Midbrain dopamine (mDA) neurons can be replaced in patients with Parkinson’s disease (PD) in order to provide long-term improvement in motor functions. The limited capacity for long-distance axonal growth in the adult brain means that cells are transplanted ectopically, into the striatal target. As a consequence, several mDA pathways are not re-instated, which may underlie the incomplete restoration of motor function in patients. Here, we show that viral delivery of GDNF to the striatum, in conjunction with homotopic transplantation of human pluripotent stem-cell-derived mDA neurons, recapitulates brain-wide mDA target innervation. The grafts provided re-instatement of striatal dopamine levels and correction of motor function and also connectivity with additional mDA target nuclei not well innervated by ectopic grafts. These results demonstrate the remarkable capacity for achieving functional and anatomically precise reconstruction of long-distance circuitry in the adult brain by matching appropriate growth-factor signaling to grafting of specific cell types.

帕金森病 (PD) 患者可以更换中脑多巴胺 (mDA) 神经元，以长期改善运动功能。成人大脑中长距离轴突生长的能力有限，这意味着细胞被异位移植到纹状体目标中。因此，一些 mDA 通路没有恢复，这可能是患者运动功能恢复不完全的基础。在这里，我们展示了将 GDNF 病毒传递到纹状体，连同人类多能干细胞衍生的 mDA 神经元的同位移植，概括了全脑 mDA 目标神经支配。移植物提供了纹状体多巴胺水平的恢复和运动功能的校正以及与未被异位移植物很好地支配的额外mDA靶核的连接。