Fly on the Wall

Making fly science approachable for everyone

Breaking Research: Bitter substances suppress sweet signaling in the brain

Imagine you’re a fly buzzing through the forest looking for something to eat, and you happen upon a sweet fruit that tastes bitter. What’s a fly to do? A sweet fruit is a nutritious meal, but the bitter taste implies toxins. In a recent paper by French et al. in the Journal of Neuroscience, researchers discovered that bitter substances can block sugar signaling in the brain to prevent flies from making questionable meal choices such as these.

The brain deals with these sorts of ambiguities every day. After all, very few foods have a single taste modality of sweet, bitter, sour, salty, or umami (savory/meaty). Instead, most foods are a combination of several of these tastes. But while sweet, umami, and sometimes salt flavors can indicate nutrition, sour and bitter often serve as a warning signals for acidity or toxins, respectively. So how does the brain decide what’s safe to eat when it encounters a meal that’s both sweet and bitter?

fly drinkingFruit flies taste and eat with their proboscis. Click here or on the image to see a video of a fruit fly eating!

To answer this question, French et al. turned to fruit flies. Like the rest of us in the animal kingdom, flies are attracted to sweet foods and avoid bitter foods, and they have taste cells in their proboscis (the fly tongue, see image). Over the past decade, fly researchers have developed quick and easy experiments to test food preferences in flies, and have even mapped the neurons corresponding to each taste modality on their proboscis, including bitter-sensing cells and sweet-sensing cells. This provided a great system to investigate how the brain decides to avoid sweet foods with a bitter aftertaste.

In flies and other animals, bitter foods activate bitter-sensing cells that cause aversion, and sweet foods activate sweet-sensing cells that cause attraction and feeding. Yet, researchers in multiple animal models had found that the presence of a bitter substance in a sweet food can suppress the eating behavior, indicating some crossover between how these flavors are represented in the brain. While this seems straightforward (you don’t want to eat something potentially deadly, even if it’s nutritious), exactly how and why the brain makes this decision was not understood. Are bitter-sensing cells suppressing sweet-sensing cells? Or do the bitter substances instead inhibit the sweet-sensing cells directly?

Interestingly, the authors of this paper discovered that bitter substances could actually inhibit the sweet-sensing cells directly. The researchers first confirmed that flies were attracted to sugar water (extending their proboscis toward it, see image), and avoided water with a bitter chemical (retracting their proboscis away from it). The authors then mixed a bitter substance into the sugar water and found that the flies quickly recoiled from the meal.

The authors hypothesized that if bitter-sensing cells themselves were suppressing sweet-sensing cell activation, then killing off the bitter-sensing cells should prevent the flies from avoiding the sugar+bitter offering. But instead, they found that the flies were still able to avoid sugar mixtures with certain bitter substances. They further investigated by recording the electrical activity of the taste neurons and found that some of the bitter substances they tested were actually interacting directly with the sweet-sensing cells to suppress their activity. This was a surprising finding, since it was previously thought that sweet-sensing cells only respond to sweet substances, bitter-sensing cells only respond to bitter, and so on.

So if bitter substances can directly suppress sugar-sensing and therefore prevent eating, why do bitter-sensing cells even need to exist? What’s the evolutionary advantage? For one, bitter chemicals may show up in other non-sweet foods that flies will need to recognize as dangerous. But even more interestingly, the researchers found that not all bitter substances could directly suppress sweet-sensing cells. For example, strychnine (a deadly pesticide) and three other bitter chemicals interacted with sweet-sensing cells, but caffeine, nicotine, and a few other bitter chemicals did not. The researchers suggest that the first group of chemicals may be much more toxic to the flies, and they therefore may have evolved a back-up system of protection from them. Thus, bitter-sensing cells are still necessary for signaling avoidance of less-toxic but still-dangerous chemicals.

fly drinkingChocolate is an example of a food with conflicting signals. Theobromine, the bitter (and stimulating) chemical in chocolate, is safe in small quantities but can be dangerous in large quantities. Yet most people love the taste of chocolate. Have we evolved to recognize that the potential nutritional benefits of chocolate outweigh the risk?

This research shows that flies have developed two methods of detecting dangerous bitter substances in potential food sources. First, bitter-sensing cells are activated and signal aversion. Second, sweet-sensing cells are directly suppressed by some bitter chemicals in order to simplify the taste messages sent to the brain, which would otherwise be conflicting. Research in other animal models, including mammals, has found that they also avoid sweet foods laced with bitter chemicals, suggesting that these organisms likely use similar strategies for deciding what’s safe to eat.

So that leaves me with one remaining question: Why does chocolate taste so good?

 

 

Reference:

  • French AS, Sellier MJ, Moutaz AA, Guigue A, Chabaud MA, Reeb PD, Mitra A, Grau Y, Soustelle L, & Marion-Poll F (2015). Dual mechanism for bitter avoidance in Drosophila. The Journal of neuroscience : the official journal of the Society for Neuroscience, 35 (9), 3990-4004 PMID: 25740527

Translational Findings: How fruit flies are helping us find cures for cancer

General Cancer Hope Ribbon

At universities and companies around the world, scientists are studying the mechanisms of cancer and tumors using fruit flies. They hope to identify failures in the genes that lead to cancer, and develop treatments to prevent or reverse these problems. Because approximately 60% of the genes associated with human cancers are shared with fruit flies, these interventions will lead to a better understanding of cancer in humans, a critical step for the development of cures. Fortunately, fruit fly research is already making huge contributions to the field of cancer research and has produced several success stories (with more on the horizon).

