恐惧与负性情绪中多巴胺神经元功能的改变与回路机制

项目名称： 恐惧与负性情绪中多巴胺神经元功能的改变与回路机制

项目编号： No.81501164

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 袁逖飞

作者单位： 南京师范大学

项目金额： 17.5万元

中文摘要： 中脑多巴胺神经元在运动调控和奖赏行为中起到重要作用。近年研究发现中脑多巴胺神经元还参与了大脑对厌恶和惩罚信息的处理，以及对压力应激的反应。我们的前期实验发现，恐惧习得24小时后，小鼠中脑腹侧被盖区(VTA)脑区多巴胺神经元的自发放电模式由规则放电转变为不规则放电，伴随着钙离子激活的小电导钾离子通道(SK) 功能的降低，从而可能改变多巴胺在投射脑区的释放。目前国际上对于多巴胺信号传递在恐惧学习中的作用尚无系统研究，因此把多巴胺神经元投射回路与传统的杏仁核-海马-皮层恐惧记忆回路相关联具有相当的重要性。本项目计划在离体脑片上研究恐惧习得后多巴胺神经元功能改变的细胞分子机制，特别是通过SK通道调控多巴胺神经元兴奋性和突触传递的机制；进一步，本项目将在体检测恐惧学习过程中多巴胺在不同脑区释放的变化，结合光遗传学以控制或逆转这些变化，从而解答多巴胺神经元投射回路参与恐惧学习记忆的回路机制。

中文关键词： 多巴胺；压力；足底电击；钾离子通道；钙离子

英文摘要： Midbrain dopamine neurons are critical for regulating movement and reward-related behaviors. In recent years it has been found that dopamine signaling is also involved in aversion and punishment, as well as responses to stress stimuli. In our preliminary results, we found that the spontaneous firing mode of ventral tegmental area (VTA) dopamine neurons switched from regular mode to bursting mode, 24 hours after fear conditioning. This was accompanied by the functional downregulation of small-conductance calcium activated potassium channel (SK) on dopamine neurons, which could result in -altered dopamine release in target areas. Currently, there were few studies examining the roles of dopamine signaling in fear learning, and it will be important to investigate the potential interaction of dopaminergic pathways with the amygdala-hippocampus-cortex circuit. The present project aims to examine the cellular mechanisms of functional changes in dopamine neurons (especially the SK channel mediated changes in excitability and synaptic integration), following fear learning. In addition, the project will investigate the in vivo dopamine release changes in different brain regions in behaving animals during and after fear learning. Last but not least, the project will employ optogenetics to control the dopamine release in VTA-projecting areas, in order to understand the dopaminergic circuit underlying fear learning and memory formation.

英文关键词： dopamine;stress; footshock; potassium channel;calcium ion