Neurobiological and Metabolic Embedding of Early Life Adversity

一般背景虽然哺乳动物的发育始于受孕，并在整个生命周期中进行，但最戏剧性的变化发生在生命的早期阶段(即出生前和出生后早期)。此外，越来越多的流行病学和实验文献表明，生物体的发育轨迹在生命的早期最容易受到干扰(即逆境)。到目前为止，大多数工作都研究了动物在早期发育过程中的环境如何影响其内分泌生理(如葡萄糖调节)，或其发展为代谢性疾病(如糖尿病)的倾向。相比之下，很少有人确定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资助的一个项目，该项目旨在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。已经进行了一些重要的观察，包括发现肥胖母亲的后代在突触可塑性方面表现出显著的损害(具体地说，长时程增强，这被认为是与记忆有关的细胞)，但不显示几个重要突触蛋白的表达变化。研究目的：长期目标是继续建立一个研究计划，研究早期生活逆境是如何在动物发育过程中嵌入的。将指导当前提议的短期目标是：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)研究早期心理社会应激(以断奶后社交隔离的形式)可能对大脑发育和肥胖相关代谢的影响。3)调查出生前逆境(以断奶后社交隔离的形式)如何影响母亲及其后代的突触功能和肥胖相关代谢产后早期逆境(表现为母亲肥胖)和产后早期逆境(表现为社会隔离)相互作用，影响大脑发育和肥胖相关的新陈代谢。计划中的实验总结拨款提案中的实验将沿着三个方向发展：1)确定突触信号转导的变化，这可以解释肥胖母亲及其后代表现出的可塑性降低。具体地说，我们将重点介绍瘦素信号，因为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)描述慢性的早期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)完成对早期逆境(即出生前和出生后的破坏)的“两次打击”模型对大脑发育和一般新陈代谢影响的广泛调查。特别是，肥胖母亲所生的动物将在出生后早期发育期间(从断奶到成年早期)在较长一段时间内被分层置于正常或隔离的环境中。前两个阶段的研究结果和技术方法将被用来指导将要完成的实验。这项拟议的研究将阐明早年生活中的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 BACKGROUNDWhile 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 OBJECTIVESMy 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 EXPERIMENTSExperiments 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 SIGNIFICANCEThe 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