Caltech Researchers Identify Neural Circuit That Causes Anxiety
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02-19-14 Category: Mental Health

A team of researchers led by biologists at the California Institute of Technology (Caltech) have discovered that a specific area of the brain, the lateral septum (LS), plays a previously unsuspected role in stress-induced anxiety.

The study, “Control of Stress-Induced Persistent Anxiety by an Extra-Amygdala Septohypothalamic Circuit,” found that the LS structure provided insights into how the brain processes anxiety, revealing a neural circuit that connects it with other structures within the brain. The mechanism “plays a causal role in promoting anxiety states,” says David Anderson, Seymour Benz Professor of Biology at Caltech, one of the paper’s authors.

Previous research into anxiety disorders has focused mainly on the amygdala, an area of the brain that is involved with fear, as well as memory and processing of emotions.  The new findings, published in the journal Cell, mean that the lateral septum can be targeted for medications, which could result in more effective pharmacological treatment of anxiety disorders, possibly within a decade.

Anxiety Disorders are Common

The National Institute of Mental Health (NIMH) estimates that in the United State, 18 percent of the adult population, or about 40 million people, suffer from anxiety disorders in a given year. Broadly defined as excessive worry or tension, anxiety disorders include social phobias, as well as post traumatic stress disorder (PTSD) and obsessive compulsive disorder, which were considered anxiety disorders until they were reclassified with the release of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, in 2013. Anti-anxiety drugs, which are widely prescribed to treat the various disorders, have limited effectiveness.

An anxiety disorder is more serious than the transitory feelings of anxiety associated with a specific event, such as public speaking.  Anxiety disorders last for months or years, and can get worse if untreated, according to the NIMH. They are often associated with other conditions including mental or physical illnesses. They also have a high rate of comorbidity with abuse of alcohol or other substances, which can mask the anxiety disorder.

Optogenetics Sheds Light on Anxiety

The researchers used optogenetics – a sophisticated technique dating back to 2005 that involves switching genetically targeted neurons on and off selectively by inserting light-responsive proteins into brain tissue of live animals – to activate targeted neurons in the brains of mice. When targeted neurons in the LS area were activated, the mice became more anxious. Even after brief activation, the mice remained anxious for at least 30 minutes.

Previous research produced evidence that the LS is connected through neural circuits to other areas of the brain, including the hippocampus, amygdala and hypothalamus. However, the nature of the connection was unclear.

Neural Circuit Controls Release of Stress Hormones

One issue that puzzled the researchers was that the targeted neurons were inhibitory, so they were expected to inhibit anxiety when activated, instead of increasing it. Further investigation revealed that the targeted neurons were inhibiting neurons in the hypothalamus that were also inhibitory. The conclusion is that there is a double-inhibitory mechanism involved, where two negative forces essentially create a positive one.  This neural circuit triggers an area of the brain that controls the release of stress hormones such as cortisol.

“The most surprising part of these findings is that the outputs from the LS, which were believed primarily to act as a brake on anxiety, actually increase anxiety,” says Anderson.

This knowledge could be invaluable for the development of medication that can inhibit the neurons and be used to control anxiety. Development of new psychiatric drugs has been limited by the lack of understanding of the brain circuitry that regulates emotions in psychiatric disorders like anxiety or depression, Anderson says. The researchers will continue mapping the LS area of the brain in order to gain a better understanding of its role in controlling stress-induced anxiety, he adds.

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