Glial–Dopamine Crosstalk: Astrocytic and Microglial Gatekeepers of Neuroinflammation, Plasticity, and Motivation

Dopamine signaling has long been framed through a neuron-centric lens, yet mounting evidence reveals that glial cells (astrocytes and microglia) serve as indispensable gatekeepers of dopaminergic tone, synaptic plasticity, and neuroimmune balance. Recent single-cell, spatial, and optical imaging studies have redefined dopamine circuits as multicellular ecosystems in which glial receptors, transporters, and gliotransmitters dynamically sculpt neuromodulation and behavior. Astrocytes fine-tune dopamine clearance, glutamate buffering, and metabolic coupling, while microglia integrate immune and stress cues recalibrate dopaminergic signaling across striatal and cortical circuits. Their bidirectional interactions, both glia–glia and glia–neuron, mediate resilience or vulnerability in contexts ranging from motivation and stress adaptation to Parkinson’s disease, depression, and post-viral fatigue syndromes. This review synthesizes emerging evidence that glial–dopamine crosstalk is a systems-level regulator of neuroinflammation and plasticity, bridging cellular metabolism, immune tone, and behavioral output. By integrating multi-omics, in vivo imaging, and computational models, we propose a translational framework for targeting astrocytic and microglial states to restore dopaminergic homeostasis. Understanding and manipulating these non-neuronal interfaces may open the next frontier in precision neuropsychiatry and neurodegeneration therapeutics.