Researchers at Baylor College of Medicine and the Jan and Dan Duncan Neurological Institute at Texas Children’s Hospital have identified new genes that play a role in regulating dopamine levels in the brain, using fruit flies as a model. The study was published in iScience.
Dopamine is important for movement, learning, motivation, and sleep. Disruptions in dopamine are linked to conditions such as Parkinson’s disease, depression, and sleep disorders. Although much is known about how dopamine functions in the brain, less is understood about how its levels are controlled by the body.
The research team used laboratory fruit flies because they share many genes with humans and their short life cycle allows for large-scale experiments. Dr. Shinya Yamamoto, corresponding author and associate professor at Baylor College of Medicine as well as investigator at the Duncan NRI, explained: “In addition to using dopamine to modulate brain activity just like humans do, flies use it to make melanin, the pigment that colors their outer shell. This suggested that changes in dopamine could show as changes in body color, a visible clue we could follow just by looking at these animals.”
The researchers applied RNA interference (RNAi) technology to silence specific genes among hundreds suspected of affecting pigmentation. They then examined whether these genes also changed dopamine levels or influenced behaviors such as sleep.
“We began by working with more than 450 genes that have been proposed to affect flies’ body color. Using our gene-silencing technique, we confirmed 153 that consistently changed pigmentation,” Yamamoto said. “Interestingly, 85% of these genes are conserved in humans, and more than half are linked to neurological disorders such as autism, epilepsy and intellectual disability.”
After further testing behavioral effects by silencing these pigmentation-related genes within dopamine-producing neurons of the flies’ brains, they found 50 were associated with altered locomotion or sleep patterns.
The study focused on 35 genes present both in flies and humans that strongly affected pigmentation and behavior; eleven significantly altered brain dopamine levels—mostly reducing it—but there was no clear relationship between pigment change and actual dopamine level.
“We then narrowed our study to two genes, mask and clu. Both genes reduced brain dopamine when silenced,” Yamamoto said. “Further experiments revealed that mask lowers dopamine by reducing the expression of tyrosine hydroxylase, the key enzyme for dopamine synthesis. The clu gene also reduced dopamine, but through a different mechanism.”
Silencing mask led to loss of normal anticipation for light before dawn—a period when flies typically become active—and increased sleep during this time; providing L-DOPA reversed this effect. Mask silencing also made caffeine less effective at promoting wakefulness.
For clu-silenced flies there was an increase in overall sleep without changes in light anticipation; L-DOPA did not rescue this effect suggesting an indirect influence on dopamine regulation.
These findings may help identify targets for restoring proper dopamine function related to human neurological or neuropsychiatric conditions including addiction or schizophrenia.
Contributors included Samantha L. Deal, Danqing Bei, Shelley B. Gibson, Harim Delgado-Seo, Yoko Fujita, Kyla Wilwayco, Elaine S. Seto and Amita Sehgal from Baylor College of Medicine (official website), Duncan NRI and University of Pennsylvania.
Support came from startup funds from Duncan NRI and Baylor’s Department of Molecular and Human Genetics; additional support was provided by IRACDA program at University of Pennsylvania (K12GM081259), Howard Hughes Medical Institute; Intellectual & Developmental Disabilities Research Center (U54HD083092) from Eunice Kennedy Shriver National Institute of Child Health & Human Development.
Baylor College of Medicine operates independently within Houston's Texas Medical Center (official website) where it focuses on education across medicine-related fields while advancing research innovation (official website). It provides patient care through partnerships alongside community service initiatives (official website).
