Uncovering the Enduring Effects of Chronic Cocaine Exposure on the Dopaminergic Circuit

Wednesday - December 6 2023, 10:04 UTC - 11 months ago

The group of Jürgen Knoblich at IMBA developed an organoid model of the dopaminergic system that replicates its structure, connectivity, and functionality. The study revealed the enduring effects of chronic cocaine exposure on the dopaminergic circuit, even after withdrawal. It also enabled an understanding of how dopaminergic neurons are lost in Parkinson's Disease, and how we can prevent or repair the dopaminergic system.

A new organoid model of the dopaminergic system sheds light on its intricate functionality and potential implications for Parkinson’s disease. The model, developed by the group of Jürgen Knoblich at the Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences, replicates the dopaminergic system’s structure, connectivity, and functionality. The study, published on December 5 in Nature Methods, also uncovers the enduring effects of chronic cocaine exposure on the dopaminergic circuit, even after withdrawal.

A completed run, the early morning hit of caffeine, the smell of cookies in the oven — these rewarding moments are all due to a hit of the neurotransmitter dopamine, released by neurons in a neural network in our brain, called the “dopaminergic reward pathway.” .

Apart from mediating the feeling of “reward,” dopaminergic neurons also play a crucial role in fine motor control, which is lost in diseases such as Parkinson’s disease. Despite dopamine’s importance, key features of the system are not yet understood, and no cure for Parkinson’s disease exists. In their new study, the group of Jürgen Knoblich at IMBA developed an organoid model of the dopaminergic system, which not only recapitulates the system’s morphology and nerve projections, but also its functionality.

Tremor and a loss of motor control are characteristic symptoms of Parkinson’s disease and are due to a loss of neurons that release the neurotransmitter dopamine, called 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 crucial in the development of Parkinson’s disease, the mechanisms how this happens, and how we can prevent — or even repair — the dopaminergic system is not yet understood.

Animal models for Parkinson’s disease have provided some insight into Parkinson’s disease, however as rodents do not naturally develop Parkinson’s disease, animal studies proved unsatisfactory in recapitulating hallmark features of the disease. In addition, 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 explains further.

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 and form connections with the striatum and cortex organoids. The team then tested the functionality of the fused organoid system by adding L-DOPA, a precursor of dopamine, and measuring its release from the diffusion of organoids.