Can flies teach us something about the genetics and potential treatments for anxiety? Surprising new findings about similarities with humans.

* Scientific study references are indicated in (). These can be found at the bottom of the article, and can be clicked on to open the original reports in a separate tab.

The question of whether we share some of our emotional experiences, such as anxiety, with other species is fascinating for many reasons. Firstly, it intrinsically touches many of us because it forces us to assess our uniqueness as members of the animal kingdom. But aside from these philosophical issues, examining the extent of human-ness in animal experience is important when we consider whether studying animals allows us to learn something about the human condition, including normal mental processes as well as psychiatric illnesses. Our tendency to view most of our mental states as fabrications of highly advanced human brains makes the idea that animals might be experiencing something similar a constantly debated topic. I suppose on an intuitive level, the idea of an anxious fly is especially absurd.

However, a study recently published in the journal Current Biology suggests otherwise. Its findings indicate that the tiny creature might have an unexpected capacity to be anxious, which could actually be used to uncover something about the biology of our own anxiety (10). It certainly doesn’t go to say that flies experience the rumination and discomfort that humans can feel in social situations, at work, or when otherwise stressed. Rather, there appears to be a fundamental property of the fly’s behaviour that can be defined as anxiety, and become dissected for a better understanding of the underpinnings of this phenomenon throughout the animal kingdom.

Clearly, we can’t think like a fly. So how could we measure its anxiety, or that of any other animal for that matter? Over the past few decades, researchers interested in anxiety have come to rely primarily on rodents, using a few classic tests now considered to be the gold standard for measuring anxiety (14,15) . Let’s look briefly into these before examining the fly. In one of the most popular tests, the elevated plus maze, a rodent is placed in a plus-shaped maze that is raised above the ground. While two of the maze’s arms are open walkways, the other two have surrounding walls that shelter the animal from the lights in the room, as well as the view of the height.Elevatedplusmaze.pngWhy might this test useful for measuring anxiety? We know that mice strongly prefer being sheltered in the dark – presumably because this bears some similarity to their natural burrow homes in the wildlife. In contrast, they avoid brightly lit open spaces that are perhaps more likely to be associated with danger, and have a general dislike of heights. Thus, the idea behind the elevated plus maze is that by placing a mouse into an environment with a choice of both shelter and an open path, it can be forced to waver between its innate fear of exposed places and its interest in exploration that is offered by the open walkway. Ultimately, anxiety is thought to win when it compels the animal to spend more time avoiding the exposed areas of the maze in favour of the dark comforting shelter.

And how do we know that this way of testing behaviour actually reflects a mouse’s anxiety, as opposed to just being a highly artificial measure derived from an unnatural situation? In fact, how do we know a mouse can feel anxious altogether? This is, of course, an essential question. If animals are to be used to ‘model’ human conditions such as anxiety, and investigate their biological causes as well as possible treatments, then we need to ensure that the tasks we are using to supposedly measure emotions such as anxiety do pick up on something legitimate.

One of the most common ways to verify that a particular test is indeed looking at something akin to anxiety involves examining how a mouse’s behaviour on this test is affected by medications that are typically used to treat anxiety in humans. Such drugs could include benzodiazepines such as Diazepam (previously marketed as Valium), and anxiolytics which act on the serotonin neurochemical system, such as sertraline and fluoxetine (aka Prozac). The underpinning logic of this drug test is quite simple. If a mouse’s behaviour on a test can be changed by classic anti-anxiety, or anxiolytic, treatments, then there is good reason to believe that this particular test might be tapping into a psychological state that has something in common with human anxiety. When it comes to the elevated plus maze, for instance, researchers have repeatedly found that mice given typical anxiolytic medications spend less of their time avoiding the exposed walkway of the maze, as well as being quicker to enter it compared to mice given a placebo (6, 11). Of course, no test could ever give us total insight into the inner workings of a mouse’s mind and verify that it truly experiences anxiousness. However, the fact that anxiolytic drugs seem to alleviate mouse behaviours that are considered indicative of anxiety presents a convincing case for the possibility that mice are capable of emotional states that are, on a fundamental level, similar to human anxiety.

Another test commonly used to measure anxiety in mice – the open field test – involves placing them in a large brightly lit enclosure and examining their initial exploration patterns. Here, mice tend to avoid the central area of the enclosure and spend most of their time in contact with the walls, as if seeking their refuge. This tendency, called thigmotaxis (from Greek ‘thigma’ – to touch), is alleviated by several anxiolytic medications, which has led researchers to assume that this phenomenon might reflect a rodent’s state of anxiety (12).

It turns out that flies, much like mice, also spend most of their time pacing close to the walls when placed inside an enclosure. In fact, the recent report in Current Biology reveals that flies are remarkably similar to rodents when we trace the movements they make in an enclosure over a period of time! What’s more, flies are similarly affected by stress,  as they spend even more time closer to the walls if they have endured extended social isolation or physical restraint.Wall_following

But would it be a stretch to suppose that such wall following behaviour might be underpinned be anxiety? Dismissing such a possibility due to intuitive disbelief would be quite unscientific, so the researchers put it to the test with several experiments.

First, they investigated whether a dose of the drug Diazepam (aka Valium) – a tranquiliser commonly used to treat anxiety, agitation, and insomnia in humans – could have an influence on the wall following behaviour of flies. In previous experiments, this drug had been found to decrease the apparent anxiousness that rodents have about venturing away from walls in enclosures (3). It turned out that in flies too, Diazepam markedly reduced the tendency to follow the walls. Is it possible that we are witnessing an emotional state that is in some way comparable across species?

