Developmental Stress and Vulnerability to Brain Injury

描述(申请人提供)：总体假设：发育中的动物暴露在严重的压力下会增加这些动物的大脑对神经元死亡的脆弱性，这种情况会持续到成年，导致神经和精神疾病的易感性增加。可能的康复途径包括丰富环境、锻炼和专门的饮食。我们正在寻求资金，以进一步开发合作研究所需的工具，以研究发育应激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：建立实验大鼠的发育应激模型。将探索三种模式：(A)母性剥夺，(B)营养剥夺，和(C)炎症性挑战。目的2：获得试验数据，以了解发育应激是否会增加大脑对神经毒素的易感性。我们将确定发育应激是否会增加应用奎师酸和6-羟基多巴胺等神经毒素造成的损害。将特别关注大脑中的多巴胺神经元，尽管也将检查其他类型的神经元。将对损害的行为和神经生物学指标进行监测。目标3：通过以下方式进一步发展开普敦大学和斯泰伦博斯大学的研究能力：(A)教员和受训人员出席国际会议；(B)关键人员参加关于研究方法的具体课程；以及(C)向教员和受训人员提供其他专业技能的指导，如口头和书面交流、申请研究资金和负责任地进行研究。在2003-2005财年(2004财年和2005财年)实现了这些目标后，我们将提交一份完整的研究提案，将于2005年7月(06财年)开始，利用这些工具来探索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向该领域的其他人提供。

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.