The scientific world has advanced immeasurably by the science of DNA and genetics. Manipulating gene expression to change the way that cells such as neurons function has helped scientists create very specific tools to use for understanding and developing treatments for human diseases. For human brain disorders, like addiction, rats are the preferred animal model for behavioral studies due to their ability to learn a wide variety of complex behaviors, but targeted genetic tools have not been easily incorporated into these studies. The emergence of a gene editing technology called CRISPR-Cas9 has expanded our ability to make modifications to many species, including agricultural crops and rodents, but there are still limitations to its use.
Cell specific CRISPR-Cas9 in the adult rat brain. Microscopic images of the midbrain of a transgenic rat that selectively edits genes in dopamine neurons. Genetic modifiers (gRNAs) were delivered to cells in the midbrain (green). The left side received control gRNAs which are present in both dopaminergic neurons (red) and non-dopaminergic neurons. The right side gRNAs were directed to a target gene (white) that is present on many cell types, but only the dopaminergic neurons lost the target gene. Modified from Bäck, Necarsulmer et al Neuron 2019 with permission from Elsevier.In a paper published in the journal Neuron, NIH funded scientists describe the development of a new set of transgenic tools ─ technologies that allow for more robust gene editing. These include novel viral vectors (tools commonly used to deliver genetic material into cells) and, in an important contribution to the field, new transgenic rat lines ─ rats that are already modified at the earliest stages of cellular life. One component of this toolkit represents the first transgenic rat made using CRISPR in spermatogonial stem cells (at a very early stage of development) and opens up new possibilities for future transgenic rat types.
The novel viral vectors and transgenic rats described in this study can be combined to enable complex genomic editing in the adult rat brain. The process used by the team of scientists is extraordinarily complex and provides new molecular machinery to potentially alter the DNA code, opening new avenues for the treatment of brain diseases like substance use disorder or Parkinson’s, thought out of reach just a decade ago.
The study was supported by the National Institute on Drug Abuse and the National Institute of Mental Health, with work done by intramural scientists at those institutions, part of the National Institutes of Health. Other investigators were from the University of Texas and the University of Helsinki.
For a copy of the paper, published in Neuron, go to Neuron-specific genome modification in the adult rat brain using CRISPR-Cas9 transgenic rats.
For more information on genetics and addiction, go to: DrugFacts: Genetics and Epigenetics of Addiction.
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