Establishing functionally segregated dopaminergic circuits

Despite accounting for only ~0.001% of all neurons in the human brain, midbrain dopaminergic neurons control numerous behaviors and are associated with many neuropsychiatric disorders that affect our physical and mental health. Dopaminergic neurons form various anatomically and functionally segregated pathways. Having such defined dopaminergic pathways is key to controlling varied sets of brain functions; therefore, segregated dopaminergic pathways must be properly and uniquely formed during development. How are these segregated pathways established? The three key developmental stages that dopaminergic neurons go through are cell migration, axon guidance, and synapse formation. In each stage, dopaminergic neurons and their processes receive unique molecular cues to guide the formation of specific dopaminergic pathways. Here, we outline the molecular mechanisms underlying the establishment of segregated dopaminergic pathways during each developmental stage in the mouse brain, focusing on the formation of the three major dopaminergic pathways: the nigrostriatal, mesolimbic, and mesocortical pathways. We propose that multiple stage-specific molecular gradients cooperate to establish functionally segregated dopaminergic circuits.