Weill Cornel Medicine Investigators have identified in a preclinical model a specific brain circuit with inhibition Their work sugges a new target for treatment anxiety disorders and related conditions and demonstrates a general strategy, based on a method called photopharmacology, for mapping druping drupting drugs on.

In their study, Published Jan. 28 in NeuronThe 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 regdala Ithout 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 approachs promise more broadly as a vay to work Therapeutics work in the brain, “said study Senior Author Dr . Joshua Levitz, an associate professor of biochemistry at weill cornel medicine.

The co-first authors of the study are drs. Hermany Munguba and IPSIT SRIVASTAVA, A Former and Current Postdoctoral Associate, Respected, In the Levitz Lab, and Dr. Vationsa 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 preachlinical and Smarall CLINICAL Stodies. However, the development of this drug class has been styned 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 Ffects.

In the new study, Dr. Levitz and his team advanced the undersrstanding of how Mglur2 Activators work on the brain with their new toolkit for mapping circuit-specific drug effects.

Initial Experiences, they confirmed that a portion of the amygdala knowledge as the basolateral amygdala (BLA) is the princess location where mglur2-activating compounds experts experts. With gentic tools and a special tracer-labeled virus that can move “Upstream” Along Nerve Fibers, Thei Islated Two Specific Circuits that Terminate in the Bla, Express HIGHLS OF MGLUR2 Y 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 Tethed 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 ragion called the ventromedial prefrontal cortex, activating Mglur2 Signaling Signaling Spatiial Avoidance, A Classic Anxity SINXINCE in MCE. However, this anxiety-reducing effect was acompanied by memory impairment, an unwanted side effect.

“This Working Memory Deficit We observed May be a Basis for the Coganitive 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 Differentry Izing Sociability and Feeding Behavior.

In this case, there was no apparent cognitive impairments-indicating that this Insula-Bla Circuit BE Investigated Furter as A Possible Side-Effect-FRE TARATING FOR TREATING ANXITY 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 everyone,” Dr. Levitz said.

He and his colleagues are now pursuing that goal, he said, and are also also using their new circuit-mapping toolkit to investigate other Drug Classes, Including opioids and antprexants.