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

## TL;DR

This study explores how different excitatory inputs cause synchronized bursts in dopamine neurons, which are important for reward processing and addiction.

## Contribution

The study reveals how NMDA and muscarinic receptor activation together induce synchronized dopamine neuron bursts through calcium accumulation.

## Key findings

- Co-activation of NMDA and muscarinic receptors enhances burst synchronization in dopamine neurons.
- Inhibitory couplings and D2-GIRK currents contribute to inducing synchronous bursts.
- Synchronous bursts depend on intracellular Ca2+ accumulation via NMDA and CAN currents.

## Abstract

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 Ca2+ accumulation. NMDA receptors directly supply Ca2+, while muscarinic receptors indirectly provide Ca2+ 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 Ca2+ 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.