What is cancer, and how can flies help?

Cancer is an encompassing term used to refer to a collection of more than 100 related diseases, and is the second leading cause of death in the United States. Although there are many kinds of cancers, all are caused by the uncontrolled growth of abnormal cells. But what causes these abnormal cells to grow out of control?

Usually, when a cell’s DNA is damaged, the cell either repairs itself or dies. But a cell becomes cancerous if it doesn’t (or can’t) repair the damage and then doesn’t die like it should. Instead, it replicates itself unchecked, forming a mass of cancerous cells called a tumor. These tumors continue to grow and invade nearby normal tissue, and can sometimes even “break off” into the bloodstream and circulate into other tissues as well.

Ideally, if researchers can identify the mutation that leads to cancer, they can use it to develop a cure. For example, they can create a drug that recognizes the specific mutation to target and kill cancerous cells, or they can develop a treatment to at least compensate for the mutation. Unfortunately, there are two main reasons why one approach doesn’t work for all cancers. First, there are different types of cancers (such as colon, liver, or lung cancer) which respond to drugs differently, so a different cure would need to be developed for each type. Second, the same type of cancer in one person can often be caused by a different mutation in another. In fact, one cancer may often be caused by mutations in multiple genes, so a drug for a single type of cancer may need to have multiple targets. This variation between and within cancer types means that there can’t be one universal cure.

So how can flies help? There are two very promising avenues for researching cures for cancer.

  1. Identifying “cancer-risk” genes – Although different cancers arise from different and often multiple mutations, scientists have found that certain mutations commonly occur in many types of cancer. For example, some of these cancer-risk genes may be categorized as “repair” genes, which are involved in fixing damaged DNA. When a repair gene is damaged, mutations in other genes are allowed to occur, increasing the chances of cancer. Other categories of cancer-risk genes include “growth” and “cell death” genes which, when mutated, allow or cause the cell to replicate itself without dying. Many of these and other cancer-risk genes were first identified in fruit flies, and further research will help us gain a better understanding of how mutations can lead to cancer and how to prevent that from happening.
  1. Personalized medicine – Many of the drugs we currently have are only effective against specific kinds of cancer, and even then with only moderate success. Doctors must often try multiple courses of treatment before finding one that can effectively target a patient’s cancer. This is due to the fact that the combination of mutations varies between patients. Personalized medicine, in which treatment is tailored for each patient, is therefore becoming more common. After identifying the specific genetic mutations causing cancer in a patient, doctors can prescribe the right combination of drugs to target their cancerous cells. Unfortunately, a lot more work needs to be done to identify every mutation and the appropriate drug to target it (see #1). One group of researchers led by Ross Cagan is attempting to bypass this step with relative success, by growing a copy of each patient’s tumor in flies and testing thousands of drug combinations until one works without killing the fly.
fly cancerA comparison of eyes from a normal fly (A) versus flies with visible signs of cancer (B-D). Image modified from Uhlirova et al., 2005.

Do flies get cancer? Flies generally don’t live long enough to naturally develop sufficient DNA damage to cause cancer, but flies with genetic mutations like those in humans will quickly develop cancer, and we can easily see abnormalities in the eye (see figure). Researchers can use these flies to investigate how mutations in specific genes led to cancer and test thousands of drug candidates to see if the tumor goes away. Even better, they can introduce the specific combination of human mutations from patients in the flies and then test drugs against it, as described in #2.

Here, I’ll go into detail about the accomplishments of fruit fly research so far, and where they might lead in the future.

Identifying cancer-risk genes and understanding how mutations lead to cancer

Dozens of genes that contribute to cancer have been identified in fruit flies. When a mutation occurs in any one of these genes, it can lead to the hallmarks of cancer, such unchecked cell growth and the formation of tumors. For example, a mutation in a gene known as scribbled (scrib) can lead to masses of disorganized cells similar to tumors.  As mentioned previously, identifying these genes and understanding the role they play in cancer is critical for developing drugs to work against them.

But one of the most important insights we’ve gained from cancer research in flies is how multiple mutations in different genes often cooperate with each other, leading to the invasive properties of cancer that are so deadly in humans. For example, a combination of a scrib mutation with a Notch mutation allows the disorganized cells to invade other tissues and spread to other parts of the fly’s body. Research in flies therefore helps us understand which of the sometimes dozens of combined mutations in patients is “driving” the cancer (so to speak), so doctors can target the most aggressive genes.

The Notch gene is part of a group of genes that make up the Notch signaling pathway, which refers to a group of genes required to do a specific job. The Notch signaling pathway is involved in detecting communications from other cells and acting upon them by controlling each cell’s replication or death. Mutations in the genes in this pathway, therefore, can lead to overactive signaling, allowing for uncontrolled growth and subsequently cancer. In humans, Notch mutations contribute to several types of human cancer, including breast, prostate, and pancreas cancers, as well as cancers of the blood (leukemias). Fortunately, identifying the genes involved in the Notch pathway has led to the development of several promising drug candidates that suppress mutated genes in this pathway, the most studied of which is known as gamma-secretase inhibitors (GSIs). Although more work is needed to confirm the effectiveness and safety of this and other drugs against Notch-based cancers in humans, it is a promising step in the right direction.

