Unlocking the Brain’s Reward Pathway: Revealing the Mysteries of the Dopaminergic System

In a groundbreaking development, scientists have introduced a revolutionary organoid model of the dopaminergic system, which has unveiled significant insights into two crucial areas of research: Parkinson’s disease and the enduring effects of cocaine on the brain. This innovative model holds promise for advancing treatments for Parkinson’s disease and deepening our understanding of the long-lasting consequences of drug addiction.

A Breakthrough Organoid Model Replicating Essential Neural Networks

A novel organoid model of the dopaminergic system has illuminated the intricate workings of this neural network and its potential implications for Parkinson’s disease. The brainchild of a team led by Jürgen Knoblich at the Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences, this model faithfully replicates the structure, connectivity, and functionality of the dopaminergic system. The study, published in Nature Methods on December 5, also unveils the persistent effects of chronic cocaine exposure on the dopaminergic circuit, even after the withdrawal.

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Understanding the Role of Dopamine in Reward and Motor Control

Dopamine, the neurotransmitter responsible for sensations of reward and fine motor control, is the star player in our brain’s dopaminergic reward pathway. However, as critical as dopamine is, there remain enigmatic aspects of this system, and a cure for Parkinson’s disease has remained elusive. In their recent research, Jürgen Knoblich’s team at IMBA has pioneered an organoid model of the dopaminergic system that not only faithfully reproduces its anatomical features and neural projections but also emulates its functionality.

Shedding Light on Parkinson’s Disease Through the Model

The hallmark symptoms of Parkinson’s disease, such as tremors and loss of motor control, stem from the degeneration of dopaminergic neurons responsible for dopamine release. As these neurons perish, fine motor control deteriorates, leading to tremors and uncontrollable movements. While the significance of dopaminergic neuron loss in Parkinson’s disease is well-established, the mechanisms behind this phenomenon and potential strategies for prevention or repair remain elusive.

Animal models have offered some insights into Parkinson’s disease, but they fall short in replicating key features of the condition. Additionally, the human brain possesses a more intricate network of dopaminergic neurons with distinct wiring patterns, projecting to the striatum and cortex. To bridge this gap, the team aimed to create an in vitro model that captures these human-specific features within brain organoids.

“Brain organoids are three-dimensional structures derived from human stem cells, providing a platform to explore both human brain development and function,” explains Daniel Reumann, the paper’s first author, and a former PhD student in Jürgen Knoblich’s lab. The team initially developed organoid models of the ventral midbrain, striatum, and cortex—regions interconnected by dopaminergic neurons—and devised a method to fuse these organoids together. Remarkably, the resulting system exhibited a high level of dopaminergic innervation and the formation of synapses between dopaminergic neurons and neurons in the striatum and cortex.

Developing and Testing the Organoid Model

To assess the functionality of these neurons and synapses, the researchers collaborated with Cedric Bardy’s group at SAHMRI and Flinders University, Australia. They investigated whether neurons within this system could form functional neural networks. Indeed, when they stimulated the midbrain, which houses dopaminergic neurons, the neurons in the striatum and cortex responded to the stimulation. In essence, they successfully replicated the dopaminergic circuit in vitro, with cells not only wiring correctly but also functioning harmoniously.

Potential Applications in Parkinson’s Disease Therapy

The organoid model of the dopaminergic system presents a valuable tool for enhancing cell therapies aimed at treating Parkinson’s disease. Initial clinical studies involved injecting precursor cells of dopaminergic neurons into the striatum to compensate for the loss of natural innervation. However, these studies yielded mixed results. In collaboration with Malin Parmar’s lab at Lund University, Sweden, the team demonstrated that dopaminergic progenitor cells injected into the dopaminergic organoid model matured into neurons and extended neuronal projections within the organoid.

Jürgen Knoblich, the corresponding author of the study, elaborates, “Our organoid system could serve as a platform to test conditions for cell therapies, allowing us to observe how precursor cells behave in a three-dimensional human environment. This facilitates the study of more efficient differentiation of progenitors and provides a platform for investigating the recruitment of dopaminergic axons to target regions, all in a high-throughput manner.”

Insights Into the Reward System

Dopaminergic neurons are activated during moments of reward, forming the foundation of our brain’s reward pathway. However, what occurs when dopaminergic signaling is disrupted, as in cases of addiction? To delve into this question, the researchers turned to a well-known dopamine reuptake inhibitor—cocaine. Chronic exposure of the organoids to cocaine over 80 days led to functional, morphological, and transcriptional changes in the dopaminergic circuit. Strikingly, these alterations persisted even when cocaine exposure ceased 25 days before the experiment’s conclusion, simulating withdrawal conditions.

“Even nearly a month after discontinuing cocaine exposure, the effects on the dopaminergic circuit remained observable, enabling us to investigate the long-term consequences of dopaminergic overstimulation in a human-specific in vitro system,” concludes Daniel Reumann.

This research, titled “In vitro modeling of the human dopaminergic system using spatially arranged ventral midbrain–striatum–cortex assembloids,” was published on December 5, 2023, in Nature Methods, and it offers promising avenues for understanding and treating neurological disorders and addiction.

Funding: This study received support from the Austrian Academy of Sciences, Austrian Federal Ministry of Education, Science and Research, City of Vienna, H2020 European Research Council, Austrian Science Fund, Austrian Lotteries, New York Stem Cell Foundation, H2020 European Research Council, Swedish Research Council, Rosetrees Trust, UK Regenerative Medicine Platform Hub, Michael J. Fox Foundation for Parkinson’s Research, Hospital Research Foundation, Shake it up Foundation, Neurosurgical Research Foundation, Australian Research Council.

Reference: “In vitro modeling of the human dopaminergic system using spatially arranged ventral midbrain–striatum–cortex assembloids,” published on December 5, 2023, in Nature Methods. DOI: 10.1038/s41592-023-02080-x.

Frequently Asked Questions (FAQs) about Dopaminergic System Study

More about Dopaminergic System Study

• Nature Methods: The journal where the study “In vitro modeling of the human dopaminergic system using spatially arranged ventral midbrain–striatum–cortex assembloids” was published.
• Austrian Academy of Sciences: A supporting institution for the research.
• New York Stem Cell Foundation: A contributor to the study’s funding.
• Michael J. Fox Foundation for Parkinson’s Research: A foundation providing support for Parkinson’s disease research.
• Swedish Research Council: A funding source for the study.
• Shake it up Foundation: A foundation involved in Parkinson’s disease research.
• Australian Research Council: A contributor to the research funding.
• Institute of Molecular Biotechnology (IMBA): The institution where the research was conducted.
• Lund University, Sweden: Collaborating institution for the study.