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

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。我的研究项目的主要重点是了解一些机制，介导早期压力对大脑发育和长期生理和行为结果的影响。利用有限床上（LB）范式作为啮齿动物早期生活逆境的模型，我们发现了应激轴活动和杏仁核功能对新生大鼠的多重影响。目前尚不清楚的是，来自分散的产妇护理的信号如何影响由中央和外周组织的昼夜节律振荡系统控制的新生儿生理发育。我们的总体假设是，有限的床上活动导致的零碎的母性护理会干扰大脑区域和外周组织生物钟基因节律变化的建立，导致关键神经元功能的不适当调节和稳态系统的控制，特别是与应激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）中央时钟以及大脑和外周振荡子的关键元件。中枢和外周振荡之间建立的关系对于控制体内平衡至关重要，并且可能对发育至关重要，在特定挑战下建立神经元和器官反应。母性节律主要是通过母性照料和喂养的顺序施加的，在幼鼠昼夜节律的早期建立中是至关重要的。事实上，我们最近发现，与对照组幼鼠相比，暴露于LB的新生大鼠的SCN和肝脏中Per2表达的昼夜节律被取消。总的来说，这组研究应该有助于确定受早期压力和产妇护理碎片化影响最严重的昼夜节律振荡器（CNS和外周），改变长期脆弱性的一些潜在效应，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。

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.