Neurobiological and Metabolic Embedding of Early Life Adversity

一般背景*虽然哺乳动物的发育从受孕开始并贯穿整个生命周期，但最显著的变化发生在生命早期阶段（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，生物的发育轨迹在生命的最初阶段最容易受到干扰（即逆境）。*迄今为止，大多数研究工作都是研究动物早期发育期间的环境如何影响其内分泌生理（如葡萄糖调节）或其发展代谢性疾病（如糖尿病）的倾向。相比之下，很少有人研究早期生活环境对大脑发育的影响，尤其是对学习和记忆的影响。*在过去的四年里，我的研究重点一直是nserc资助的一个项目，研究一种形式的产前逆境（母亲肥胖）对后代大脑发育和新陈代谢的影响。许多重要的观察结果已经被发现，包括肥胖母亲的后代在突触可塑性（特别是长期增强，被认为是记忆的细胞相关）方面表现出显著的损害，但在几种重要的突触蛋白的表达方面没有表现出变化。*研究目标*我的长期目标是继续建立一个研究项目，研究早期生活中的逆境是如何在动物发育过程中根深蒂固的。*短期目标将指导当前的建议：*1)探索饮食诱导的母亲肥胖如何影响雌性亲本及其后代突触功能和肥胖相关代谢的机制。*2)研究早期生活心理社会压力（以断奶后社会孤立的形式）可能对大脑发育和肥胖相关代谢的影响。*3)研究产前逆境（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。*计划实验总结*拨款提案中的实验将沿着三条线发展：*1)确定突触信号转导的变化，解释肥胖母亲及其后代所表现出的可塑性降低。具体来说，我们将关注瘦素信号传导，考虑到这种激素参与突触功能，并在肥胖期间经历改变的信号转导。*2)描述长期的早期社会孤立对大脑发育和一般代谢的影响。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)完成一项关于早期逆境（即产前和产后双重干扰）对大脑发育和一般代谢的影响的广泛调查。特别是，在早期产后发育期间（从断奶到成年早期），由肥胖母亲所生的动物将被分层到正常或隔离的住房条件中，在较长的时间内。前两个阶段的研究结果和技术方法将用于指导即将完成的实验。*预期意义*提出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本质

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