The astonishing new organoid model of the dopaminergic system developed by the group of Jürgen Knoblich at the Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences is shedding light on the complex functionality and potential implications for Parkinson’s disease. This groundbreaking study, published on December 5 in Nature Methods, unveils the enduring effects of chronic cocaine exposure on the dopaminergic circuit, even after withdrawal.
From the satisfying effects of a morning caffeine boost to the aroma of fresh-baked cookies, these rewarding moments are all thanks to a hit of the neurotransmitter dopamine released by neurons in our brain’s “dopaminergic reward pathway.” Beyond providing feelings of “reward,” dopaminergic neurons also play a crucial role in fine motor control, which is diminished in diseases such as Parkinson’s. Despite the importance of dopamine, several key features of the system remain unknown, and a cure for Parkinson’s disease still eludes us. In their new study, the group of Jürgen Knoblich at IMBA developed an organoid model of the dopaminergic system that not only replicates the system’s structure and nerve projections, but also its functionality.
A model of Parkinson’s disease is created
Tremor and a loss of motor control are characteristic symptoms of Parkinson’s disease, stemming from the loss of neurons that release dopamine, known as dopaminergic neurons. When dopaminergic neurons die, fine motor control is lost, and patients develop tremors and uncontrollable movements. Although the loss of dopaminergic neurons is critical in the development of Parkinson’s disease, the mechanisms behind this process, and how we can prevent — or even repair — the dopaminergic system are not yet understood.
Animal models have provided some insight into Parkinson’s disease, however, they do not naturally develop Parkinson’s disease, making it challenging to replicate hallmark features of the disease. Moreover, the human brain contains many more dopaminergic neurons, which also wire up differently within the human brain, sending projections to the striatum and the cortex. “We sought to develop an in vitro model that recapitulates these human features in so-called brain organoids,” explains Daniel Reumann, previously a PhD student in the lab of Jürgen Knoblich at IMBA, and first author of the paper. “Brain organoids are human stem cell-derived three-dimensional structures, which can be used to understand both human brain development, as well as function,” he further explains.
The team first developed organoid models of the so-called ventral midbrain, striatum, and cortex — the regions linked by neurons in the dopaminergic system — and then developed a method for fusing these organoids together. As happens in the human brain, the dopaminergic neurons of the midbrain organoid send out projections to the striatum and the cortex organoids. “Somewhat surprisingly, we observed a high level of dopaminergic innervation, as well as synapses forming between dopaminergic neurons and neurons in the striatum and cortex,” Reumann recalls.