The reward system is at the heart of human behavior – from eating delicious food to falling in love. Researchers from EU projects have sought detailed information on the molecular basis of zebra fish, which is why many neuropsychiatric diseases develop.
The forebrain dopaminergic (DA) system has many roles in brain function, including working memory, and is a key determinant of the development of Parkinson’s disease. It is also important under some neuropsychological conditions, and drugs that are commonly abused, such as alcohol, exert influence through this so-called reward DA system.
Using the emerging technologies of in vivo imaging, ontogenetic and transgenic technology, the FISHDOPA team studied the complex DA neural network of the famous model zebra fish.
Genes involved in learning reward behavior. Prof. Petronella Kettunen, FISHDOPA Project Coordinator, outlines how researchers analyze brain regions and signaling pathways involved in the initiation of DA systems and lead to altered behavioral patterns. “The results show that the DA neuron population in both forebrain regions is consistently activated, called the dorsal (Vd) and ventral (Vv) portions of the ventral telencephalon,” explains Professor Ketunun.
Using a laser capture microscope, they then collect mRNA samples from the Vd and Vv regions, and after sequencing for the next generation, the team can see which genes were expressed during the learning reward behavior. “Our preliminary bioinformatics analysis showed that although Vd showed up-regulated genes associated with dopamine signaling prior to reward learning, Vv showed up-regulation of genes associated with post-learning learning,” Professor Kettunen outlined. This clearly shows that Vd is important for reward processing and Vv for reward learning.
The significance of FISHDOPA results for learning and addiction. FISHDOPA has developed a behavioral paradigm for studying rewards and learning to understand the molecular mechanisms behind this behavior. In addition, using a laser capture microscope to cut and sample the cerebellar region from the sliced adult zebrafish brain, extracting mRNA and performing next-generation sequencing of the sample is a new approach.
As the first in the field of reward behavior, FISHDOPA has proven to be able to use both larvae and adult zebrafish. This opens up future applications and research in important areas such as neurotransmission, learning and addiction. “The most important thing is that we have identified different areas of the brain involved in the reward system,” Professor Kettunen stressed. “Our data suggests that different brain regions and signaling pathways are recruited in different aspects of behavior.”
Clearing obstacles in behavioral research challenges
As the forefront of research in the field of reward-related behaviors, the FISHDOPA team faces many challenges. “There are many methods/tools and there is limited information about brain function in fish. Therefore, we must develop or improve most of the methods used, including behavioral testing, antibody evaluation and available transgenic fish,” explains Professor Ketunun.
Another challenge is to manipulate and follow the subtle and complex behaviors involved in learning to move freely in the zebrafish and to investigate at what point in time during development that reward behavior develops in the larvae. As Professor Ketunun pointed out, “The older the animal, the more limited you are to use existing in vivo imaging techniques as a scientist.”
Next steps in applying the DA system in the clinic. The focus of the future will be to study the function of new genes discovered during project research and extend the research to the human genetic cascade. “In addition to dopamine, you can investigate other signaling pathways that participate in reward learning, which can be pharmacologically or genetically tested in future experiments,” Professor Kettenun noted.
Disorders in the dopaminergic system are associated with several psychiatric and neurological diseases and syndromes, such as Parkinson’s disease, Alzheimer’s disease, ADHD, and depression. In addition, dopamine plays a key role in addiction. As Professor Ketunun concludes, “For many diseases associated with dopaminergic dysfunction, we still lack effective and safe treatments, and new tools developed by FISHDOPA may be of great help in finding new treatments.”