The Development of the Mesoprefrontal Dopaminergic System in Health and Disease.

Midbrain dopaminergic neurons located in the substantia nigra and the ventral tegmental area are the main source of dopamine in the brain. They send out projections to a variety of forebrain structures, including dorsal striatum, nucleus accumbens, and prefrontal cortex (PFC), establishing the nigrostriatal, mesolimbic, and mesoprefrontal pathways, respectively. The dopaminergic input to the PFC is essential for the performance of higher cognitive functions such as working memory, attention, planning, and decision making. The gradual maturation of these cognitive skills during postnatal development correlates with the maturation of PFC local circuits, which undergo a lengthy functional remodeling process during the neonatal and adolescence stage. During this period, the mesoprefrontal dopaminergic innervation also matures: the fibers are rather sparse at prenatal stages and slowly increase in density during postnatal development to finally reach a stable pattern in early adulthood. Despite the prominent role of dopamine in the regulation of PFC function, relatively little is known about how the dopaminergic innervation is established in the PFC, whether and how it influences the maturation of local circuits and how exactly it facilitates cognitive functions in the PFC. In this review, we provide an overview of the development of the mesoprefrontal dopaminergic system in rodents and primates and discuss the role of altered dopaminergic signaling in neuropsychiatric and neurodevelopmental disorders.

The transcription factor BCL11A defines distinct subsets of midbrain dopaminergic neurons.

Midbrain dopaminergic (mDA) neurons are diverse in their projection targets, effect on behavior, and susceptibility to neurodegeneration. Little is known about the molecular mechanisms establishing this diversity during development. We show that the transcription factor BCL11A is expressed in a subset of mDA neurons in the developing and adult murine brain and in a subpopulation of pluripotent-stem-cell-derived human mDA neurons. By combining intersectional labeling and viral-mediated tracing, we demonstrate that Bcl11a-expressing mDA neurons form a highly specific subcircuit within the murine dopaminergic system. In the substantia nigra, the Bcl11a-expressing mDA subset is particularly vulnerable to neurodegeneration upon α-synuclein overexpression or oxidative stress. Inactivation of Bcl11a in murine mDA neurons increases this susceptibility further, alters the distribution of mDA neurons, and results in deficits in skilled motor behavior. In summary, BCL11A defines mDA subpopulations with highly distinctive characteristics and is required for establishing and maintaining their normal physiology.