UCLA researchers link astrocyte changes to stress-induced anxiety and depression

For decades, neuroscientists studying stress and mood disorders have trained their attention almost entirely on neurons—the brain's signal-firing cells. A team at UCLA Health has now turned that lens elsewhere, toward the supporting cast of brain cells called astrocytes, and discovered something unexpected: when stress hits, these bushy support cells undergo measurable physical changes that may help explain why chronic strain so often leads to anxiety and depression.

The research, published in Nature, focused on astrocytes in the amygdala, the brain region responsible for processing fear and emotion. The researchers found that under stress, these cells develop a specific problem: their primary cilia—tiny antenna-like structures that protrude from the cell surface and help cells sense and respond to their environment—actually shorten. Using mouse models of chronic stress, the team observed not just the physical shortening of these cilia, but also altered patterns of gene and protein expression tied to cilium function. The discovery reframes how we think about the brain's response to adversity. As Sara Gutierrez Pelaz, a postdoctoral researcher in the lab of UCLA professor Baljit Khakh, and Katsukuni Mitsui, a visiting scientist from ONO Pharmaceutical Co., Ltd., noted in their work: the brain's stress response involves far more than neurons talking to one another.

What makes this finding potentially actionable is what the researchers did next. They tested two different approaches to restoring the shortened cilia in stressed mice. The first was a laboratory technique that manipulated specific receptors on the astrocyte surface. The second was a drug targeting a receptor called S1PR1. Both methods reversed many of the molecular changes and, importantly, improved stress-related behaviors in the animals—reducing signs of anxiety and restoring interest in normally pleasurable activities, a proxy for depression-like symptoms.

The S1PR1 receptor already has a drug attached to it. Ponesimod, an FDA-approved medication for multiple sclerosis, targets this same receptor. When the researchers administered ponesimod to stressed mice, it produced similar improvements to their experimental approaches. This matters because it offers a concrete pathway forward. Rather than developing an entirely new compound from scratch, researchers now have an existing, approved drug that might be tested in human trials. Baljit Khakh, the study's senior author, emphasized this practical advantage: the receptor is already being targeted by medicine in clinical use, providing a realistic starting point for exploring new treatment approaches.

To strengthen their case, the team examined gene activity in brain tissue from people living with major depressive disorder, bipolar disorder, and psychosis-related conditions. They found that cilium-related genes in astrocytes were disrupted in those conditions as well—a finding that mirrors what they observed in the stressed mice and suggests the mechanism may translate to human biology.

Stress-related conditions like anxiety and depression affect a substantial portion of the population, and existing treatments fail to help everyone. By identifying a specific cellular structure that changes under stress and can be restored, this research opens a new angle for treatment development, one that moves beyond the traditional focus on neurons alone and considers the role of glial support cells. The findings remain early-stage and based on animal models. Significant additional research will be required to determine whether targeting astrocyte primary cilia could become a practical treatment strategy in humans, but the presence of an existing drug that shows promise in mice offers a genuine foothold for the next phase of investigation.