In vitro modelling of dopamine pathways in fused organoids.

Our group is interested in understanding human brain development in health and disease. A major challenge in the effort to study the biology and disease of human tissues is material accessibility. To overcome this obstacle, our group developed new technology by generating a 3D model system called brain organoids. This model system is derived from human stem cells and can recapitulate human-specific aspects of brain development. Using organoids permits us to model disorders which affect the nervous system and consequently offers the potential to fundamentally change disease research. In this project, we aim to bring brain organoid technology to the next level by instating neurological diseases in the lab, to understand them with the ultimate purpose to drive the generation of novel therapies. We hypothesize that the cross talk between cells of different brain regions can be studied in our model system making it a valuable tool to investigate the initial stages of a specific brain disorder before this becomes a recognizable pathology. To achieve this, we will generate organoids fusing distinct brain regions that are associated with specific brain circuits in a developmentally representative way. This will allow us to study neurological interactions between these regions in a petridish, for the first time. The new organoid model enables us to study disease related aspects of a neurological circuit, which is particularly targeted by addictive drugs and pharmaceutical compounds. The proposed project will recreate neurological disease pathology in the lab going far beyond existing models and establishing an innovative human disease model that can refine and complement existing research into these neurological disorders.

Recreating the Human Brain's Dopamine System in the Lab Animal models have historically provided foundational insights into neuroscience; however, developing precise treatments for human neurological disorders requires establishing human-specific models to reduce and ultimately replace their use. The human brain relies on a chemical messenger called dopamine to control our movements and process feelings of reward. When this system breaks down, it can lead to severe movement disorders like Parkinson's disease or contribute to psychiatric conditions and addiction. Because animal brains develop differently and much faster than human brains, certain aspects of human diseases-like the specific loss of dopamine in Parkinson's-cannot be completely or accurately recreated in animals. To bridge this gap, our research team has successfully built living, three-dimensional models of the human brain's reward and movement system to study neurological diseases without relying on animal testing. We utilised stem cells to grow miniaturised human brain tissues, known as "organoids", specifically focusing on three distinct regions: the midbrain (where dopamine is produced), the striatum, and the cortex. By placing these tissues next to each other in a custom-designed mould, they naturally fused together into a single, connected structure. Remarkably, the dopamine-producing cells in the midbrain grew long, functional connections that reached out and wired into the other brain regions, exactly as they do in a real developing human brain. We confirmed that these lab-grown networks were electrically active and fully capable of releasing dopamine. This technological leap has profound implications for medicine, society, and research ethics. First, it advances the development of Parkinson's treatments. By injecting healthy dopamine-producing stem cells into our model, we observed them surviving, maturing, and integrating into the existing brain network, demonstrating that this system is an excellent testing ground for promising stem cell replacement therapies. Second, it offers unprecedented insights into addiction. When we exposed these brain models to cocaine, we discovered that chronic exposure caused long-lasting changes to the brain's physical connections and electrical activity, which persisted even after the drug was removed. Most importantly, this human-specific model provides a powerful, ethical alternative to animal testing. It directly supports the "3Rs" initiative (Replacement, Reduction, and Refinement) by providing a more accurate and highly effective platform for testing pharmaceutical drugs and exploring brain diseases in a human context.