Neurobiological and Metabolic Embedding of Early Life Adversity

早期生活逆境的神经生物学和代谢嵌入

• 批准号: RGPIN-2014-06216
• 负责人: Mielke, John
• 金额: $ 1.89万
• 依托单位: University of Waterloo
• 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=659763
• 关键词: Neurobiological; Metabolic; Embedding; Early; Life

GENERAL BACKGROUND*While mammalian development begins at conception and proceeds throughout the lifespan, the most dramatic period of change occurs during the early life segment (that is, the pre-natal and early post-natal periods). In addition, a growing body of epidemiological and experimental literature has shown that an organism's developmental trajectory is most susceptible to disruption (i.e., adversity) during the earliest parts of the lifespan.*To date, the majority of work has examined how an animal's environment during early development affects either its endocrine physiology (e.g., glucose regulation), or its tendency to develop metabolic disease (e.g., diabetes). In comparison, very little has been done to determine the influence that early life environment can have upon brain development, particularly in relation to learning and memory.*For the past four years, the focus of my research has been an NSERC-funded project examining the role that one form of pre-natal adversity (maternal obesity) can have upon brain development and metabolism in offspring. A number of important observations have been made, including the discovery that offspring of obese mothers show a significant impairment in synaptic plasticity (specifically, long-term potentiation, which is believed to be a cellular correlate of memory), but do not display changes in the expression of several important synaptic proteins.*RESEARCH OBJECTIVES*My long term objective is to continue building a research programme that examines how early life adversity becomes embedded during animal development.*The short term objectives that will guide the current proposal are:*1) Exploring the mechanisms underlying how diet-induced maternal obesity affects both synaptic function and obesity-related metabolism in the female parent and her offspring.*2) Examining the influence that early life psychosocial stress (in the form of post-weaning social isolation) may have upon brain development and obesity-related metabolism.*3) Investigating how pre-natal adversity (in the form of maternal obesity) and early post-natal adversity (in the form of social isolation) interact to affect brain development and obesity-related metabolism.*SUMMARY OF PLANNED EXPERIMENTS*Experiments in the grant proposal will be developed along three lines:*1) Determining the changes in synaptic signal transduction that explain the reduced plasticity displayed by both obese mothers and their offspring. Specifically, we will focus on leptin signalling, given that this hormone participates in synaptic function and experiences altered signal transduction during obesity.*2) Characterising the effects that chronic, early-life social isolation has upon both brain development and general metabolism. In particular, we will study changes in protein expression and distribution, look for differences in synaptic plasticity, and examine signal transduction of hormones related to both obesity and synaptic function.*3) Completing a broad survey of the effect that a "two-hit" model of early adversity (that is, combined pre and post-natal disruption) can have upon brain development and general metabolism. In particular, animals born from obese mothers will be stratified into either normal, or isolated housing conditions for an extended period of time during early post-natal development (from the point of weaning to early adulthood). The results and technical approaches from the previous two phases of the study will be used to guide the experiments that will be completed.*EXPECTED SIGNIFICANCE*The proposed study will clarify the magnitude of change that early life adversity can have upon formation of both the nervous and endocrine systems, and help to demonstrate the nature of their developmental plasticity

哺乳动物的发育从受孕开始，贯穿整个生命周期，但最显著的变化发生在生命早期（即产前和产后早期）。此外，越来越多的流行病学和实验文献表明，生物体的发育轨迹最容易受到破坏（即，在人生的最初阶段，到目前为止，大多数工作已经研究了动物在早期发育期间的环境如何影响其内分泌生理学（例如，葡萄糖调节），或其发展代谢疾病的倾向（例如，糖尿病）。相比之下，很少有人研究早期生活环境对大脑发育的影响，特别是与学习和记忆有关的影响。在过去的四年里，我的研究重点一直是NSERC资助的项目，研究一种形式的产前逆境（母亲肥胖）对后代大脑发育和代谢的作用。人们已经进行了许多重要的观察，包括发现肥胖母亲的后代在突触可塑性（特别是长时程增强，这被认为是记忆的细胞相关性）方面表现出明显的损伤，但在几种重要的突触蛋白的表达方面没有表现出变化。我的长期目标是继续建立一个研究项目，研究早期生活逆境如何在动物发育过程中嵌入。指导当前提案的短期目标是：*1）探索饮食诱导的母体肥胖如何影响母体及其后代的突触功能和肥胖相关代谢的潜在机制。2)研究早期生活心理社会压力（以断奶后社会隔离的形式）可能对大脑发育和肥胖相关代谢的影响。3)调查产前逆境（以母亲肥胖的形式）和产后早期逆境（以社会孤立的形式）如何相互作用，影响大脑发育和肥胖相关的代谢。计划的实验概要 * 拨款申请中的实验将沿着沿着三条路线发展：*1）确定突触信号转导的变化，这些变化解释了肥胖母亲及其后代表现出的可塑性降低。具体来说，我们将关注瘦素信号，因为这种激素参与突触功能，并在肥胖期间改变信号转导。2)描述了慢性的，早期的社会隔离对大脑发育和一般新陈代谢的影响。特别是，我们将研究蛋白质表达和分布的变化，寻找突触可塑性的差异，并检查与肥胖和突触功能相关的激素的信号转导。3)完成了一项广泛的调查，即早期逆境的“两次打击”模型（即产前和产后的综合破坏）对大脑发育和一般代谢的影响。特别是，在出生后早期发育期间（从断奶到成年早期），将肥胖母亲出生的动物分层为正常或隔离饲养条件。前两个研究阶段的结果和技术方法将用于指导将要完成的实验。预期意义 * 拟议的研究将阐明早期生活逆境对神经和内分泌系统形成的影响程度，并有助于证明其发育可塑性的性质