Perhaps one of the greatest contributions the fly has made to cancer research was the discovery of the Ras signaling pathway, which is also involved in regulating cell growth. Each of the genes involved in this pathway have also been found in mammals, and the Ras gene itself is estimated to play a role in 30-50% of human cancers. Continued research in this pathway is critical for developing drugs to target mutations in these genes, as these drugs may have broader success against human cancers due to the pervasiveness of this pathway in cancer.

Once cancer-risk genes and pathways have been identified, drug candidates can be tested against them. Thousands of drugs can be screened against cancerous cells in petri dishes, but once drugs that successfully target mutations in cancer-risk genes have been found, they need to be tested in live animals for effectiveness and lethality. Fruit flies, with their short lifespans and massive numbers of offspring, are a great resource as a first step for rapidly testing promising drug candidates.

Personalized medicine: Flies with human tumors 

Thanks to improvements in the speed and cost of genome sequencing, doctors can now take a “genetic snapshot” of a person’s cancerous tumors to find out which genes have mutated. Dr. Ross Cagan and his team at the Center for Personalized Cancer Therapeutics at Mt. Sinai Hospital in New York City are using this approach to identify the mutations causing cancer in individual patients, and then introduce that combination of mutations in fruit flies. Essentially, these scientists are growing personalized tumors in fruit flies, which can be seen in the flies’ eyes (see figure above).

Using those flies, the researchers can test thousands of drug combinations until they find a cocktail that works. Usually, drugs approved for certain types of cancer are hit-or-miss—what works for one patient may not work for others. To make matters worse, cancer drugs tend to damage healthy cells at the same time, albeit less so than the cancerous ones. But using this new personalized technique, Dr. Cagan and crew can figure out what combination of drug works best to kill the tumor without killing the flies.

Besides helping cure cancer in some individual patients, this technique has also inspired the development of a new drug called vandetanib. Dr. Cagan and his colleagues found that this drug (originally known by the catchy name of ZD6474) seemed to work against certain types of cancerous growths, and eventually the drug was picked up by AstraZeneca and approved for the treatment of advanced thyroid cancer.

The future of fruit fly cancer research 

The technique pioneered by Dr. Cagan and his colleagues will also improve researchers’ ability to identify new cancer-risk genes and understand how they lead to cancer. As these scientists uncover more mutations in their patients, they may start to see patterns emerging, hopefully leading to treatments that have more success across patients, such as those that target the pervasive Notch and Ras signaling pathways.

Using the techniques described here (and others), fruit fly research will likely revolutionize the way we approach cancer research and think about cures. In humans with cancer, we see only the end point without being able to determine how the cancer began. With flies, researchers can go back and study the genes involved in the triggering event. And with luck, we’ll figure out how to keep that trigger from being pulled.

 

References:

Breaking Research: How the brain recognizes hot and cold

When you walk outside into sweltering heat or biting cold, your body responds by sweating or shivering to regulate body temperature. It starts with cells in your skin called thermoreceptor neurons, which sense the temperature of your environment and send that information to the brain for processing. But how does the brain process this information to initiate behavioral responses such as sweating, shivering, or pulling your hand from a hot pan? Two studies published together in Nature have mapped the brain’s representation of temperature in fruit flies, and the findings will provide more insights into how our own human bodies tick.

Fruit flies are a great model for studying how the brain processes temperature. Because even a small temperature change can be deadly to these tiny insects (they can’t regulate their own body temperature internally), fruit flies need a quick and efficient system for sensing dangerous temperatures and escaping. Although humans have more options for responding to uncomfortable temperatures, the brain’s logic for representing temperature is likely similar in both species.

Previously, fly researchers had found that fruit flies have “hot” and “cold” thermoreceptor neurons in their antenna, similar to the ones we have in our skin. The “hot cells” are activated by heat while the “cold cells” are activated by cold. Interestingly, each cell type is also inhibited by the other temperature—heat makes it harder for cold cells to be activated, and vice versa.

Frank et al schemaThermoreceptor neurons from the antenna relay temperature signals to projection neurons in the brain. Image modified from Florence and Reiser, 2015.

These thermoreceptor neurons are the first step for temperature sensing in the fruit fly, but what’s the next step? How does this temperature information get processed in the brain? In their recently published papers, Frank et al. and Liu et al. used different approaches to answer these questions.

Both groups independently discovered neurons that receive information from the hot and cold cells in the antenna and carry it to the brain. These cells, called projection neurons (PNs), can be separated into three main groups: cold-PNs, which are activated by the cold thermoreceptor neurons; hot-PNs activated by the hot thermoreceptor neurons; and mixed-PNs, which receive information from both types of thermoreceptor neurons and are activated by rapid temperature changes in both directions. Frank and colleagues found that the mixed-PNs were important for fruit flies to recognize and quickly escape from dangerous temperature environments.

Liu et al schemaCold projection neurons are directly activated by cold thermoreceptor neurons. In contract, hot projection neurons are not only directly activated by hot thermoreceptor neurons, but also indirectly activated when the cold pathway is inhibited by heat. Image modified from Florence and Reiser, 2015.

These results suggest that the fruit flies’ temperature-sensing system is relatively straightforward: hot and cold information each has its own pathway to the brain. In a small group of PNs, this information also overlaps to provide the brain with a quick escape warning, regardless of whether the dangerous temperature is too high or low.

