Advanced brain circuit-mapping technique reveals new anxiety drug target

In their study, published Jan. 28 in Neuron, the researchers examined the effects of experimental drug compounds that activate a type of brain-cell receptor called the metabotropic glutamate receptor 2 (mGluR2). While these receptors are found on neurons within many brain circuits, the team showed that activating them in a specific circuit terminating in an emotion-related brain region called the amygdala reduces signs of anxiety without apparent adverse side effects. Current treatments for anxiety disorders, panic disorder and associated conditions can have unwanted side effects including cognitive impairments.

"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 study senior author Dr. Joshua Levitz, an associate professor of biochemistry at Weill Cornell Medicine.

The co-first authors of the study are Drs. Hermany Munguba and Ipsit Srivastava, a former and current postdoctoral associate, respectively, in the Levitz lab, and Dr. Vanessa Gutzeit, a doctoral student in the Levitz lab at the time of the study.

Activating mGluR2 -- a tiny "dimmer switch" that reduces the synaptic transmission of its host neuron -- has been shown to have anxiety-reducing effects in prior preclinical and small clinical studies. However, the development of this drug class has been stymied in part by concerns over potential side effects. mGluR2 is found within many different brain circuits, and the drugs that target them often activate other members of the mGluR family as well, contributing to the possibility that these drugs will have unwanted side effects.

In the new study, Dr. Levitz and his team advanced the understanding of how mGluR2 activators work on the brain with their new toolkit for mapping circuit-specific drug effects. In initial experiments, they confirmed that a portion of the amygdala known as the basolateral amygdala (BLA) is the principal location where mGluR2-activating compounds exert their anxiety-reducing effects. With genetic tools and a special tracer-labeled virus that can move "upstream" along nerve fibers, they isolated two specific circuits that terminate in the BLA, express high levels of mGluR2 and induce anxiety signs in mice when active.

They next deployed a photopharmacology technique that was first developed by Dr. Levitz when he was a graduate student in the early 2010s. The technique uses small molecules that are tethered to mGluR2 and can activate the receptor -- in any brain circuit of interest -- when "switched on" by specific colors of light. The team found that in one of the BLA circuits, which runs from a brain region called the ventromedial prefrontal cortex, activating mGluR2 signaling reduced spatial avoidance, a classic anxiety sign in mice. However, this anxiety-reducing effect was accompanied by memory impairment, an unwanted side effect.

"This working memory deficit we observed may be a basis for the cognitive impairment associated with typical anxiety drugs," Dr. Levitz said.

In the other circuit, which runs to the BLA from a sensory and interoception (internal body-sensing)-integrating part of the brain called the insula, activating mGluR2 had different anxiety-reducing effects, normalizing sociability and feeding behavior. In this case, there were no apparent cognitive impairments -- indicating that this insula-BLA circuit could be investigated further as a possible side-effect-free target for treating anxiety and related conditions.

"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 said.

He and his colleagues are now pursuing that goal, he said, and are also using their new circuit-mapping toolkit to investigate other drug classes, including opioids and antidepressants.