Human stem cell-derived A10 dopaminergic neurons specifically integrate into mouse circuits and improve depression-like behaviors

Abstract

A10 dopaminergic neurons located in the ventral tegmental area play central roles in reward-related and goal-directed behaviors and are proposed to be target cells for treatment of various psychiatric disorders, including depression. Here, we report an efficient differentiation method to generate A10-like midbrain dopaminergic (mDA) neurons from human pluripotent stem cells (hPSCs) and found that post-mitotic patterning by Notch inhibitor, glial cell line-derived neurotrophic factor (GDNF), and ascorbic acid (AA) induced A10 subtype specification. These hPSC-derived mDA neurons exhibited characteristics of the A10 subtype, including gene expression profiles and electrophysiological properties. Moreover, grafted A10-like mDA neurons specifically project to their endogenous target brain regions and induce the anxiolytic phenotype in normal mice or antidepressant-like phenotypes in depression model mice. These results indicate that grafted A10-like mDA neurons can reconstruct specific circuits and functionally restore impaired circuits, highlighting the promising application of hPSC-derived neuron subtypes in the treatment of neuropsychiatric disorders.

Keywords: A10 dopaminergic neurons; cell therapy; circuit reconstruction; depression; human pluripotent stem cells; major depressive disorder; neural differentiation.