But Liu and colleagues obtained more results that remind us that brains are never as simple as we expect. The researchers found that hot-PNs not only receive input from the hot pathway, but they are also affected by the cold pathway. Under cool conditions, the hot-PNs are suppressed by the cold pathway and unable to activate. As the environment gets warmer, however, hot-PNs are activated by the hot thermoreceptor neurons and also released from the cold pathway’s inhibitory influence. Florence and Reiser worded it best in their Nature review on these studies:

Liu et al. revealed that hot projection neurons exploit both the excitatory ‘getting hotter’ signal from the hot receptors and the inhibitory ‘getting less cold’ signal from the cold receptors, and suggest that this not-quite-redundant use of both pathways leads to more-sensitive measurements of temperature change.

So what happens to the temperature information after the PNs carry it to the brain? Both groups found that the PNs connect with brain regions important for learned and instinctual behaviors. The next research step will therefore be to uncover the processes by which these brain regions initiate behaviors to protect the fly—whether it be a simple quick escape, or storing a memory of a dangerous place.

 

 

References:

Breaking Research: Separable short- and long-term memories can form after a momentous occasion

When was your first kiss? What were you doing the last time you heard life-changing news? After only a single experience, your brain was somehow able to form a long-term memory of these events. This phenomenon has baffled neuroscientists for decades, but in a recent paper published in PNAS, Yamagata et al. report a surprising discovery that may finally provide some answers.

Scientists have long thought that memory storage follows a standard path: short-term memory is stored in one part of the brain, then eventually strengthened and transferred into long-term storage somewhere else. This transfer from short- to long-term memory typically requires repetition (think of memorizing song lyrics or studying for an exam). So how, then, does your brain form a long-term memory after a single momentous event?

training paradigmFigure 1. Flies can learn that a particular odor is associated with a reward. (1) Fly trained with odor and sugar reward, (2) Fly trained with odor and researcher-activated reward neurons.

Imagine that you are a starving fruit fly, desperately searching for food in a new area. Suddenly, you encounter a mysterious new odor and discover a nearby source of life-sustaining food. After a single experience such as this, flies can instantly form an association between that new odor and food, and will follow the odor if it encounters it again (Figure 1-1). Yamagata et al. took advantage of this instinctual behavior to study how the fly brain stores a long-term memory after one event.

They trained groups of flies to associate a particular odor (A) with a sugar reward by presenting them with both stimuli at the same time. They confirmed that the flies formed a memory by giving them a choice between odor A and a different odor (B), and found that flies preferably flocked to an area scented with odor A.

They also identified a large group of dopamine neurons (known as PAM neurons) that were activated by the sugar reward. If the researchers activated the PAM neurons instead of providing sugar when the flies encountered odor A, the flies still associated that odor with a reward (Figure 1-2).

Now the question: how does PAM neuron activity paired with an odor form a long-term memory?  The researchers found that the PAM neurons could actually be grouped into two types. When they activated one type, which they dubbed stm-PAM, the flies only formed a short-term memory. The researchers tested their memory immediately after training and found most of the flies hanging around odor A. But 24 hours later, the memory was gone.

Surprisingly, when the researchers activated the other type of PAM neurons during training (called ltm-PAM), the flies only formed a long-term memory! The flies weren’t particularly interested in odor A immediately after training, but 24 hours later the flies flocked toward it. This incredible result showed that long-term memory doesn’t necessarily require a short-term counterpart. So, instead of the reward pathway forming a short-term memory that later transforms into a long-term memory, this sugar reward formed two complementary memories.

separable memory componentsFigure 2. Long-term memory (LTM) doesn’t always form from short-term memory (STM). In some cases, STM and LTM form independently, with STM degrading over time, and LTM progressively strengthening.

How can you have a long-term memory without a short-term memory? Imagine again that you are a starving fly, and you just ate something that didn’t taste very good. You’ve moved on, but later realize that you feel satisfied and energetic. You didn’t form a rewarding short-term memory because the food wasn’t very tasty, but now you have a positive long-term memory because it was nutritious. This is precisely what the researchers discovered when they investigated the PAM neurons further.

The researchers trained the flies using arabinose, an artificial sweetener that tastes sweet but isn’t nutritious, and sorbitol, a nutritious but tasteless sugar. Flies that ate arabinose formed a short-term memory that required stm-PAM activity, while the flies that ate sorbitol formed a long-term memory that required ltm-PAM activity. Thus, the researchers found that the PAM neurons seem to carry two separate pieces of information about the sugar reward: a “delicious” signal, which creates a short-term rewarding memory, and a “nutritious” signal, which creates a long-term memory.

These findings show that long-term memory doesn’t always form from a short-term memory. Instead, they can be independent processes created from different information signals about the same stimulus, such as taste and nutrition from sugar. In humans, our rewards are even more complex (such as the feelings associated with your first kiss), and our memory system likely works in a similar way.

Now, how can I apply this strategy while studying for my next exam?

 

 

 

 

 

 

Reference:

  • Yamagata N., Yoshinori Aso, Pierre-Yves Plaçais, Anja B. Friedrich, Richard J. Sima, Thomas Preat, Gerald M. Rubin & Hiromu Tanimoto (2014). Distinct dopamine neurons mediate reward signals for short- and long-term memories, Proceedings of the National Academy of Sciences, 112 (2) 578-583. DOI: http://dx.doi.org/10.1073/pnas.1421930112

Valentine’s Day Special: Drosophila in lust

Valentine’s Day is quickly approaching, which means that men (and women) all over the U.S. are performing courtship rituals to woo a companion. But while we humans often have trouble figuring out the right moves to attract a potential mate, fruit flies have it down to a science. And incredibly, researchers can study fruit fly courtship to gain a better understanding of our own brains.

