Scientists have identified a cerebral circuit which, when activated, reduces anxiety without altering memory.
Using light -sensitive drugs, they have identified a promising neuronal route that could lead to more efficient and safer anxious treatments.
Target anxiety with research on brain circuits
Weill Cornell Medicine researchers identified a specific cerebral circuit which, when inhibited, reduces anxiety without causing significant side effects – at least in preclinical models. Their results highlight a new potential target to treat anxiety disorders and introduce a broader strategy to study the effects of drugs in the brain using a technique called photopharmacology.
Posted on January 28 in the scientific journal NeuronThe study examined how the compounds of experimental drugs interact with a receptor of the brain cells known under the name of receptor 2 of the Metabotropic Glutamate 2 (MGLUR2). While MGLUR2 receptors are present in many brain circuits, researchers have discovered that activating in a particular path leading to the amygdal – an area involved in the treatment of emotions – has considerably reduced behaviors related to anxiety without cause harmful side effects. This is promising development, as many treatments existing for anxiety and panic disorders can cause cognitive deficiencies and other unwanted consequences.
A new path for the development of drugs
“Our results indicate an important new target for the treatment of disorders related to anxiety and show that our approach based on photopharmacology is promising more widely as a means of precisely retreating the functioning of therapy in the brain,” said the ‘Study, principal author, Dr Dr.. Joshua Levitz, associate professor of biochemistry at Weill Cornell Medicine.
The co-prime of the study are the DRS. Hermany Munguba and Ipsit Srivastava, an old and current postdoctoral partner, respectively, in the Labory Levitz, and Dr. Vanessa Gutzeit, doctoral student at Labory Levitz at the time of the study.
MGLUR2 activation has been shown – a tiny “gradator” which reduces the synaptic transmission of its host neuron – has had anxiety reduction effects in preliminary preliminary and small clinics studies. However, the development of this class of drugs has been partly blocked by concerns about potential side effects. MGLUR2 is found in many different brain circuits, and the drugs that target them often activate other members of the MGLUR family, also contributing to the possibility that these drugs have unwanted side effects.
Cartography of anxiety circuits in the brain
In the new study, Dr. Levitz and his team have advanced understanding of how MGLUR2 activators work on the brain with their new toolbox to map the effects of specific drugs. In the first experiences, they confirmed that part of the amygdal known as the baslateral amygdal (BL) is the main place where compounds activating MGLUR2 have their reductive anxiety effects. With genetic tools and a special tracker marked
“Data-Gt-translate-attrattes =” ({“attribute =” “tabindex =” 0 “role =” link “> virus This can move “upstream” along the nerve fibers, they have isolated two specific circuits that end in the BLA, express high levels of MGLUR2 and induce signs of anxiety in mice when active.
They then deployed a photopharmacology technique which was developed for the first time by Dr Levitz when he was a graduate student in the early 2010s. The technique uses small molecules which are attached to MGLUR2 and can activate the receiver – in Any cerebral circuit of interest – when it is “lit” by specific light colors. The team noted that in one of the BLA circuits, which extends from a region of the brain called the Ventromedial prefrontal cortex, activating the MGLUR2 signaling reduced spatial avoidance, a sign of conventional anxiety in mice. However, this reducing effect of anxiety was accompanied by memory disorders, an undesirable side effect.
“This working memory deficit that we have observed can be a basis for cognitive disorders associated with typical anxiety drugs,” said Dr. Levitz.
Taking the right circuit for the relief of anxiety
In the other circuit, which takes place towards the Bla from a sensory part and interoception (internal detection of the body), an integral part of the brain called insula, the activation of MGLUR2 has had reduced effects of the different anxiety, normalizing sociability and food behavior. In this case, there was no apparent cognitive impairment – indicating that this insula -blah circuit could also be studied as a possible target without side effect to treat anxiety and related conditions.
Future orientations in the treatment of anxiety
“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,” said Dr. Levitz.
He and his colleagues now pursue this goal, he said, and also use their new circuit cartography toolbox to investigate other classes of drugs, including opioids and antidepressants.
Reference: “Projection-Targeted Photopharmacology Displant Anxiolytic Roles for Presyyptic Mglur2 in Prefrontal- and Insula-Amygdala Synaps” by Hermany Munguba, Ipsit Srivastava, Vanessa A. Gutzeit, Ashna Singh, Akshara Vijay, , Sonal Thukral, Johannes Broichhagen, Joseph M. Studenske, Conor Liston and Joshua Levitz, January 28, 2025, Neuron.
DOI: 10.1016 / J. ENERON.2025.01.002
The research reported in this history was partly supported by the National Institute of Mental Health and the National Institute of Neurological Disorders and Cerebral Vascular Accidents, both part of
“Data-Gt-translate-attrattes =” ({“attribute =” “tabindex =” 0 “role =” link “> National Institutes of HealthVia subsidy numbers R01MH129693, R01MH123154, R01MH118451, R01NS126073, F31MH123130 and K08MH127383.
