Human pluripotent stem cell?derived A10 dopaminergic neurons specifically integrate into host circuits and relieve depression

Ventral Tegmental Area (VTA) dopaminergic neuron group (A10) one of the important subtype of midbrain dopaminergic (mDA) neurons plays a crucial role in regulation of mainly brain functions and has been related into various psychiatric disorders. Despite the great achievements in generation of mDA neurons from pluripotent stem cells, the subtype-specific mDA differentiation especially A10 group still remains challenging. Here, we report an efficient differentiation paradigm for hPSCs to generate specific A10 subtype mDA neurons. The differentiation paradigm revealed that post-mitotic patterning by NOTCH inhibitor, GDNF and AA induced the specification of A10 subtype. The hPSC-derived neurons exhibited characteristic of A10 subtype from molecular expression, electrophysiological properties and neural innervation. Considering the dysfunction of A10 mDA neurons has been implicated in depression, we detected that specific activation of the grafted-A10-like-mDA-neurons induced anxiolytic and antidepressant-like phenotypes on the transplanted mice. Our approach provides deep insights into the subtype specification of mDA neurons and offers a promising clinical application of these derived cells in cell transplantation therapy for disorders related to A10 mDA neurons.