In today’s fast-paced, pressured, often-violent and unstable world, everybody feels anxious from time to time. It’s a normal emotion to be anxious before making a difficult decision, when having to cope with pressure at work or before taking an exam.

But anxiety disorders – a group of mental illnesses that cause distress that can prevent normal daily functioning – are different. According to some estimates, up to one in three people around the world may experience severe anxiety in their lifetime. People who suffer from these conditions feel constant and overwhelming fear and worry.

The symptoms in common with all types include uneasiness, sleeping problems, panic, fear, dry mouth, cold and sweaty hands or feet, shortness of breath, nausea, tense muscles and dizziness. Disruptions in various part of the brain, including the amygdala and hippocampus, are believed to be involved in anxiety disorders. No laboratory tests can specifically diagnose anxiety disorders, but talking to one’s physician, psychologist or psychiatrist can uncover the problem.

Panic disorder can cause a person to feel as if he’s had a heart attack – sweating and palpitations and chest pain – but these worrisome symptoms are in fact due to anxiety.
Social phobia or social anxiety disorder is when you feel enormous worry and self-consciousness about everyday social situations. You fear being embarrassed or made fun of and that others are judging you.

Then there are people with generalized anxiety, tension and worry even if there is little or no reason for their feelings. Others suffer from specific phobias such as when being in a small place (claustrophobia), when being in a larger place where it would difficult to escape (agoraphobia), when seeing insects or snakes or when flying in a plane.

Treatments include systematic desensitization (cognitive behavioral therapy), progressive relaxation, virtual reality and hypnotherapy, but they don’t solve the problem for many sufferers. Drugs have focused on several hormones and neurotransmitters believed to be involved, but medications’ ability to solve the problem is limited, and they often have undesirable side effects.
But now, a new neural mechanism underlying serious anxiety disorders has been proposed by researchers at the Weizmann Institute of Science in Rehovot, Israel that seem likely to lead to more effective treatments in the future.

Prof. Mike Fainzilber in the institute’s biomolecular sciences department and colleagues have studied for nearly two decades the neuronal roles of proteins called importins. These proteins, found in all cells, shuttle molecules into the cell nucleus. The lab’s previous work focused on the peripheral nervous system (all nerve tissue in the body except the brain and spinal cord).
In a study just published in the journal Cell Reports, his postdoctoral fellow Dr. Nicolas Panayotis, who joined the group in 2012, decided to find out whether any of the importins also play a role in the central nervous system (the brain and spinal cord).

Panayotis and colleagues studied five lines of mice that had been genetically engineered by Prof. Michael Bader’s laboratory in Berlin’s Max Delbrück Center for Molecular Medicine to lack genes from the alpha subfamily of importins. The researchers subjected the mice to a series of behavioral tests and found that one line of mice – those lacking importin alpha-5 – stood out in a unique manner: They showed no anxiety in stressful situations, for example, when they were placed in large, exposed arenas or on a highly elevated, open platform.

The researchers then checked how these “calmer” mice differed from regular ones in terms of gene expression in certain brain regions involved in controlling anxiety. Analyses pointed to MeCP2, a regulatory gene known to affect anxiety behaviors. It turned out that importin alpha-5 was critical for enabling the entry of MeCP2 into the nuclei of neurons. Changes in the levels of MeCP2 in the nucleus, in turn, affected the levels of an enzyme involved in the production of a signaling molecule called S1P.

In mice lacking importin alpha-5, MeCP2 failed to enter the nuclei of anxiety-controlling neurons, reducing S1P signaling and lowering anxiety. After performing additional experiments to confirm that they had indeed discovered a new anxiety-regulating mechanism in the brain, the researchers searched for molecules that could modify this mechanism. They realized that drugs that modulate S1P signaling already exist; one such drug, fingolimod, is used to treat multiple sclerosis.

When the researchers tested the effects of fingolimod on regular mice, these mice showed reduced anxiety, similarly to the genetically engineered mice lacking the importin alpha-5 gene. Moreover, the researchers found an earlier report from a clinical trial of fingolimod, according to which the drug had a calming effect on patients with multiple sclerosis. The new study might now help explain why this was the case.

“Our findings have opened up a new direction for research into the mechanisms of anxiety,” Panayotis noted. “If we understand exactly how the circuitry that we’ve discovered controls anxiety, this may help develop new drugs, or direct the use existing ones, to alleviate its symptoms.” Fainzilber:

“Current drugs for anxiety are limited in their efficacy or have undesirable side effects, which also limit their usefulness,” concluded Fainzilber. “Our findings may help overcome these limitations. In follow-up research, we have already identified a number of drug candidates that target the newly discovered pathway.”