Modeling long-range human nigrostriatal connectivity in vitro reveals striatal target-dependent maturation of dopamine neurons.

Target engagement with spatially separated striatal neurons in a human nigrostriatal microfluidic organoid model promotes maturation of human dopaminergic neurons and activates neurotransmitter secretion programs.

• Why it matters: The assembly of long-range nigrostriatal connectivity during human development is poorly understood, and in vitro systems that preserve spatial topography are lacking.
• What they did: Ventral midbrain and dorsolateral striatal organoids were integrated in a custom microfluidic device to guide axons, with connectivity validated using retrograde rabies tracing plus optogenetic and pharmacological stimulation.
• The result: Single-nucleus transcriptomics showed that axonal target engagement is linked to dopaminergic maturation and transcriptional programs tied to neurotransmitter secretion, enabling modeling of Parkinson’s disease features.

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