Fly courtshipThe fruit fly courtship ritual has a set of specific steps. Image modified from Greenspan and Ferveur, 2000.

In polite fruit fly society, males have the responsibility of wooing a female. The mating behavior is composed of several specific steps (see figure), which the males perform in repetition until the female responds (or until the male gives up trying). This courtship behavior is very well understood by researchers, due in part because the courtship ritual is so stereotyped and predictable. Courtship is a complex innate behavior, which means that all flies are born with the knowledge of how to do it. Successful mating means passing your genes on to the next generation, so the networks of neurons responsible for this behavior are critical for survival and therefore consistent among flies. This consistency provides a perfect system for studying how neurons interact to give rise to a behavior.

Fly researchers have made great progress in unraveling the anatomy underlying courtship, and found that the behavior arises from the integration of multiple sensory cues, including smell (is the female releasing “come and get me” pheromones?), vision (does the female look interested?), and touch (am I in the right spot?). The fruit fly brain has to combine all of this information to influence the fly’s decision making. Should he start the next step of the courtship ritual, or try this one again? Can he approach the female and try to mate?

“But who cares about fruit fly sex?” you might ask. The fly researchers studying courtship aren’t necessarily interested in exactly how flies get it on. They’re more interested in a general understanding of how the brain integrates multiple sensory cues to influence decisions. The fact that the “courtship circuit” is critical for survival suggests that it is also used by other important behaviors, and is shared by other species. Think about how much information needs to be integrated for you to hunt for food, drive a car, or even court another human. The complexity is amazing… how does our brain manage that?!  By first studying it in the simpler brains of fruit flies, we can gain a basic understanding that we can apply to our complex mammalian brains.

Studying courtship behavior can provide us with an understanding for how neurons communicate and integrate information to make decisions, but researchers can do even more with it. As our understanding of courtship increases, we can use it to investigate other behaviors that seem more directly related to human health, such as learning and memory, sleep, and addiction.

For example, the courtship ritual is most commonly used to study memory. Researchers have noticed that male flies tend to “give up” after too many rejections, so they’ve developed a learning experiment that exposes males to uninterested females. Normal males quickly learn to give up on trying to mate with them, but what happens if a scientist mutates a particular gene or “turns off” a certain molecule? Now researchers can use courtship to investigate the genes and molecules involved in learning and memory. If a mutant male never learns to stop courting, the gene might be involved in learning. If the mutant male initially learns to give up, but then quickly forgets the experience and tries again, the gene might be involved in long-term memory.

The predictable steps of courtship also allows researchers to easily recognize when a male is impaired in this innate behavior, providing a system for studying brain development. Last year, the Seghal lab published a study in which they used courtship behavior to show that sleep is necessary for normal brain development. They deprived young flies of sleep and found that, as adults, the flies were impaired in courtship. The impairment was due to lack of growth in a brain region important for the behavior, suggesting that sleep deprivation stunts brain development.

As a final example (and one of my favorites), in 2012 the Heberlein lab produced a paper showing that sexual rejection makes male flies turn to booze. Natural rewards such as sex activate the brain’s reward system, which is also activated by abused drugs and alcohol (did you know that flies can be alcoholics too?). Understanding how natural rewards, drugs, and rejections affect the reward system is important for treating or preventing addiction. From this study, the researchers in the Heberlein lab found that levels of neuropeptide F (NPF), a signaling chemical, rose and fell with reward and rejection. Low levels of NPF drove flies to drink, and artificially raising NPF levels prevented this behavior. Their finding that the same chemical is involved in both natural and artificial rewards directly helps research aimed at understanding a similar chemical in mammals called NPY.

In these research examples, the goal of studying courtship wasn’t to learn about fruit fly sex, it was to use what we know to answer more important questions. Because of these studies, researchers have identified dozens of genes and molecules involved in learning and memory, uncovered more reasons for why sleep is important, and progressed our understanding of how alcohol affects the brain. All of these findings have direct implications for human health because we also share those memory genes, need sleep, and use drugs and alcohol.

Flies in love

So the next time you see some flies getting it on near your bananas… swat them, because they’ll make hundreds of new nuisances for you to deal with. But afterward, you can smile knowingly to yourself and remember that scientists are studying the act to answer long-standing questions in neuroscience.

 

 

General references:

  • Pavlou H.J. and S.F. Goodwin (2013). Courtship behavior in Drosophila melanogaster: towards a ‘courtship connectome’, Current Opinion in Neurobiology, 23 (1) 76-83. DOI: http://dx.doi.org/10.1016/j.conb.2012.09.002
  • Griffith L.C. and A. Ejima (2009). Courtship learning in Drosophila melanogaster: Diverse plasticity of a reproductive behavior, Learning , 16 (12) 743-750. DOI: http://dx.doi.org/10.1101/lm.956309

“Why do we have to learn this stuff?” — establishing Drosophila as a MODERN teaching tool in schools

This guest post is written by Dr. Andreas Prokop from the University of Manchester. He is passionately engaged in Drosophila-related outreach activities and science communication and writes here about the importance of using fruit flies in the classroom and calls on other fruit fly researchers to help develop strategies to achieve this goal.

