Researchers have discovered that an area of the brain that was previously assumed to dampen response to stress, in fact does the opposite and directly promotes anxiety. In reporting their findings in the journal Cell, the investigators add a new dimension to the science of anxiety.
They describe how they found a brain circuit that connects an area called the lateral septum (LS) with other brain structures in a way that directly affects anxiety.
Corresponding author David Anderson, the Seymour Benzer Professor of Biology at California Institute of Technology (Caltech) in Pasadena, says:
"Our study has identified a new neural circuit that plays a causal role in promoting anxiety states. Part of the reason we lack more effective and specific drugs for anxiety is that we don't know enough about how the brain processes anxiety. This study opens up a new line of investigation into the brain circuitry that controls anxiety."
Figures from the National Institutes of Mental Health show over 18% of adults in the US are affected by anxiety disorders, where people experience excessive worry or tension, often leading to physical symptoms.
Although previous research has focused primarily on the amygdala as being the region in the brain that processes anxiety, Prof. Anderson and colleagues had a hunch that the LS might also be involved, so they decided to study it using mice.
Does the lateral septum promote or inhibit anxiety?
The team set out to investigate a circuit called the septohippocampal axis because previous studies had already mentioned it in connection with anxiety. These had shown that in mice, stress-induced anxious behavior is accompanied by activation of brain cells in the LS, which sits inside this circuit.
But if the LS is active during stress, is it promoting anxiety, or is it limiting it?
Until this study, the belief was the LS dampened the response to stressors. But the team showed in fact the opposite was the case.
They used a technique called optogenetics, where light controls neurons or brain cells, to activate a set of neurons in the LS of mice. The particular neurons had a gene that made them active in response to light.
During this activation, the mice became more anxious. When they tested the effect further, the team found that even a brief burst of activation induced a state of anxiety that persisted for at least half an hour.
This showed that not only were these particular brain cells involved at the start of the anxiety state, but also that this state persists when they are no longer active.
But the reason that - until now - it was thought these brain cells inhibited anxiety was because they are of a type that inhibits other brain cells, says Prof. Anderson. So what was going on?
The lateral septum promotes anxiety via a double-inhibitory circuit
Prof. Anderson and his colleagues decided to test the idea that a double-negative system was involved. Neurons inhibiting inhibitory neurons. And that is indeed what they found.
When they looked at the types of connections the LS made in the brain, they found it was inhibiting neurons in the neighboring hypothalamus, most of which were themselves inhibitors.
Plus, the hypothalamic inhibitory neurons were connected to a third brain structure, the paraventricular nucleus (PVN), which controls the release of hormones like cortisol in response to stress and is known to be involved in anxiety.
The team found a circuit that appeared to act as a double-inhibitor where activating the LS neurons could result in increased stress and anxiety. When they activated the LS neurons, the levels of circulating stress hormones increased, suggesting the PVN was being activated.
And they also tested the converse: inhibiting the LS connections to the hypothalamus reduced the rise in stress hormones when the mice were under stress.
They concluded that this set of results confirms the double-negative idea.
"The most surprising part of these findings is that the outputs from the LS," Prof. Anderson says, "which were believed primarily to act as a brake on anxiety, actually increase anxiety."
He explains their findings are important for drug developers - they need to know that the target LS neurons promote rather than inhibit anxiety.
He cautions that it will take about 10 years to move from this lab result to a therapy for humans, but he hopes the findings point to a better direction for developing new therapies and adds:
"There have been very few new psychiatric drugs developed in the last 40 to 50 years, and that's because we know so little about the brain circuitry that controls the emotions that go wrong in a psychiatric disorder like depression or anxiety."
The research was sponsored by the Beckman Institute at Caltech, the National Institutes of Health, and the Howard Hughes Medical Institute.
Medical News Today recently reported a review of 47 randomized clinical trials involving a total of 3,515 participants that concluded mindfulness meditation can help some people with anxiety.
Written by Catharine Paddock PhD