For years, scientists have observed a correlation between certain neural processes and an observed anxiety in tests subjects. But they haven’t been able to pin down whether the processes respond to the stress, as a way to cope with it, or produce that stress. Now researchers from California Institute of Technology (Caltech) have discovered it is, indeed, the latter.

Fretting about an overdue assignment? Wondering if that blind date will ever show? Your brain needs a way to respond to these situations, and if the stakes are high enough — a final dissertation, a timid first step back into the dating pool — steady supplies of cortisol will be flooding your system. Science has known this for quite some time. What has been less clear is the mechanism that releases that cortisol in the first place. In other words, what happens in between the time you realize your date seems to be running late and when you nervously check your watch to confirm it? What is your brain up to? The answer, to the surprise of Caltech researchers, is a bit of backward thinking.

The team began its search for stress-producing pathways at a region of the brain called the septohippocampal axis. It’s an area nestled deep in the brain that has been shown in prior research to deal heavily in anxiety-related responses. Within the region is a patch of neurons, known as the lateral septum (LS), which lit up like crazy when mice were made to feel anxious. This is the correlation the Caltech team wanted to learn more about, and they published their findings in the journal Cell.

They used optogenetics to answer their questions. Basically, the technique involves manipulating individual neurons with distinct patterns of light, and in this case, the team focused on the LS. The effect of artificial activation was so strong, in fact, that the team’s mouse models remained in an anxious state for more than half an hour after only brief exposure to the researchers’ probing. This suggested not only that the LS played a role in stress activation, but that the effect persisted when the neurons weren’t even being toyed with.

"The counterintuitive feature of these neurons is that even though activating them causes more anxiety, the neurons are actually inhibitory neurons, meaning that we would expect them to shut off other neurons in the brain," said David Anderson, the Seymour Benzer professor of biology at Caltech and co-author of the study, in a statement. The fact these inhibitory neurons shut off other neurons should imply that anxiety gets reduced. In fact, the exact opposite happened.

Turning Negatives Into A Positive

To the researchers’ great surprise, the double-negative relationship between neurons resulted in a positive: they essentially canceled each other out. When the LS neurons were activated, they triggered a response among the neurons in a related area, the hypothalamus. Both sets of inhibitory neurons connected to a third neighboring region, called the paraventricular nucleus, or PVN. The PVN is chiefly responsible for opening the floodgates for cortisol — the stress hormone — to be released in the brain.

This circuit implied a curious fact: Could activating the inhibitory neurons in the LS trigger an inhibitory response in the hypothalamus, making the two cancel each other out, and thus activating the cortisol-release system? The answer, simply and rather elegantly, was yes.

Each time the team activated the LS, cortisol bathed the mice’s brain. And each time they inhibited the LS, cortisol levels dropped, both via the PVN pathway consistent with their hypothesis. "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," remarked Anderson.

The real upshot to this discovery is that scientists may finally be able to build a more precise set of anxiety drugs, the team noted. "There have been very few new psychiatric drugs developed in the last 40 to 50 years,” Anderson said, “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."

Understanding the brain is never an easy task. A research team’s findings, if they bear any fruit at all, are often correlative. Like prior studies into stress mechanisms, they tend to show one area of the brain lights up in tandem with a physiological response or other brain functions. But whether these responses are a symptom or a cause of these other processes generally remains a mystery, left up to future research to investigate. Anderson concedes his team’s study still has some of those mysteries, but at least they know they’re pursuing the proper hunch.

"There is no shortage of new questions that have been raised by these findings," he said, adding that actual drug development is still a decade away. "It may seem like all that we've done here is dissect a tiny little piece of brain circuitry, but it's a foothold onto a very big mountain. You have to start climbing someplace."

 

Source: Anthony T, Dee N, Bernard A, Lerchner W, Heintz N, Anderson DJ. Control of Stress-Induced Persistent Anxiety by an Extra-Amygdala Septohypothalamic Circuit. Cell. 2014.