Dynamics of synchronous bursts in functionally coupled midbrain dopamine neurons driven by diverse excitatory inputs

Phasic dopamine (DA) release is related to reward processing and addiction. The prevailing view posits that this DA release originates from synchronous bursts of DA neuron groups, rather than individual neuron bursts. However, the mechanism by which diverse excitatory inputs synergistically induce synchronous bursts remains unclear. In biophysically realistic networks with complex structure, the responses of functionally connected DA neurons to various excitatory inputs are examined. Activating NMDA receptors alone results in asynchronous bursts, while co-activating with muscarinic receptors significantly enhances burst synchronization. The synchronization trends display qualitatively similar characteristics across all tested topological networks, indicating that these synchronous bursts are universal. Research on a dual-node network reveals that inhibitory couplings, specifically the inward rectifying K + currents activated by G protein linked to D2 receptors (D2-GIRK currents), participate in inducing synchronous bursts. A detailed analysis of decoupled DA neurons shows that these synchronous bursts are induced by transitioning bursts from integrator-like to resonator-like behavior, a process dependent on sufficient intracellular Ca 2+ accumulation. NMDA receptors directly supply Ca 2+ , while muscarinic receptors indirectly provide Ca 2+ by enhancing calcium-activated, nonspecific cation (CAN) current, causing depolarization, and activating L-type calcium channels. Therefore, simultaneous activation of both receptors is more effective in achieving the required Ca 2+ accumulation than activating either receptor alone. These findings elucidate the mechanism by which diverse excitatory inputs work together to induce synchronous bursts, providing new insights into their inductions and regulations, potentially advancing our understanding of the physiological diversity of phasic DA releases and their addictive abnormalities.