Researchers at Weill Cornell Medicine have uncovered a promising new target in the brain that could lead to treatments for anxiety disorders without the common side effects associated with current medications. In a study published on January 28, 2025, in Neuron, the team identified a specific brain circuit where activating certain receptors could reduce anxiety without causing negative cognitive impacts—a significant advancement in the search for safer treatments.
The Role of mGluR2 Receptors in Anxiety Reduction
The focus of the study was on metabotropic glutamate receptor 2 (mGluR2), a type of receptor found on neurons in several key brain circuits. While mGluR2 is known to be involved in regulating brain activity, it had not been fully understood how targeting these receptors might specifically affect anxiety. The team’s breakthrough came when they found that activating mGluR2 in a specific brain circuit—one that ends in the amygdala, a region critical to emotional processing—reduced anxiety symptoms in a preclinical mouse model.
The amygdala plays a central role in processing fear and anxiety, and the researchers demonstrated that when mGluR2 receptors in circuits ending in this region were activated, anxiety levels in the mice significantly decreased. Importantly, the team found that these effects were achieved without impairing cognitive functions, a common drawback of existing anxiolytic treatments.
“Our findings indicate a new and important target for the treatment of anxiety-related disorders and show that our photopharmacology-based approach holds promise more broadly as a way to precisely reverse-engineer how therapeutics work in the brain,” said Dr. Joshua Levitz, the senior author of the study and an associate professor of biochemistry at Weill Cornell Medicine.
A Revolutionary Approach to Mapping Drug Effects
The study also marks a significant leap forward in the field of neuroscience and pharmacology, as the researchers employed an innovative method known as photopharmacology to identify and map the effects of drugs in specific brain circuits. This technique, developed by Dr. Levitz during his early years as a graduate student, involves the use of small molecules that can be activated by light. When tethered to the mGluR2 receptor, these molecules allow the researchers to precisely activate the receptor in any part of the brain by shining specific colors of light on it.
Through this approach, the team was able to isolate the two brain circuits that are crucial to the anxiety-reducing effects of mGluR2 activation. One of these circuits originates from the ventromedial prefrontal cortex, while the other is connected to the insula, a region involved in sensory and internal body perception.
Finding the Right Circuit for Anxiety Reduction
The team’s experiments revealed distinct results depending on which brain circuit was targeted. When mGluR2 receptors were activated in the ventromedial prefrontal cortex-to-amygdala circuit, anxiety signs, such as spatial avoidance behavior, were reduced. However, this came at a cost—mice exhibited working memory deficits, a known side effect of many current anxiety medications. This cognitive impairment is thought to contribute to the mental fog or memory loss that some patients experience when using traditional anxiolytics.
In contrast, when mGluR2 was activated in the second circuit—the one that runs from the insula to the amygdala—the anxiety-reducing effects were observed without any apparent cognitive impairments. Specifically, this activation normalized social behavior and feeding behavior in the mice, both of which are often disrupted in anxious individuals. These findings suggest that the insula-to-amygdala circuit could potentially be a side-effect-free target for future anxiety treatments.
“One of the next steps will be to find a way to target this circuit selectively—in other words, not via mGluR2, because mGluR2 is everywhere,” Dr. Levitz explained. This raises the exciting possibility that more specific targeting of the insula-to-amygdala pathway could provide a way to treat anxiety disorders without the drawbacks of traditional medications.
The Promise of Photopharmacology for Brain Research
The study’s success in using photopharmacology to map out the brain’s reaction to mGluR2 activation is a promising development for drug discovery. This method offers a more precise way to study the effects of experimental compounds, allowing scientists to selectively target brain circuits and observe their specific effects. This could revolutionize how new treatments for various neurological and psychiatric disorders are developed, offering the potential for drugs that work with minimal side effects.
“Photopharmacology is a tool that lets us fine-tune drug effects with spatial and temporal precision,” Dr. Levitz said. “It allows us to answer questions about how specific brain circuits contribute to behavior and disease, and it can ultimately help us develop better, safer treatments.”
Future Directions: Targeting Anxiety Without Side Effects
Looking ahead, Dr. Levitz and his team are working to refine their approach and investigate ways to selectively target the insula-to-amygdala circuit for anxiety treatments. Since mGluR2 is found throughout the brain, targeting it directly might not be ideal for precise treatments. The researchers hope to find ways to either target this circuit more directly or to discover molecules that can selectively activate the anxiety-reducing effects of mGluR2 in this pathway without affecting other areas of the brain.
In addition to anxiety, the research team plans to use their circuit-mapping toolkit to investigate other drug classes, including opioids and antidepressants. Understanding how these drugs affect different circuits in the brain could lead to the development of new therapies that address the root causes of conditions like chronic pain and depression without the common side effects.
Conclusion: A New Hope for Treating Anxiety Disorders
This groundbreaking research at Weill Cornell Medicine offers fresh hope for those suffering from anxiety disorders, which currently affect millions worldwide. Traditional anxiety medications, such as benzodiazepines, are often effective but can cause unwanted side effects, including cognitive impairment and dependency. The discovery of a specific brain circuit that can reduce anxiety without these drawbacks opens the door to the development of more targeted, effective treatments.
With the help of advanced tools like photopharmacology, scientists are gaining unprecedented insight into the brain’s complex circuitry. The ability to map drug effects in specific circuits could lead to more personalized and safer therapies for a wide range of psychiatric and neurological conditions.
As Dr. Levitz and his team continue to explore these new frontiers in brain science, the potential for more effective treatments for anxiety, depression, chronic pain, and other disorders seems brighter than ever.
Reference: Hermany Munguba et al, Projection-targeted photopharmacology reveals distinct anxiolytic roles for presynaptic mGluR2 in prefrontal- and insula-amygdala synapses, Neuron (2025). DOI: 10.1016/j.neuron.2025.01.002