Investigators have discovered a particular brain circuit in a preclinical model that, when inhibited, seems to alleviate anxiety without causing any side effects. Their research points to a new potential target for treating anxiety disorders and related issues, while also showcasing a comprehensive strategy utilizing a technique known as photopharmacology to understand how drugs impact the brain.
Researchers at Weill Cornell Medicine have made a significant discovery of a specific brain circuit that, when inhibited, may help reduce anxiety without accompanying negative effects. Their findings indicate a new potential target for the treatment of anxiety disorders and similar conditions, and they illustrate a broader approach using a technique called photopharmacology for mapping the effects of drugs on the brain.
In their research, published on January 28 in Neuron, the team explored the impact of experimental drug compounds that activate a type of brain cell receptor known as the metabotropic glutamate receptor 2 (mGluR2). These receptors are present in numerous brain circuits, but the researchers demonstrated that activating them in a particular circuit that connects to an emotion-related brain region called the amygdala effectively reduces anxiety without significant side effects. Many current treatments for anxiety disorders and panic disorder can lead to undesirable side effects, including cognitive impairments.
“Our results reveal a new and crucial target for treating anxiety-related disorders, and our approach using photopharmacology shows potential for more accurately reversing how therapies work in the brain,” stated Dr. Joshua Levitz, the study’s senior author and an associate professor of biochemistry at Weill Cornell Medicine.
The co-first authors of this study are Drs. Hermany Munguba and Ipsit Srivastava, who are a former and current postdoctoral associate in the Levitz lab, as well as Dr. Vanessa Gutzeit, who was a doctoral student in the lab during the research.
Activating mGluR2, which acts like a small “dimmer switch” reducing synaptic transmission in its host neuron, has previously been linked to reducing anxiety in earlier preclinical and small clinical studies. However, the development of drugs in this class has faced challenges due to worries about possible side effects. Since mGluR2 is present in numerous brain circuits, substances targeting these receptors often activate other members of the mGluR family, raising the risk of unwanted effects.
In their recent study, Dr. Levitz and his team improved the understanding of how mGluR2 activators function in the brain by introducing a new toolkit designed to map drug effects specific to certain circuits. Their initial experiments confirmed that a section of the amygdala, known as the basolateral amygdala (BLA), is the main area where mGluR2-activating compounds provide anxiety relief. By utilizing genetic tools and a specialized tracer-labeled virus that can travel along nerve fibers, they identified two specific circuits that connect to the BLA, demonstrate high levels of mGluR2, and show signs of anxiety in mice when stimulated.
The team applied a photopharmacology method, which Dr. Levitz developed during his graduate studies in the early 2010s. This technique uses small molecules linked to mGluR2 that can activate the receptor in any chosen brain circuit when triggered by specific light colors. They discovered that activating mGluR2 signaling in one of the BLA circuits, originating from a brain region called the ventromedial prefrontal cortex, diminished spatial avoidance, a common anxiety indicator in mice. Yet, this anxiety-reducing effect came with memory impairment—an undesirable side effect.
“The working memory deficit we observed might explain the cognitive impairment linked to conventional anxiety medications,” Dr. Levitz noted.
In contrast, when they activated mGluR2 in another circuit, which connects the insula—a region that integrates sensory and internal body-sensing information—to the BLA, they observed different anxiety-reducing effects, which improved sociability and feeding behavior. This time around, there were no noticeable cognitive impairments, suggesting that the insula-BLA circuit could be further explored as a potential target for anxiety treatments without side effects.
“One of our next objectives will be to find a way to selectively target this circuit—essentially avoiding mGluR2 since it exists throughout the brain,” Dr. Levitz mentioned.
He and his colleagues are actively working towards this goal, and they are also utilizing their new circuit-mapping toolkit to study other classes of drugs, including opioids and antidepressants.
