If we could, many of us would choose to never feel anxiety again. But unfortunately, this unpleasant emotion serves a profound and necessary purpose.

“Anxiety is thought to play a role in the anticipation of danger,” Dr. Adam Claridge-Chang of Duke NUS Medical School told Medical Daily. “Unlike fear, which is associated with flight, anxiety is related to conflicted approach and risk assessment.”

When excessive, dread can become dysfunction, and this emotional problem is common; currently, anxiety disorders are the most prevalent of all brain disorders. To speed progress on new treatments, Claridge-Chang and his colleagues suggested research on simple fruit flies might help illuminate the biological mechanisms underlying this emotion. In a new study published in Current Biology, they show the very same factors that govern our own anxiety also control defensive behaviors in flies. When searching for possible genes as treatment targets, then, scientists might benefit from investigating the simple fly alongside the more standard rodent research.

“For experiments, flies are faster and cheaper than mice or rats. The fly brain is much smaller, simpler, and easier to study,” said Claridge-Chang, adding that the genetic tools available for flies are also superior to those for mice. Yet, there’s a final benefit that is underappreciated, he said: “The [low] cost means each fly experiment can be done with many more animals, leading to more reliable results.”

Us and Them

The same emotional states we experience are shared by some animals. Scientists use three signs to identify human emotions in animals: behavior, physiologic response, and gene conversation — strings of DNA sequences. When these signs are common to both humans and animals, they are believed to regulate similar emotional and behavioral responses. To better understand the neuronal and molecular basis of an emotion, scientists “model” the emotion in a small animal, which commonly ends up being rodents.

Unfortunately, the rodent brain is needlessly complex for experimental purposes, and, for ethical and other reasons, only small numbers of animals can be used. These two limitations have led anxiety drug research in rodents to stall, Claridge-Chang explained. So, along with his colleagues, the team decided to find a new model for understanding the nervous system mechanism underlying anxiety. Enter the fly.

“Because of the deep evolutionary relationship between flies and humans, about half of all genes are shared between the two species, so many of the oldest anxiety genes will be present in flies,” Claridge-Chang said.

The experiments began with an observation that flies tend to stay close to walls when in an enclosed space. Proposing this behavior related to anxiety, the team tested its hypothesis by treating the flies with Valium, an anti-anxiety drug. Voila, the flies stopped clinging to the walls.

Next, the research team verified the anxiety-like state by examining the flies’ GABA receptors, serotonin signaling, and stress response. Here, they found similar effects to those in rodents. These steps enabled the team to identify several new anxiety genes, all of which have counterparts in humans.

“Understanding what they do in the fly will give a clear roadmap of hypotheses to test in the mouse. More genes and a better understanding of fly/mouse anxiety gives more opportunities to find new anxiety drug targets,” Claridge-Chang said. Going forward, he plans to research the role of serotonin, a neurotransmitter that may play a role in anxiety. While the current research shows serotonin is involved, paradoxically, the serotonin drugs currently on the market do not always alleviate anxiety.

One such drug is Prozac (fluoxetine), which Dr. Trevor James Hamilton of Canada’s Grant MacEwan University recently studied using another unusual animal model: crabs. Unlikely though it may seem, this invertebrate exhibits aggression and anxiety-like behavior similar to vertebrates that’s modulated by serotonin.

SSRIs

“We were investigating whether large doses of Prozac were first going to alter their anxiety-like behavior or their aggression,” Hamilton told Medical Daily in an email.

Prozac is a selective-serotonin reuptake inhibitor (SSRI), meaning it blocks specialized proteins on neurons from moving serotonin back into the neurons. Taking Prozac or any SSRI — the most commonly prescribed category of antidepressant — results in more serotonin flowing around the brain’s cells.

For their experiment, Hamilton and his colleagues dosed the crabs with Prozac and observed a significant decrease in anxiety-like behavior. Yet, the mobility and aggression of the crabs remained unchanged. These results suggest anxiety-like behavior is more sensitive to serotonin modulations than aggressiveness (in the shore crab), and also support the idea that serotonin plays a key role in anxiety.

Serotonin-related drugs like Prozac, however, show little efficacy on emotional disorders, according to Claridge-Chang. While Valium, a benzodiazepine originally launched in 1963, is effective, it also comes with some undesirable side effects, including drowsiness, dizziness, and mental impairment. New and improved anxiety treatments are long overdue, Claridge-Chang said. By studying the "serotonin paradox" in flies, he and his team hope to gain insights that might someday, someway, apply to our very own human anxieties.

Source: Mohammad F, Aryal S, Ho J, et al. Ancient Anxiety Pathways Influence Drosophila Defense Behaviors. Current Biology. 2016.