Mouse study links stress to shortened astrocyte cilia in amygdala

In a mouse model of chronic stress, researchers at UCLA Health found that astrocytes in the amygdala developed shorter primary cilia, antenna-like structures on the cell surface that help cells sense and respond to their surroundings. Restoring the cilia through two experimental approaches reversed many associated molecular changes and improved some stress-related behaviors, including signs of anxiety and reduced interest in normally pleasurable activities. The peer-reviewed study, published in Nature, identifies a possible cellular target for stress-disorder research, but its findings do not establish a treatment for humans.

Astrocytes are bushy support cells, also known as glial cells, that have received less attention in stress research than neurons. Led by UCLA Health researchers Sara Gutierrez Pelaz, Katsukuni Mitsui and senior author Baljit Khakh, the team observed changes in amygdala astrocytes after chronic stress. These changes included altered gene and protein levels, some of it tied to primary cilium function, as well as physically shorter cilia. The investigators focused on the amygdala, the brain region that governs fear and emotion, and examined how changes in a non-neuronal cell type and its surface structure accompanied the animals’ stress response.

The researchers used two methods to restore astrocyte cilia in the mice. One was a laboratory technique that switches specific receptors on astrocytes on or off; the second was a drug targeting the receptor S1PR1. Both approaches reversed many of the observed molecular changes and improved some stress-related behaviors. The mice showed fewer signs of anxiety and greater interest in normally pleasurable activities, according to the study. These results support a role for astrocyte primary cilia in the stress response in this mouse model, but the work does not demonstrate that the same intervention would produce clinical benefits in people with anxiety, depression or other psychiatric conditions.

S1PR1 is also present in human amygdala tissue and is targeted by ponesimod, an FDA-approved drug for multiple sclerosis. When the researchers gave ponesimod to stressed mice, it produced improvements similar to those observed with the experimental approach, suggesting a potential route for testing the mechanism in people. The team also examined gene activity in brain tissue from people with major depressive disorder, bipolar disorder and psychosis-related disorders. They found that cilium-related genes in astrocytes were disrupted in those conditions as well. This human tissue association is consistent with the mouse findings, but it does not show that disrupted cilium-related gene activity causes those disorders or that targeting astrocyte cilia would treat them. The study was an experimental animal study, and further research is needed to determine whether manipulating astrocyte primary cilia or S1PR1 could become a viable treatment strategy for stress-related conditions in humans.

Subject of Research: Experimental evidence that chronic stress alters amygdala astrocyte primary cilia and that restoring them affects stress-related behaviors in mice.

Article Title: Study identifies stress-response cells, points to new treatment target

Article References: Study identifies stress-response cells, points to new treatment target. Original publication (Bibliographic details unavailable.)

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Keywords: astrocytes, amygdala, chronic stress, primary cilia, S1PR1, ponesimod, anxiety, depression, glia, mouse models, identifies, stress-response