Drosophila clearly is the animal in which biology is conceptually best understood. But how well do we sell this fact to the public and in schools? Certainly, Drosophila is far more than an animal substitute for Mendel’s peas, and the recent post by Bethany gives wonderful examples of what can be done with flies as modern and effective teaching tools in class rooms. The enormous power of bringing Drosophila into schools becomes unmistakably clear when talking to members of the public: those who experienced flies in schools, even decades ago, tend to respond with noticeably greater curiosity and interest to fly-related topics than those without such memories. Importantly, there are many biology specifications of the curriculum that can be explained extremely well using flies – and this can usually be spiced up with exciting, simple and cheap experiments that are likely to stick in pupils’ minds for the future. However, in this scenario, flies should not necessarily dominate but rather be used as teaching tools wherever they can help teachers to achieve a lesson’s learning objectives. Learning modern biology through flies, shoulder-to-shoulder with related human examples, clearly conveys the value of simple invertebrate model organisms without any further need to emphasise and explain. If we can establish flies in this way as modern teaching tools in schools, this will in the long term be more powerful than labour-intense Drosophila days at schools organised by scientists, and will have a chance to be applied on a far larger scale.

In Manchester, we are experimenting with the above ideas very successfully. However, it has become clear that a key challenge is the creation of resources for teachers. Such resources will only work if they are concise, explained in simple terms and conceptually mature, so that they meet the needs of busy teachers in each and every aspect and help them gain quick understanding which they can then pass on to their students. To acquire the necessary expertise for this task, we have started to place PhD students for several weeks as active teacher assistants in schools, which allows them to experience school realities first, before generating adequate and tailor made resources. However, this is only one strategy and more effort is needed. It would therefore be great if other members of the fly community contributed, thus generating a wider choice of materials to meet the individual needs and personal tastes of a greater range of teachers. If you are interested in this kind of activity and are attending the American Drosophila Research Conference in 2015 in Chicago, please come to the Drosophila science communication workshop to discuss possible strategies.

Clearly, long-term strategies are needed if we want to promote the wider understanding of invertebrate model organisms, thus also addressing the current downturn in Drosophila funding recently highlighted by Hugo and his colleagues. Tragically, this decline occurs in times where Drosophila research is perhaps more urgently needed than ever, when considering that Human Genetics and “omics” approaches bring up more questions than could possibly be answered without the fly. Starting in schools addresses this problem at its roots and lays important foundations for the future. But there is also personal benefit from these activities: engaging with the public in any way (and this clearly includes engagement at schools!) helps to develop the right arguments that work with members of the public – hence, naturally, also with members on grant panels! In my experience, it forces one to think about the essentials of one’s science leading to new ideas and thoughts, thus becoming a win-win activity that pays off in two directions.

 

Fly Human ComparisonWhy Drosophila can be used to explain fundamental and even human biology or biology of disease: Humans share a surprising amount in common with Drosophila. In particular, the genes that tell cells how to divide, develop, and function and what the basic body plan should look like are often the same as in humans. This new understanding yielded a wealth of exciting discoveries – even about the brain and the processes of learning and memory – and about mechanisms of disease (taken from the short educational film “Small fly – BIG impact“)

 

Interesting links:

Fly Life: Fruit flies in the science classroom

Do you remember sitting in the science classroom in grade school, looking at pictures of pea plants to learn about inheritance? What if you could have tested Gregor Mendel’s theories of inheritance yourself (without watching plants grow)?

Well, you can! As it turns out, fruit flies are a great teaching resource for the science classroom. They are cheap, easy to maintain and store, and are well-understood, since they’ve been studied by researchers for over a century. These characteristics allow teachers to set up hands-on experiments for their students, and quickly adapt to students’ curiosity-driven questions.

Fruit flies can be used for teaching a variety of scientific concepts, from genetics to behavior, and the related experiments can be engaging, fun, and easy to understand. I want to talk about some of my favorite examples (some of which have gone from science fair projects to published peer-reviewed articles!).

Inheritance and Evolution

Punnet square for red- and white-eyed fliesAn example of a punnet square for mating a white-eyed and red-eyed fly. The white eye is caused by a sex-linked recessive genetic mutation. Male offspring have white eyes because they only have one copy of the gene (the mutation) from the white-eyed “mother”, while female offspring have a backup normal “red” copy inherited from the “father”.

Do you remember doing the punnet squares for Mendel’s pea plants? Punnet squares are diagrams used to predict what traits offspring will inherit from two different parents, and is the most common way to teach inheritance in the classroom. Fruit flies, with their short lifespan and quick generation time (offspring are available in only two weeks!), are perfect for a hands-on version of this experiment. Flies with different traits (such as red eyes and white eyes, or curly wings and straight wings) can be mated. While waiting for the next generation, students can predict what percentage of the offspring will have each trait. Two weeks later, they can sort the flies to test their predictions.

UNC’s The Wonderful Fruit Fly website is great for seeing how punnet square experiments can be performed with fruit flies.

Red- vs white-eyed fliesThe fly on the top has a mutation that causes white eyes. The fly on the bottom has normal red eyes. source

Another great example for an experiment was described in an article published in the journal Evolution. Because multiple generations of fruit flies can be studied in a matter of months, students can actually see evolution “in action”. In the published example, students added a single red-eyed fly to a large population of white-eyed flies. Flies with white eyes have poor eyesight and are less healthy than flies with red eyes. Over the course of the experiment, students watched as the healthier red-eye gene spread through the population, simulating the way a random advantageous mutation in nature can spread via natural selection.

