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, Ph.D., 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, Ph.D., 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.
(ANI)