项目名称： 青少期早期社会应激对抑郁样行为和前额叶GABA能系统的影响及其关系研究

项目编号： No.81471122

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 王玮文

作者单位： 中国科学院心理研究所

项目金额： 70万元

中文摘要： 青少期社会应激是导致成年抑郁症发生发展的重要风险因素，但上述过程涉及的神经和分子机理目前并不清楚。采用一种拟人类社会挫败应激模型，前期研究发现青少期早期是社会应激导致以社交行为减少和前额叶执行功能障碍为特征的抑郁样行为持久改变的关键阶段，同时伴随前额叶GABA能活动改变。 在此基础上，本项目将深入研究抑郁样行为发生发展和抗抑郁治疗过程中前额叶GABA能作用机制。 采用转基因小鼠，综合运用药物学，行为学，分子生物学，神经化学和电生理等方法，研究青少期早期社会应激对行为及前额叶GABA能神经元形态和功能发育的影响及其相互关系，抗抑郁药物是否通过调节前额叶GABA能系统改善应激诱导的抑郁样行为，进一步直接通过前额叶GABA能药物拮抗应激诱导的抑郁样行为，从而为确立抑郁症高风险人群早期识别的行为和生物学指标，建立以GABA能调控为基础的新型抗抑郁分子靶标提供实验依据

中文关键词： 心理应激；脑机制；动物模型；神经递质

英文摘要： Adolescent social stress is an important risk factor for the development and onset of major depression during adulthood. However, the underlying neural and molecular mechanisms remain to be illustrated. Using a social defeat stress model, we found in the previous study that early adolescence (EA, PND28-37) was a critical time window during which social stress induced long-term changes in depressive behaviors characterized by the reduced social interaction and impaired cortically-mediated cognitive function, as well as in GABAergic activities of prefrontal cortex (PFC). Based on these findings, we will combine with brain region specific pharmacological, electrophysiological, molecular biological techniques such as western blotting, PCR, immunohistochemistry, behavioral and other methods to investigate the roles of PFC GABAergic system in the depressive behavior caused by EA social stress. This project aimed to determine whether developmental dysfunction of PFC GABAergic system induced by EA social stress is involved in the onset and development of depressive behavior. Moreover, the role of PFC GABAergic target molecules in mediating the negative effects of EA social stress will be further determined by using transgenic mice. We also determined the effects of direct PFC GABAergic pharmaceutical manipulation on depressive behavior induced by EA social stress. The proposed project will help to reveal the neurobiological mechanisms of EA social stress-induced social behavior, emotional and cognitive impairment, and a better understanding of GABAergic actions and their alteration by early stress will lead to improved antidepressant treatment strategies.

英文关键词： psychological stress;brain mechanism;animal model;neurotransmitter