This is only a couple of the dozens of interesting genetic experiments that can be performed in class. For more examples, the Tree of Life web project site is a great resource. 

Behavior and Health

Dyed food experimentFlies that eat dyed food have colored abdomens. Image modified from Isono and Morita, 2010.

Although fruit flies are most commonly associated with genetics experiments, they can also be used for behavioral experiments. One of my favorite examples is testing flies for food preference, in which students can give a group of flies a choice between two or more food sources, and count the number of flies that land on each. To make it even more interesting, the food can be dyed different colors. Once ingested, the dye is visible through the flies’ abdomens, allowing students to count how many flies have chosen each food based on color. Wouldn’t it be cool to see blue and purple flies under a microscope?!

Food preference experiments from middle school science fairs have actually made the news a couple of times over the past two years. In 2013, student Ria Chhabra developed an experiment to test whether organic food really is better than conventional food. She raised flies on each type, and found that flies raised with organic foods lived longer and healthier lives. The results were published in the peer-reviewed scientific journal PLoS One.

A similar story was released in 2014, when student Simon Kaschock-Marenda wondered whether fruit flies would like artificial sweeteners as much as normal sugar. He raised flies on sugar and several different sweeteners, including Truvia. His results, also published in PLoS One, showed that erythritol, the main ingredient of Truvia, was actually toxic to fruit flies.

These two heartwarming stories demonstrate how fruit flies can be used in the classroom to inspire students to pursue curiosity-driven science.

Want to start using flies in your classroom? There are many resources available online for experiment ideas, as well as “How-to” guides for setting up and maintaining a fly lab. One of the most comprehensive is the “How-to Fly Manual” from the researchers at the University of Manchester’s Fly Facility.  Another great resource is the “Drosophila Melanogaster in the classroom” blog, which details how to set up a classroom using fruit flies.  

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Many thanks to my friend Brittney for her help with resources and ideas for this post, gathered from her own volunteer experiences teaching fruit fly science to eager young minds.

I would also like to thank Dr. Andreas Prokop at the University of Manchester for some of the resources and inspiration for this post.  He and other fly researchers at the University of Manchester maintain an impressive array of lay information about fruit fly research and resources on their website (not just about how flies can be used in the classroom, but also how flies can be used to conduct high-quality research in disadvantaged regions and countries, where resources and funds may be limited).

 

Breaking Research: Fruit flies help uncover the brain’s link between sleep and memory

Researchers at Brandeis University have found that the link between sleep and memory is stronger than we thought. It is well known that sleep is important for learning and memory, and many people can attest to having a hard time focusing and remembering things after a bad night’s sleep. Students often receive advice about getting a good night’s sleep instead of late-night cramming before a test. Simply put, scientists have learned that the brain takes advantage of the quiet hours during sleep to transfer newly-learned memories into long-term storage.

But how exactly are these complex behaviors connected in the brain? Does sleep simply permit memory storage to take place, such that the part of the brain involved in memory just takes advantage of sleep whenever it can? Or are sleep and memory physically connected, and the same mechanism in the brain is involved in both? In a recent study published in eLife, researchers in the Griffith lab may have finally uncovered the answer. They found that a single pair of neurons, known as the DPM neurons, are actively involved in both sleep and memory storage in fruit flies.

Why the fly? Fruit flies may be less complex than humans, but they have similar behaviors such as sleep and memory, and their brains have a similar organization. You may have heard of the hippocampus: the seahorse-shaped brain region in mammals that is responsible for learning and memory. The hippocampus receives a lot of information from other parts of the brain, and it has been very difficult for researchers to sort it all out. Fortunately, fruit flies have a similar region called the mushroom bodies (MBs), which are also important for learning and memory. Even better, fruit fly researchers have identified many of the neurons that send information to the MBs. One such example is the DPM neurons, which are critical for long-term memory storage. If the DPM neurons (there’s just two of them!) are “turned off” so that they can’t communicate with the MBs, flies can’t form long-term memories. This gave the researchers a great place to start for studying how sleep and memory are linked in the brain.

To find out if the DPM neurons are also involved in sleep, the group manipulated the activity levels of the DPM neurons and observed whether the flies showed any changes in their sleep patterns (Click here if you want to learn more about exactly how we study sleep in flies). They found that the DPM neurons had a dramatic effect: hyper-activating them increased the amount of time the flies slept, while silencing them decreased sleep (remember that silencing them also shut down long-term memory storage). Thus, sleep doesn’t just permit memory storage. These behaviors are actually tied to the same mechanism—the same neurons!—in the fruit fly brain.

Dream WaterThe fact that DPM neurons use GABA and serotonin is another similarity to us. Those chemical promote sleep in humans too, and many sleep aids include GABA and/or serotonin supplements.

As the researchers delved further, they found that the DPM neurons were dampening part of the MBs’ activity using GABA and serotonin (both are chemical messengers that neurons use for communicating with each other). That part of the MBs was important for learning and, as it turns out, also signaling wakefulness. It’s almost as if that section of the MBs were saying “Hey, stay awake and learn this”. After a while, however, the DPM neurons may start signaling to suppress the MBs, as if to say “You’re going to need sleep if you want to remember this later”.

