"The dopaminergic system is vital for the control of both motor control (nigrostriatal pathway, A9 dopaminergic neurons), and reward (mesocorticolimbic pathway, A10 dopaminergic neurons). Both pathways are associated with different types of diseases: the nigrostriatal pathway is most commonly associated with Parkinson’s disease, whereas the mesocorticolimbic pathway becomes dysregulated in addiction. During development, dopaminergic neurons emerge from the floor plate of the ventral midbrain, from where they project to the striatum (A9 and A10) and cortex (A10).
Brain organoids are a powerful iPSC or hES derived system to model both human-specific neurodevelopmental as well as neuropathological aspects which to date could not reliably be studied due to the lack of appropriate model systems.
To model the above mentioned disorders on the circuit level, we have developed an assembloid culture model recapitulating the dopaminergic system. We confirm the faithful recapitulation of development and differentiation of the appropriate cell types by both antibody staining and single cell RNA sequencing. Using a recently published 3D IHC and tissue clearing protocol, we could demonstrate that dopaminergic neurons innervate the striatal and cortical part of the assembloids and mature structurally over time. Currently, we perform experiments to investigate maturation from structural to functional synapses of these dopaminergic long range projections, with the aim to study dysregulation of the dopaminergic system and its effects in striatal and cortical neurons.
Using our assembloid culture model of the dopaminergic system will provide further insights into both the development of the dopaminergic system, but also in diseases associated with dopaminergic neurons, such as addiction and Parkinson’s disease."