Reconstruction of the human nigrostriatal pathway in vitro reveals target-dependent dopamine neuron maturation

How this circuit assembles during development and how it degenerates under pathological conditions remains poorly understood in a human context. Additionally, in vitro models capturing its long-range connectivity and spatial organization have been lacking.

Here, we introduce the connectoid, a compartmentalized, human stem cell-based model of the nigrostriatal pathway that integrates vMB and striatal organoids within a custom-engineered microfluidic device, confining cell bodies while guiding axonal growth, mimicking the in vivo topography. Functional connectivity was confirmed by retrograde rabies tracing, and optogenetic and pharmacological stimulation, while 6-hydroxydopamine-induced selective dopaminergic degeneration recapitulated PD pathology.