Huang Limeng, Chang Yuanyu, Yang Zhipeng, Lynch Wendy J, Venton B Jill
Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22903, USA.
Department of Chemistry, University of Virginia, Charlottesville, VA 22904, USA.
Sci Adv. 2025 May 30;11(22):eadx6367. doi: 10.1126/sciadv.adx6367. Epub 2025 May 28.
Dopaminergic neurons influence diverse behaviors with varied firing patterns, yet the precise mechanisms remain unclear. We introduce a multiplexed genetically encoded sensor-based imaging and voltammetry method to simultaneously record synaptic, perisynaptic, and extrasynaptic dopaminergic transmission at mouse central neurons. Using this method alongside a genetically encoded sensor-based image analysis program, we found that heterogeneous dopaminergic firing patterns create various transmission modes, encoding frequency, number, and synchrony of firing pulses using neurotransmitter quantity, releasing synapse count, and synaptic and/or volume transmission. Under both tonic and low-frequency phasic activities, transporters effectively reuptake dopamine at perisynaptic sites, confining dopamine within synaptic clefts to mediate synaptic transmission. In contrast, under high-frequency, particularly synchronized firing activity or transporter inhibition, released dopamine may overwhelm transporters, escaping from synaptic clefts via one to three outlet channels, triggering volume transmission. Our study illuminates a collaborative mechanism of synaptic enclosures, properties, and transporters that defines the coding principles of activity pattern-dependent dopaminergic transmission modes.
多巴胺能神经元通过不同的放电模式影响多种行为，但其确切机制仍不清楚。我们引入了一种基于多重基因编码传感器的成像和伏安法，以同时记录小鼠中枢神经元突触、突触周围和突触外的多巴胺能传递。使用这种方法并结合基于基因编码传感器的图像分析程序，我们发现异质性多巴胺能放电模式产生了各种传递模式，利用神经递质数量、释放突触计数以及突触和/或容积传递来编码放电脉冲的频率、数量和同步性。在紧张性和低频相位活动下，转运体在突触周围位点有效地重新摄取多巴胺，将多巴胺限制在突触间隙内以介导突触传递。相比之下，在高频，特别是同步放电活动或转运体抑制的情况下，释放的多巴胺可能会使转运体不堪重负，通过一到三个出口通道从突触间隙逸出，触发容积传递。我们的研究阐明了突触包被、特性和转运体的协同机制，该机制定义了依赖活动模式的多巴胺能传递模式的编码原则。
