How Serotonin Affects Behavior: A Comprehensive Study on C. elegans Model
Serotonin is a primary chemical the brain uses to influence mood and behavior. It is also the most common target of psychiatric drugs. In order to improve those drugs and to invent better ones, scientists need to know much more about how the molecule affects brain cells and circuits both in health and amid disease. In a new study, researchers at The Picower Institute for Learning and Memory at MIT working in a simple animal model present a comprehensive accounting of how serotonin affects behavior from the scale of individual molecules all the way to the animal’s whole brain.
C. Elegans Model: A Manageable Solution
These same complexities that scientists face in people are all afoot in the nematode worm C. elegans but to a more manageably limited degree. 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.
The Functional Roles of Serotonin Receptors
First, they focused on identifying the functional roles of the worm’s six serotonin receptors. To do that, they created 64 different mutant strains covering the different combinations of knocking out the various receptors. In each of these worms, the team stimulated serotonin release from the NSM neuron to prompt slowing behaviors. Analysis of all the resulting data revealed at least two key findings: One was that three receptors primarily drove the slowing behavior. The second was that the other three receptors “interacted” with the receptors that drive slowing and modulated how they function.
Serotonin Receptors and Brain-Wide Mapping
Different receptors respond to different patterns of serotonin release in live animals. For example, the SER-4 receptor only responded to sudden increases in serotonin release by the NSM neuron. 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. About half of the worm’s neurons express serotonin receptors, with some neurons expressing as many as five different types. Finally, the team used their ability to track all neuron activity and all behaviors to watch how the serotonergic neuron NSM affected other cells’ activity as worms freely explored their surroundings.
Predictive Power of Serotonin Receptors
Knowing which receptors were expressed in each neuron and its input neurons gave strong predictive power of how each neuron was impacted by serotonin. “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.
The Complexities and Opportunities Facing Drug Developers
All these findings shed light on the kinds of complexities and opportunities facing drug developers. The study’s findings show how the effects of targeting one serotonin receptor could depend on how other receptors or the cell types that express them are functioning. In particular, the study highlights how the serotonin receptors act in concert to change the activity states of neural circuits.
Conclusion
The study has revealed 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 researchers have gained important insights into serotonin’s actions and the functional roles of serotonin receptors. These findings shed light on the kinds of complexities and opportunities facing drug developers. The study has provided us with valuable insights into the little-known world of neurotransmitter release for better drug development.
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