The most popular target of psychiatric medications is serotonin because it is one of the main substances the brain utilizes to affect mood and behavior. Scientists need to learn much more about how the chemical impacts brain cells and circuits in health and sickness in order to improve those medications and develop better ones.
Researchers from The Picower Institute for Learning and Memory at MIT give a thorough explanation of how serotonin influences behavior from the level of individual molecules all the way up to the animal’s entire brain in a recent study using a straightforward animal model.
“There have been major challenges in rationally developing psychiatric drugs that target the serotonergic system,” said Steve Flavell, associate professor in The Picower Institute and MIT’s Department of Brain and Cognitive Sciences, and senior author of the study in Cell. “The system is wildly complex. There are many different types of serotonergic neurons with widespread projections throughout the brain and serotonin acts through many different receptors, which are often activated in concert to change the way that neural circuits work.”
The nematode worm C. elegans exhibits the same complexity as humans, albeit to a much smaller and more manageable extent. C. elegans has only 302 neurons (rather than billions) and only six serotonin receptors (rather than the 14 found in people). Moreover, all C. elegans neurons and their connections have been mapped out and its cells are accessible for genetic manipulation.
Finally, Flavell’s team has developed imaging technologies that enable them to track and map neural activity across the worm’s brain simultaneously. Due to all of these factors, the group was able to create a groundbreaking study that explains how serotonin’s extensive chemical activity alters activity and behavior across the brain.
“These results provide a global view of how serotonin acts on a diverse set of receptors distributed across a connectome to modulate brain-wide activity and behavior,” the research team wrote in Cell.
The study’s co-lead authors are Picower Institute postdoc Ugur Dag, MIT Brain and Cognitive Sciences graduate student Di Kang, and former research technician Ijeoma Nwabudike, who is now a MD-PhD student at Yale.
There have been major challenges in rationally developing psychiatric drugs that target the serotonergic system. The system is wildly complex. There are many different types of serotonergic neurons with widespread projections throughout the brain and serotonin acts through many different receptors, which are often activated in concert to change the way that neural circuits work.
Steve Flavell
Slowing for savoring
Flavell showed in Cell in 2013 that C. elegans uses serotonin to slow down when it reaches a patch of food and traced its source to a neuron called NSM. The scientists employed a variety of recent advancements at MIT to thoroughly investigate serotonin’s effects in the current study.
They first concentrated on figuring out the six serotonin receptors in the worm’s functioning capacities. In order to achieve this, they developed 64 unique mutant strains that covered the various combinations of knocking off the various receptors. For instance, one strain might only have one receptor left, while another might have all but that one removed, and still another might have three absent.
The scientists induced slowing behaviors in each of these worms by stimulating serotonin release from the NSM neuron. Analysis of all the resulting data revealed at least two key findings: One was that three receptors primarily drove the slowing behavior. The other three receptors “interacted” with the receptors that cause slowness and altered how they worked, which was the second factor. These complex interactions between serotonin receptors in the control of behavior is likely to be directly relevant to psychiatric drugs that target these receptors, Flavell said.
The researchers also gained other important insights into serotonin’s actions. One was that in living animals, different receptors react to various patterns of serotonin release. For instance, only abrupt increases in serotonin release by the NSM neuron elicited a response from the SER-4 receptor. But, the MOD-1 receptor responded to continuous “tonic” changes in serotonin release by NSM. This suggests that different serotonin receptors are engaged at different times in the live animal.
Brain-wide mapping
The study team used imaging tools to examine how serotonin’s effects operated at a circuit level after elucidating the roles of the serotonin receptors in the regulation of C. elegans behavior.
For instance, they created a brain-wide map of the serotonin receptor locations in C. elegans by fluorescently labeling every receptor gene in every neuron so they could observe which particular cells produced each receptor. Serotonin receptors are expressed by over 50% of the worm’s neurons, with some neurons expressing as many as five distinct types.
Finally, the team used their ability to track all neuron activity (based on their calcium fluctuations) and all behaviors to watch how the serotonergic neuron NSM affected other cells’ activity as worms freely explored their surroundings. About half of the neurons across the worm’s brain changed activity when serotonin was released.
The study team wondered if they could predict how each cell would react to serotonin by knowing which specific neurons they were recording from and which serotonin receptors each cell expressed. The ability to predict how each neuron would respond to serotonin was much enhanced by knowing which receptors were expressed in each neuron and its input neurons.
“We performed brain-wide calcium imaging in freely-moving animals with knowledge of cellular identity during serotonin release, providing, for the first time, a view of how serotonin release is associated with changes in activity across the defined cell types of an animal’s brain,” the researchers concluded.
All these findings shed light on the kinds of complexities and opportunities facing drug developers, Flavell noted. The results of the study demonstrate how the consequences of targeting a single serotonin receptor may vary depending on the activity of other receptors or the cell types that express those receptors. The study particularly emphasizes how serotonin receptors collaborate to alter the activity states of brain networks.
In addition to Flavell, Dag, Nwabudike, and Kang, the paper’s other authors are Matthew Gomes, Jungsoo Kim, Adam Atanas, Eric Bueno, Cassi Estrem, Sarah Pugliese, Ziyu Wang, and Emma Towlson.
Study funders included the National Institutes of Health, the National Science Foundation, the McKnight Foundation, the Alfred P. Sloan Foundation, the Picower Institute, and the JPB Foundation.
