恐惧与负性情绪中多巴胺神经元功能的改变与回路机制

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.

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。

本项目旨在揭示恐惧与负性情绪中多巴胺神经元功能的改变与回路机制，重点研究了不同强度/程度的恐惧学习中，中脑腹侧被盖区多巴胺神经元的放电模式及离子通道机制的变化。项目资助成果已在Molecular Psychiatry（本项目排名第一资助）, Biological Psychiatry（本项目排名第一资助）, Nature Neuroscience等期刊上发表，部分成果正在投稿中。项目经费严格按照预算执行，支付率超过95%。已培养硕士生四名，博士生一名，博士后一名出站、两名在站。项目的研究结论有望为开发应激疾病的相关药物提供理论基础。