Finally, there was another interesting insight uncovered by this study. It is widely believed that long-term memory is stored when groups of neurons signal back and forth in an excitatory manner, progressively strengthening their connections with one another (you may have heard the adage “neurons that fire together, wire together”). Yet, the authors of this study found that the DPM neurons, which are critical for memory storage, are not actually excitatory. To the contrary, they inhibit a section of the MBs necessary for learning. What role does inhibition play in memory? This finding doesn’t answer that question, but it does demonstrate just how much work is left to be done.

 

 
Reference:

  • Haynes P.R., Christmann, B.L. & Leslie C. Griffith (2015). A single pair of neurons links sleep to memory consolidation in Drosophila melanogaster , eLife, 4 DOI: http://dx.doi.org/10.7554/elife.03868

New Year’s Special: Flies in Space (and other news from 2014)

Fruit fly researchers published thousands of papers in 2014, and several of them were picked up by the media. I even reviewed a couple of these popular stories on this blog. In April, the Seghal lab published a paper showing that sleep loss in young flies led to abnormal brain development and behavioral deficits in adulthood. In September, researchers in the Walker lab showed that increasing the levels of a molecule called AMPK in the guts of fruit flies could extend their lifespan, providing hope that we may one day be able to develop a pill to slow aging.

The most heartwarming story of 2014 came out in June, after a sixth-grader’s science fair project was published in the peer-reviewed journal PLoS One. Father and son worked together to discover that the artificial sweetener Truvia is toxic to fruit flies. Erythritol, the main ingredient of Truvia, is safe to consume for humans but quickly kills these winged pests. The researchers who worked on the project are now pursuing the possibility of using erythritol as a safe insecticide for fruit flies and other insects.

But perhaps the biggest news from 2014 involves flies… in space! Although many animals have been to space over the past several decades, fruit flies have recently proven to be ideal for studying the effects of zero gravity on earthly bodies. It’s widely known that microgravity (zero gravity) leads to rapid loss of bone density and muscle weakness, which is why astronauts spend a lot of time exercising while they’re in space. But did you know that microgravity also negatively affects the cardiovascular and immune systems? NASA recently announced a plan to send humans to Mars by 2030, but first, they need a better understanding of the long-term effects of microgravity on the body.

Fruit fly with fungusThis fruit fly is covered with a fungal infection after its immune system was compromised by 2 weeks in space. Image credit: Deborah Kimbrell/UC Davis

Space flies made the news in January 2014 after the results of a successful experiment were published in PLoS One by the Kimbrell lab. Researchers sent flies into space for 12 days to determine how zero gravity affects their immune system. It may seem like a short trip, but that’s about half the lifespan of your average fly (roughly the equivalent of sending a human into space for 40 years!). The researchers reported that flies subjected to microgravity had reduced ability to fight off a fungal infection compared to their earthbound brethren. Also interestingly, flies exposed to hypergravity (even stronger than Earth’s gravity) showed an increased ability to fight off the infection. The difference in immunity was caused by changes in the Toll pathway, an immune response which is also present in humans and other mammals. These promising results provided a leap forward in understanding how astronauts’ immune system may also be affected by microgravity.

Three more fruit fly experiments were launched into space in 2014. In April, a collaborative group led by Dr. Peter Lee sent flies into space for 30 days to study the effects of microgravity on the cardiovascular system (the experiment was named The HEART FLIES study). The second experiment was launched in September by a team at NASA’s Ames Research Center led by Dr. Sharmila Bhattacharya. The researchers hope to better understand how flies adapt to microgravity by studying changes in behavior.

The final experiment, launched in December 2014, was the maiden voyage of NASA’s newly-developed Fruit Fly Lab-01 project. NASA’s Fruit Fly Lab is a collaborative effort with a sophisticated set-up that researchers hope will improve our understanding of how spaceflight affects immune function. After 30 days in space, researchers will analyze the immune systems from three generations of flies exposed to various levels of gravity.

The results of these three missions should be published this year. Researchers at NASA are hoping that the findings will help them predict the physical challenges that astronauts will face during future space exploration, including the first human mission to Mars. NASA is also planning yearly sequels to their Fruit Fly Lab’s debut mission, so stay tuned!

References:

  • Baudier K.M., Nirali Patel, Katherine L. Diangelus, Sean O’Donnell & Daniel R. Marenda (2014). Erythritol, a Non-Nutritive Sugar Alcohol Sweetener and the Main Component of Truvia®, Is a Palatable Ingested Insecticide, PLoS ONE, 9 (6) e98949. DOI: http://dx.doi.org/10.1371/journal.pone.0098949
  • Taylor K., Michael D. George, Rachel Morgan, Tangi Smallwood, Ann S. Hammonds, Patrick M. Fuller, Perot Saelao, Jeff Alley, Charles A. Fuller & Deborah A. Kimbrell (2014). Toll Mediated Infection Response Is Altered by Gravity and Spaceflight in Drosophila, PLoS ONE, 9 (1) e86485. DOI: http://dx.doi.org/10.1371/journal.pone.0086485
  • NASA.gov

Christmas Special: Drosophila art

Happy Holidays!

Larval christmas tree
Green fluorescent protein (GFP) is expressed in motor neurons in the Drosophila melanogaster larval ventral ganglion. The larva is superimposed on an image of a starry night sky with the North star aligned at the top of the “tree”. The North star stays fixed in the night sky at this time of year, which inspired the tradition of stars on top of evergreen Christmas trees.
Image created by Dr. James Hodge
Image source Griffith lab

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