In a further turn of events, the researchers uncovered some fundamental parallels between the genetics of human anxiety and anxious-like behaviours in rodents and flies. In one of their experiments, they engineered flies that mimicked one of the most talked about genotypes in the human population that is associated with increased risk of developing anxiety (7, 8, 9). The diagram below explains the basics of this genotype.

 

5HTT_polymorphism.png

In 2003, a group of researchers that followed the lives of over 1000 individuals published a famous report suggesting that those with 1+ copies of the short version of the serotonin transporter gene have relatively low emotional resilience compared to others (8). Specifically, experiencing life stress was found to make these individuals substantially more likely to develop anxiety or depression symptoms than those who had inherited two copies of the long version of the gene, which is associated with higher levels of serotonin transporter production. I should mention that this finding has not gone without being contested, as it has stimulated hundreds of follow-up studies, some of which failed to support the genotype’s risky reputation (4). Despite this, researchers acknowledge that there appears to be reason to believe that reduced function of the serotonin transporter makes a significant, albeit small, contribution to individuals’ chances of developing anxiety at some point in their lives (9). Interestingly, eliminating the activity of the serotonin transporter in mice, also known as ‘knocking it out’, seems to make mice behave more anxiously on the various tests I have described (5). It seems that the genotype has a role to play in the emotional states of several species.

But does this anxiety-risk genotype have a similar effect in flies? Indeed, it does. Researchers behind the recent publication in Current Biology found that artificially reducing the production of the serotonin transporter in flies further strengthened their tendency to follow walls in enclosures. These results provide us with some food for thought, as wall following might reflect a mental state of anxiety in a creature we probably didn’t imagine having any room for emotions!

The wall following phenomenon of the fly might be an ‘ancient’ form of anxiety that serves as the original blueprint for anxious experiences in species separated by as much as hundreds of millions of years of evolution. It’s possible that higher animals like us have elaborated on this rudimentary emotional scaffold by building ourselves an intricate social world that brings with it an immense diversity of situations that can provoke worry. And in spite of the vast complexity of our subjective anxieties, the core of this experience might be more shared across the species than we suspect.

Indeed, there is good reason to believe that this should be the case. The ability to learn about situations associated with threat and produce emotional reactions that discourage us from approaching such situations is undoubtedly critical for survival. In light of this, researchers have repeatedly argued that the brain mechanisms that underpin the ability to be anxious must have evolved in the earliest mammalian species, if not in even more primitive organisms (13). Ultimately, the existence of some rudimentary commonality between human and fly anxiety might mean that flies could make useful subjects of further study in anxiety research. This could open the door to quicker development of potential new treatments, as well as genetic screens aiming to identify possible new anxiety risk genes.

Drosophila

References

  1. Canli, T. and Lesch, K. (2007). Long story short: the serotonin transporter in emotion regulation and social cognition. Nature Neuroscience 10, 1103-1109.
  2. Eisenberg, D. T. A. and Hayes, M. G. (2011). Testing the null hypothesis: comments on ‘Culture-gene coevolution of individualism-collectivism and the serotonin transporter gene’. Proceedings of the Royal Society 278, 329-332.
  3. Griebel, G. and Holmes, A. (2013). 50 years of hurdles and hope in anxiolytic drug discovery. Nature Reviews Drug Discovery 12, 667-687.
  4. Gustavsson, J. P. et al. (1999). No association between serotonin transporter gene polymorphisms and personality traits. American Journal of Medical Genetics 88, 430-436.
  5. Holmes, A. et al. (2003). Mice lacking the serotonin transporter exhibit 5-HT(1A) receptor-mediated abnormalities in tests for anxiety-like behavior. Neuropsychopharmacology 12, 2077-2088.
  6. Kurt, M. et al. (2000). The effects of sertraline and fluoxetine on anxiety in the elevated plus-maze test in mice. Journal of Basic and Clinical Physiology and Pharmacology 11, 173-180.
  7. Lesch, K. P. et al. (1996). Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274, 1527-1531.
  8. Caspi, A. et al. (2003). Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301, 386-389.
  9. McGuffin, P. et al. (2011). The truth about genetic variation in the serotonin transporter gene and response to stress and medication. British Journal of Psychiatry 198, 424-427.
  10. Mohammad, F. et al. (2016). Ancient anxiety pathways influence Drosophila defense behaviors. Current Biology 26, 981-986.
  11. Pellow, S. et al. (1985). Validation of open: closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. Journal of Neuroscience Methods 14, 149-167.
  12. Prut, L. and Belzung, C. (2003). The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. European Journal of Pharmacology 463, 3-33.
  13. Steimer, T. (2011). Animal models of anxiety disorders in rats and mice: some conceptual issues. Dialogues in Clinical Neuroscience 13, 495-506.
  14. Varty, G. B. et al. (2002). The gerbil elevated plus-maze I: behavioural characterization and pharmacological validation. Neuropsychopharmacology 27, 357-370.
  15. Walf, A. A. and Frye, C. A. (2007). The use of the elevated plus maze as an assay of anxiety-related behavior in rodents. Nature Protocols 2, 322-328.

 

 

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3 thoughts on “Can flies teach us something about the genetics and potential treatments for anxiety? Surprising new findings about similarities with humans.

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