Coding principles of dopaminergic transmission modes

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.