AI-Designed Serotonin Sensor May Help Scientists Study Sleep, Mental Health
In an article in Cell, National Institutes of Health-funded researchers
described how they used advanced genetic engineering techniques to
transform a bacterial protein into a new research tool that may help
monitor serotonin transmission with greater fidelity than current
methods.
Preclinical experiments, primarily in mice, showed that
the sensor could detect subtle, real-time changes in brain serotonin
levels during sleep, fear, and social interactions, as well as test the
effectiveness of new psychoactive drugs.
The study was funded, in
part, by the NIH''s Brain Research through Advancing Innovative
Neurotechnologies (BRAIN) Initiative which aims to revolutionize our
understanding of the brain under healthy and disease conditions.
The
study was led by researchers in the lab of Lin Tian, PhD, principal
investigator at the University of California Davis School of Medicine.
Current methods can only detect broad changes in serotonin signaling. In
this study, the researchers transformed a nutrient-grabbing, Venus
flytrap-shaped bacterial protein into a highly sensitive sensor that
fluorescently lights up when it captures serotonin.
Previously,
scientists in the lab of Loren L. Looger, PhD, Howard Hughes Medical
Institute Janelia Research Campus, Ashburn, Virginia, used traditional
genetic engineering techniques to convert the bacterial protein into a
sensor of the neurotransmitter acetylcholine.
The protein, called
OpuBC, normally snags the nutrient choline, which has a similar shape
to acetylcholine. For this study, the Tian lab worked with Dr. Looger''s
team and the lab of Viviana Gradinaru, Ph.D., Caltech, Pasadena,
California, to show that they needed the added help of artificial
intelligence to completely redesign OpuBC as a serotonin catcher.
The
researchers used machine learning algorithms to help a computer ''think
up'' 250,000 new designs. After three rounds of testing, the scientists
settled on one. Initial experiments suggested that the new sensor
reliably detected serotonin at different levels in the brain while
having little or no reaction to other neurotransmitters or similarly
shaped drugs.
Experiments in mouse brain slices showed that the
sensor responded to serotonin signals sent between neurons at synaptic
communications points. Meanwhile, experiments on cells in petri dishes
suggested that the sensor could effectively monitor changes in these
signals caused by drugs, including cocaine, MDMA (also known as ecstasy)
and several commonly used antidepressants.
Finally, experiments
in mice showed that the sensor could help scientists study serotonin
neurotransmission under more natural conditions. For instance, the
researchers witnessed an expected rise in serotonin levels when mice
were awake and a fall as mice fell asleep.
They also spotted a
greater drop when the mice eventually entered the deeper, R.E.M. sleep
states. Traditional serotonin monitoring methods would have missed these
changes. In addition, the scientists saw serotonin levels rise
differently in two separate brain fear circuits when mice were warned of
a foot shock by a ringing bell.
In one circuit - the medial
prefrontal cortex - the bell triggered serotonin levels to rise fast and
high whereas in the other - the basolateral amygdala - the transmitter
crept up to slightly lower levels.
In the spirit of the BRAIN
Initiative, the researchers plan to make the sensor readily available to
other scientists. They hope that it will help researchers gain a better
understanding of the critical role serotonin plays in our daily lives
and in many psychiatric conditions.