Developmental Stress and Vulnerability to Brain Injury

描述（由申请人提供）：总体假设：发育中的动物暴露于严重的压力下，导致这些动物的大脑对神经元死亡的脆弱性增加，这种情况持续到成年，导致对神经和精神疾病的易感性增加。可能的康复途径包括环境丰富、锻炼和专门饮食。我们正在寻求资金，以进一步开发必要的工具，以合作研究发育压力的影响和成人大脑对神经毒素暴露的脆弱性。在接下来的两年里，我们有三个主要的具体目标：目标1：建立实验室大鼠发育应激模型。将探讨三种模型：(a)产妇剥夺，(b)营养剥夺，和(c)炎症挑战。目的2：获得试点数据，看看发育压力是否会增加大脑对神经毒素的脆弱性。我们将确定发育应激是否会增加准质酸和6-羟多巴胺等神经毒素的应用所造成的损害。尽管其他类型的神经元也将被检查，但我们将特别关注大脑中的多巴胺神经元。损伤的行为和神经生物学指标都将被监测。目标3：进一步发展开普敦大学和斯泰伦博斯大学的研究能力，通过(a)教师和学员参加国际会议，(b)关键人物参加研究方法的具体课程，以及(c)向教师和学员提供其他专业技能的指导，如口头和书面沟通，申请研究基金，以及负责任的研究行为。在2003-2005财年（2004财年和2005财年）完成这些目标后，我们将提交一份完整的研究提案，于2005年7月（2006财年）开始，利用这些工具探索DA神经元细胞死亡和保护的分子和细胞基础。此外，我们开发的方法和试剂将提供给该领域的其他人。

DESCRIPTION (provided by applicant): Overall hypothesis: Exposure of developing animals to severe stress causes an increase in the vulnerability of the brains of those animals to neuronal death, which persists into adulthood, leading to an increase in the susceptibility to neurological and psychiatric disease. Possible routes of rehabilitation include environmental enrichment, exercise, and specialized diets. We are seeking funds to further develop the tools necessary for collaborative studies on the impact of developmental stress and the vulnerability of the adult brain to neurotoxin exposure. Over the next two years, we have three major Specific Aims: Aim 1: To develop models of developmental stress in laboratory rats. Three models will be explored: (a) maternal deprivation, (b) nutritional deprivation, and (c) an inflammatory challenge. Aim 2: To obtain pilot data to see if developmental stress increases the vulnerability of the brain to neurotoxins. We will determine whether developmental stress increases the damage done by application of such neurotoxins as quisqualic acid and 6-hydroxydopamine. Special attention will be given to dopamine neurons in the brain, although other types of neurons also will be examined. Both behavioral and neurobiological indices of damage will be monitored. Aim 3: To further develop the research capacity of the University of Cape Town and the University of Stellenbosch through (a) attendance by faculty and trainees at international meetings, (b) attendance of key individuals at specific courses on research methodology, and (c) provision of instruction to faculty and trainees other professional skills such as oral and written communication, applying for research funds, and responsible conduct of research. Having accomplished these aims in 2003-2005 (FY 04 and FY05), we will submit a full proposal for research to begin in July 2005 (FY 06) that utilizes these tools to explore the molecular and cellular basis of DA neuron cell death and protection. Moreover, the methods and reagents that we develop will be made available to others in the field.