The neurotransmitter serotonin is a key component of mood regulation. While increased levels of serotonin can help with certain mood issues like depression — as evidenced by the use of selective serotonin reuptake inhibitors for depression — they can also contribute to anxiety. 

“It’s really pretty much central dogma that serotonin goes up during anxiety,” said George Augustine, a neuroscientist at Temasek Life Sciences Laboratory.

The relationship between serotonin and anxiety is well-documented in much of the brain, including the amygdala, a hub for emotion processing that heightens anxiety when activated (1). But no one had yet explored what the neurotransmitter does in the cerebellum, a small region between the cerebrum and the brainstem long known as a center for motor control. Researchers have only recently recognized its role in cognition and mood regulation, raising new questions about how the “little brain” contributes to emotions.

In a new study, Augustine and his doctoral student Pei Wern Chin found that serotonin in this brain region increases as a mouse prepares to engage in an anxiety-invoking behavior and decreases when returning to a calm state — the opposite effect seen in other regions of the brain (2).

“What’s really nice about this study is it’s yet another example giving evidence that the cerebellum is involved in regulating emotions,” said Charlotte Lawrenson, a neuroscientist at the University of Exeter who was not involved in the work.

The research is preliminary, Augustine said, but it identified a new possible target for anxiety treatments.

“I’m not going to be patenting any anti-anxiety drugs today based on the work that Pei did,” he said, “but it’s not a leap of faith to say that what she’s discovered about the role of serotonin and anxiety in the cerebellum could be important for those of us suffering from anxiety somewhere down the line.”

It’s not a leap of faith to say that what she’s discovered about the role of serotonin and anxiety in the cerebellum could be important for those of us suffering from anxiety somewhere down the line.
- George Augustine, Temasek Life Sciences Laboratory

The cerebellum’s three lobes are divided into 10 lobules, each with largely discrete functions. To understand whether serotonin was responsible for the cerebellum’s effects on anxiety, Augustine and Chin focused on lobule VII, a region that researchers had linked to anxiety in previous work in mice (3,4).

Augustine and Chin placed mice bred to express a fluorescent marker in the presence of serotonin in an elevated maze with two open quadrants and two closed quadrants. They found that serotonin increased in lobule VII as the mice prepared to enter an open quadrant and remained high until they moved to a closed quadrant.

The team then used optogenetics to either increase or shut off the flow of serotonin in lobule VII. Mice spent more time exploring open quadrants — a sign of reduced anxiety — when the researchers stimulated serotonergic neurons. When they silenced the serotonergic neurons, the mice spent more time in the safer closed quadrants.

“It’s [the] first real study that has shown direct evidence that serotonergic inputs [in the cerebellum] can modulate anxiety-like behaviors in rodents,” Lawrenson said. 

The findings suggest that some anti-anxiety drugs work in part via the serotonergic system in the cerebellum, she said. 

It’s still unclear why serotonin’s relationship with anxiety is reversed in the cerebellum, Augustine said. It’s possible that the neurotransmitter is acting as a kind of “brake,” regulating the flow of serotonin in the rest of the brain.

Examining connections between the neurons releasing serotonin in the cerebellum and in other parts of the brain is an important next step, Augustine said: The route serotonin travels along could be a “druggable target.”

It’s also possible that the cerebellum has its own serotonin receptors that differ from those in other regions of the brain.

“That would be a Big Pharma dream come true,” Augustine said, “because then you know exactly the right target to design your drugs to turn on or turn off the serotonin receptors exclusively in the cerebellum, to either turn on the brake or turn off the brake.”

 References

1. Marcinkiewcz, C.A. et al. Serotonin engages an anxiety and fear-promoting circuit in the extended amygdala. Nature 537, 97–101 (2016). 
2. Chin, P.W. & Augustine, G.J. Serotonergic input into the cerebellar cortex modulates anxiety-like behavior. J Neurosci, e1825242024 (2025).
3. Badura, A. et al. Normal cognitive and social development require posterior cerebellar activity. eLife  7, e36401 (2018).
4. Chin, P.W. & Augustine, G.J. The cerebellum and anxiety. Front Cell Neurosci  17, 1130505 (2023).