Development Stress, Exercise, and Vulnerability to Neuronal Injury

描述（由申请人提供）：代表匹兹堡大学和南非两所机构，开普敦大学和斯泰伦博斯大学的研究人员正在寻求资金，作为我们机构之间整体努力的一部分，以检验与环境对大脑和行为的影响有关的特定假设，并帮助在开普敦的学术界建立一个卓越的神经科学和专业技能培训区域中心。他们的假设是，将发育中的动物暴露在严重的压力下会对大脑产生重大的有害影响，并增加其对神经元死亡的脆弱性，但这可以通过锻炼干预计划来抵消。具体目标有五个：四个是研究目标，一个是一套能力建设目标。研究目标：目的1 -通过蛋白质组学筛选，研究发育应激源（母亲分离）对与大脑易损性相关的几个变量的影响，包括(a)下丘脑-垂体-肾上腺（HPA）轴，(b)线粒体功能，以及(c)特定类别蛋白质（神经营养因子）的改变。目的2 -此外，将仔细检查中央多巴胺神经元的状态。目的3 -检查运动（自主跑步）对这些变量的影响，然后确定母亲分离的影响是否可以通过后来的运动来抵消。目的4：以6-羟多巴胺为应激源，研究母体分离对多巴胺能神经元氧化应激易感性的影响，并确定母体分离引起的易感性增加是否可以通过运动来抵消。目标5 -能力建设目标：通过教师和学员参加国际会议，参与研究方法的具体课程，以及提供其他专业技能的指导，进一步发展开普敦大学和斯泰伦博斯大学以及西开普省其他机构的研究能力，如口头和书面沟通，申请研究基金，以及负责任的研究行为。该研究小组认为，他们的研究项目将为更普遍地了解表观遗传对行为和大脑功能的影响提供重要的见解，并为促进南部非洲两个关键机构的研究能力提供背景。

DESCRIPTION (provided by applicant): Researchers representing the University of Pittsburgh and two institutions in South Africa, the University of Cape Town and the University of Stellenbosch are seeking funds as part of an overall effort between our institutions to examine a specific hypothesis pertaining to the impact of environment on brain and behavior and also to help create within the academic community in Cape Town a regional center of excellence in neuroscience and in professional skill training. Their hypothesis is that exposure of developing animals to severe stress will have a significant detrimental effect on brain and increase its vulnerability to neuronal death, but that this can be offset through an exercise intervention program. There are five specific aims: four are research aims and one is a set of capacity building objectives. Research objectives: Aim 1 - To examine the impact of a developmental stressor (maternal separation) on several variables related to the vulnerability of the brain, including (a) the hypothalamic-pituitary-adrenal (HPA) axis, (b) mitochondrial function, and (c) alterations in a specific class of proteins (neurotrophic factors) by using a proteomic screen. Aim 2 - In addition, the state of central dopamine neurons will be carefully examined. Aim 3 - To examine the effects of exercise (voluntary running) on these same variables, and then to determine whether the effect of maternal separation can be offset by later exposure to exercise. Aim 4 -To examine the effects of maternal separation on the vulnerability of dopaminergic neurons to oxidative stress using 6- hydroxydopamine as the stressor, then determine whether any increase in vulnerability caused by the maternal separation can be offset by exercise. Aim 5 - Capacity building objectives: To further develop the research capacity of the Universities of Cape Town and Stellenbosch as well as other institutions in the Western Cape through attendance by faculty and trainees at international meetings, participation in specific courses on research methodology, and provision of instruction in other professional skills, such as oral and written communication, applying for research funds, and responsible conduct of research. The research team believes that their research project will provide important insights into epigenetic influences on behavior and brain function more generally, and also serve as a context for promoting the research capacity of two key institutions in southern Africa.