Advanced Brain Circuit-Mapping Technique Reveals New Anxiety Drug Target

Weill Cornell Medicine Investigators have identified in a preculinical model A SPECIFIC BRAIN CIRCUIT WHOE INHIBITION APPEARS TO REDUCE ANXIETY WITHHOUT SIDE Effects. Their Work Suggests a New Target for Treating Anxiethy Disorders and Related Conditions and Demonstrates to General Strategy, Based on A Method Called Photopharmacology, for Mapping Drug Effects on the Brain.

In Their Study, published Jan. 28 in NeuronThe Researchers Examined the Effects of Experimental Drug Compounds That Activate A Type of Brain-Cell Receiver Called the Metabotropic Glutamate Receiver 2 (MGLUR2).

While these receptors are Found on Neurons Within Many Brain Circuits, The Team Showed That Activating Them in a Specific Circuitting in Anx Emoti-Related Brain Called the Amygdala Reduces Signs of Anxiethy Without Appent Advernt Adverntes Side Effects. Current Treatments for Anxiethy Disorders, Panic Disorder and Associated Conditions Can have unwanted Side Effects Including Cognitive Impairments.

“Our Findings Indicates the new and Important Target for the Treatment of Anxiethy-Relanted Disorders and Show that our photopharmacology-Based Approach Holds Promise More Broadly As A Precisell Reverse-Engineer How Therapeutics Work in the Brain,” Said Study Senior 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, the Former and Current Postdoctoral Associate, respective, in the Levitz Lab, and Dr. Vanessa Gutzeit, the Doctoral Student in the Levitz Lab at the Time of the Study .

Activating Mglur2-Tyy “dimmer switch” that reduces the synaptic transmission of its host neuron-has benwn to have anxiethy-reducing effects in prior precline 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 WITHHIN MANY DIFFERENT BRAIN CIRCUITS, AND THE DRUGS THAT TARGET THEM OFTEN ATTENT ATTRENSE OF THE MGLUR FAMILY AS WELL, CONTRIBUTING TO THE POSSIBILITY THAT 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 New Toolkit for Mapping Circuit-Specific Drug Effects.

Initial Experiments, They Confermed That a Portion of the Amygdala Known As The Basolateral Amygdala (BLA) is the main location where Mglur2-Activating Compounds Exert Their Anxiethy-Reducing Effects. With genetic tools and a special tracer -bered virus that can move “upstream” allong nerve fibers, they isolated Two Specific circuits that terminate in the bla, Express High Levels of Mglur2 and induce anxiey Signs in Mice when active.

They Next Deployed a photopharmacology technique that was first developed by Dr. Levitz when he was graduate student in the early 2010s. The Technique Uses Small Molecules That Are Tethered to Mglur2 and Can Activate The Receiver – 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 Ventomedial Prefrontal Cortex, Activating Mglur2 Signaling Reduced Spatial Avoidance, A Classic Anxiet Sign in Mice. However, this anxiety-reducing effect was accumpanied by memory impairment, an unwanted side effect.

“This Working Memory Deficit We Observed May Be A Basis for the Cognitive Impairment Associated with Typical Anxieth Drugs,” Dr. Levitz Said.

In the other circuit, Which Runs to the Bla from A Sensory and Internal Body-Sensing-Integrating Part of the Brain Called the Insula, Activating Mglur2 Had Different Anxiethy-Reducing Effects, Normalizing Socability and Feeding Behavior.

In this Case, There Were No Apparent Cognitive Impairments-Indicating That This Insula-Bla Circuit Could Be Investigated Further as Possible Side-Effect-Free Target for Treating Anxiet and Related Conditions.

“One of the Next Steps Will Be To Find A Way To Target This Circuit Selective –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.