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: $ 2.4万
• 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: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=667977
• 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一些机制介导的早期压力对大脑发育和长期的生理和行为结果的影响。使用有限的床上用品（LB）的范例作为啮齿动物模型的早期生活的逆境，产生支离破碎的孕产妇护理，我们确定了多种后果的活动的压力轴和杏仁核功能的新生大鼠。目前尚不清楚的是，来自分散的孕产妇护理的信号如何影响由中枢和外周组织中的昼夜节律振荡系统控制的新生儿生理学的发展。我们的总体假设是，由有限的床上用品引起的支离破碎的孕产妇护理会干扰大脑区域和外周组织中时钟基因的节律变化的建立，导致关键神经元功能的不适当调节和稳态系统的控制，特别是那些与压力和代谢调节有关的系统。时钟基因及其调节的蛋白质是视交叉上核（SCN）中的中央时钟以及大脑和外周中的外周振荡器的关键元件。在中枢和外周振荡器之间建立的关系对于控制稳态是必不可少的，并且可能在发育中至关重要，以在特定的挑战下建立神经元和器官的反应性。母亲的节律性施加主要是通过序列的母亲护理和喂养回合是至关重要的，在早期建立的昼夜节律的幼崽。事实上，我们最近发现，与对照幼崽相比，暴露于LB的新生大鼠的SCN和肝脏中Per2表达的昼夜节律被消除。总的来说，这组研究应该有助于确定昼夜节律振荡器（中枢神经系统和外周），最严重的影响，早期的压力和碎片在孕产妇保健，一些潜在的效应器的长期脆弱性的改变和机制，链接在时钟振荡的早期修改成人生理结果。这些研究将为在时间生物学以及分子，细胞和行为神经科学方面具有不同专业知识的学生提供许多培训机会。