The study shows that serotonin in the cerebellum acts as a “brake” on anxiety, helping to control emotional states. The results may have clinical implications, suggesting that serotonin-based therapies, such as selective serotonin reuptake inhibitors (SSRIs), used to treat anxiety in humans, may act not only on brain regions traditionally associated with anxiety, but also on the cerebellum.
Anxiety is a natural response of the body to situations of danger or stress, but when excessive or persistent, it can become a debilitating disorder. Serotonin (5-HT) is a neurotransmitter that is essential in regulating mood and emotions, and plays a key role in modulating anxiety.
Reduced levels of serotonin in certain areas of the brain are often associated with increased vulnerability to anxiety, which has led to the development of treatments such as selective serotonin reuptake inhibitors (SSRIs), used to reduce anxiety symptoms by increasing the availability of this neurotransmitter in the nervous system.
Understanding how brain circuits regulate anxiety is essential to developing more effective and targeted treatments.
Previous research has identified that both serotonin (5-HT) and the cerebellum play roles in regulating anxiety, but the connection between the two has been poorly understood.
To investigate this relationship, Pei Chin of the University of Pennsylvania and George Augustine of the Temasek Life Sciences Laboratory conducted a study to examine how serotonin in the cerebellum influences anxiety behavior in mice.
The researchers implanted a fluorescent sensor in lobule VII of the cerebellum to measure serotonin levels in real time as the mice explored an anxiety-provoking environment, the elevated zero maze.
Scientists measure rodents’ anxiety by observing how much time they spend in the enclosed or exposed sections of the zero maze. Since mice and rats instinctively avoid open areas to protect themselves from predators, spending more time in the exposed sections indicates less anxiety. Unlike other tests, such as the elevated plus maze, this method eliminates the influence of indecision, since the rodents choose only between light and dark areas. Source: By Andrew S
The results yielded an unexpected finding: Contrary to what was previously thought, the most anxious mice had reduced levels of serotonin in their cerebellum, while those that showed less anxiety had higher levels.
This finding contrasts with previous studies, which suggested that higher serotonin levels were associated with increased anxiety.
To test whether cerebellar serotonin actually influences anxious behavior, the researchers used optogenetic techniques to artificially stimulate or inhibit serotonin release in lobule VII of the cerebellum.
When serotonin release in this region was increased, the mice exhibited less anxious behavior. Conversely, when serotonin was reduced, the mice exhibited greater anxiety. This suggests that serotonin in the cerebellum acts as a “brake” on anxiety, helping to control emotional states.
These findings provide new insight into the role of the cerebellum in emotional regulation and may pave the way for the development of more targeted treatments for anxiety disorders.
The possibility of directly modulating serotonin in this brain region could lead to innovative therapies that go beyond conventional treatments, such as selective serotonin reuptake inhibitors (SSRIs), expanding the options for controlling anxiety.
These findings provide new evidence that lobule VII of the cerebellum plays a fundamental role in regulating anxiety and that serotonin is a key player in this process.
In addition, the results may have clinical implications, suggesting that serotonin-based therapies, such as selective serotonin reuptake inhibitors (SSRIs), used to treat anxiety in humans, may act not only on brain regions traditionally associated with anxiety, but also on the cerebellum.
READ MORE:
Serotonergic input into the cerebellar cortex modulates anxiety-like behavior
Pei Wern Chin and George J. Augustine
Journal of Neuroscience. 10 February 2025, e1825242024
Abstract:
Because of the important roles of both serotonin (5-HT) and the cerebellum in regulating anxiety, we asked whether 5-HT signaling within the cerebellum is involved in anxiety behavior. Physiological 5-HT levels were measured in vivo by expressing a fluorescent sensor for 5-HT in lobule VII of the cerebellum, while using fiber photometry to measure sensor fluorescence during anxiety behavior on the elevated zero maze. Serotonin increased in lobule VII when male mice were less anxious and decreased when mice were more anxious. To establish a causal role for this serotonergic input in anxiety behavior, we photostimulated or photoinhibited serotonergic terminals in lobule VII while mice were in an elevated zero maze. Photostimulating these terminals reduced anxiety behavior in mice, while photoinhibiting them enhanced anxiety behavior. Our findings add to evidence that cerebellar lobule VII is a topographical locus for anxiety behavior and establish that 5-HT input into this lobule is necessary and sufficient to bidirectionally influence anxiety behavior. These results represent progress toward understanding how the cerebellum regulates anxiety behavior and provide new evidence for a functional connection between the cerebellum and the serotonin system within the anxiety circuit.
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