The mechanism of action of anxiety medications is not well understood. “Existing treatments for anxiety are often helpful; however, the effects of these medications may not be persistent and are often accompanied by drowsiness and cognitive side effects,” says Conor Liston, M.D., Ph.D., a psychiatrist at NewYork-Presbyterian and Weill Cornell Medicine. “New treatments are urgently needed to provide better options to our patients living with anxiety and related conditions.”
To better understand how exactly these medications in the brain, a research team including Joshua Levitz, Ph.D., a biochemist at Weill Cornell Medicine, and Dr. Liston recently conducted a study to examine how metabotropic glutamate receptor 2 (mGluR2), a brain-cell receptor found on neurons within many brain circuits, controls anxiety. The researchers identified in a preclinical model a specific brain circuit whose inhibition appears to reduce anxiety without side effects. The results of the study were recently published in Neuron.
Determining the Role of mGluR2 in Anxiety
mGluR2 has been previously implicated in the pathophysiology and treatment of anxiety disorders. In their study, Dr. Levitz, Dr. Liston, and their colleagues examined how presynaptic mGluR2 in the basolateral amygdala (BLA) controls anxiety-related behavior in mice. The team first determined which BLA-targeting projections contained mGluR2 and then examined if activation of these mGluR2 projections could alter anxiety-related behaviors in the mice. They deployed projection-specific photopharmacology, a technique Dr. Levitz’s lab has developed, to do this. This technique uses a genetic and chemical strategy to tag mGluR2, which can then be activated and de-activated by specific wavelengths light.
Fluorescent image of the BLA (outlined) showing projections from the insular cortex (red) and the prefrontal cortex (green). Credit: Dr. Ipsit Srivastava
“The most important takeaway from this research is that two major projections from the cortex to the amygdala express mGluR2, including the medial prefrontal cortex and the posterior insular cortex,” said Dr. Levitz. “If you activate mGluR2 in these projections, they both have anxiolytic effects that manifest differently.”
Targeting the insular cortex to amygdala pathway via mGluR2 may offer a viable therapeutic strategy for achieving anxiolytic effects, especially for social anxiety, without causing major cognitive impairment.
— Dr. Joshua Levitz
They found that manipulating the medial prefrontal cortex pathway alleviated spatial avoidance but led to some cognitive impairment and increased social anxiety. However, the more novel finding was that that by activating mGluR2 in the insular cortex – a sensory and interoception-integrating part of the brain – had anxiety-reducing effects without cognitive impairments. This suggests that the insula-BLA circuit could be investigated further as a possible side-effect free target for treatment anxiety and related conditions.
“Targeting the insular cortex to amygdala pathway via mGluR2 may offer a viable therapeutic strategy for achieving anxiolytic effects, especially for social anxiety, without causing major cognitive impairment,” said Dr. Levitz.
Future Directions
Dr. Levitz has plans to continue studying this target and its potential as a treatment target for anxiety. First, he wants to examine how different circuit elements respond to various types of stress and how stress may reshape these circuits. Then, he wants to understand how different circuits and receptors may be differentially involved in anxiety versus fear. Finally, he wants to harness these circuit insights to find new molecular targets for new therapeutics.
This work shows how targeting a specific molecular signaling pathway in the insular cortex could provide potent relief from specific types of anxiety with fewer side effects.
— Dr. Conor Liston
“By understanding these underlying neural circuits and the receptors expressed within them, we can now more rationally engineer better drugs that may target a next generation of receptors that are more restricted to the pathways we've identified,” said Dr. Levitz.
Dr. Liston adds, “This work shows how targeting a specific molecular signaling pathway in the insular cortex could provide potent relief from specific types of anxiety with fewer side effects. I’m excited about the potential for this novel approach to change the treatment paradigm for anxiety disorders.”
