in development, to establish neuronal and organ responsiveness under specific challenges. Maternal rhythmicity imposed mainly through sequences of maternal care and feeding bouts is critical in the early establishment of the circadian rhythmicity in the pups. Indeed, we recently found that the circadian rhythm of Per2 expression in the SCN and liver was abolished in neonatal rats exposed to LB compared to control pups. Overall, this set of studies should help identify the circadian oscillators (CNS and periphery) that are most critically affected by early stress and fragmentation in maternal care, some of the potential effectors of long term vulnerability that are altered and the mechanisms that link early modifications in clock oscillations to adult physiological outcomes. These studies will provide many training opportunities for students with a diverse expertise in chronobiology as well as molecular, cellular and behavioral neuroscience.

生命早期的遗传和环境因素相互作用，形成正常和异常的大脑发育，对健康和疾病有重大影响。我的研究计划的主要重点是了解早期应激对大脑发育和长期生理和行为结果的影响的一些机制。使用有限卧床(LB)范式作为早期生活逆境的啮齿动物模型，产生支离破碎的母婴护理，我们确定了对新生大鼠应激轴活动和杏仁核功能的多重后果。目前尚不清楚的是，来自支离破碎的产妇护理的信号如何影响由中枢和外周组织的昼夜振荡系统控制的新生儿生理学的发展。我们的总体假设是，有限的床上用品导致的零散的产妇护理将扰乱脑区和周围组织时钟基因节律性变化的建立，导致关键神经元功能的不适当调节和动态平衡系统的控制，特别是与应激和代谢调节相关的系统。时钟基因及其调控的蛋白质是视交叉上核(SCN)中央时钟的关键元素，也是大脑和外周的外周振荡器。中枢和外周振荡器之间建立的关系对于控制动态平衡是必不可少的，在发育过程中可能是关键的，以建立在特定挑战下的神经元和器官反应。母体节律性主要是通过母体照料和喂食的顺序施加的，在幼崽的昼夜节律性的早期建立中是关键的。事实上，我们最近发现，与对照组相比，暴露于LB的新生大鼠SCN和肝脏中PER2表达的昼夜节律被取消。总体而言，这组研究应该有助于确定在产妇护理中受早期应激和碎片化影响最严重的昼夜节律振荡器(中枢神经系统和外周)，一些被改变的长期脆弱性的潜在影响因素，以及将时钟振荡的早期修改与成人生理结果联系起来的机制。这些研究将为拥有不同时间生物学以及分子、细胞和行为神经科学专业知识的学生提供许多培训机会。