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Category: Breaking Research (page 1 of 2)

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?




  • 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

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.




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?








  • 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:

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.



  • 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:

Breaking Research: A new technique for studying axon death using fruit fly wings

labeled neuronThe axon is the part of a neuron that carries outgoing information. (cb = cell body)

In neurodegenerative diseases such as Parkinson’s disease or amyotrophic lateral sclerosis (ALS), a genetic mutation leads to widespread neuron damage. When a neuron is damaged, its axon—the part of the neuron that carries outgoing signals—is actively broken down and cleared away by maintenance cells (called glia). This destructive process is known as Wallerian degeneration (WD) and disrupts signaling between neurons due to the loss of their axons. By studying WD in animal models, scientists hope to figure out how to interfere with it and possibly slow the progression of the neurodegenerative diseases.

Because Wallerian degeneration also occurs after physical trauma such as in a spinal cord injury, scientists usually study it by cutting or crushing bundles of axons. Traditionally, researchers have induced random genetic mutations in a population of animals (a forward genetic screen), dissected and damaged a bundle of axons in individual animals, and watched the degradation process to see if the mutation had an effect. This process allows them to determine which genes are involved in breaking down and/or clearing away the damaged axons. So far, studies in mammals and fruit flies have found three genes that are required for WD (Wld, Sarm, and highwire/Phr1). Mutating these genes slows WD significantly, and researchers may be able to target these genes in the future to slow axon death.

But progress so far has been slow due to limitations in the current methods used for studying this phenomenon. In a recent paper published in PNAS by the Freeman lab, researchers describe a new technique for studying Wallerian degeneration in fruit flies that overcomes many of these limitations. Previous work has already shown that WD occurs in fruit fly axons and uses the same known genes, so they are an ideal model for quickly identifying the genes involved in axon death.

The authors developed a system in the fly wing that fulfilled three key requirements they believed were necessary for efficiency:

  1. Rapid observation of individual axons (rather than an entire axon bundle) with minimal dissection
  2. The opportunity to sever only a subset of axons so that one could observe axon death alongside healthy, uninjured axons
  3. The ability to initiate and visualize axon death without killing the fly
fly wingTop: A fly wing with sensory neurons labeled in green. (cb = cell body). Inset: a bundle of labeled axons makes up the L1 vein. Bottom: A schematic of the fly wing and cutting a subset of axons (dashed line). Axons with cell bodies closer to the fly’s body are spared.

The Drosophila wing is transparent and contains a large bundle of sensory neuron axons known as the L1 vein. The cell bodies of the neurons are located around the edge of the wing, and their axons extend through the L1 vein back into the body of the fly. Using genetic tools (check out this article on MARCM for details), the authors added a protein called GFP (which glows green) in a small number of these sensory neurons. This setup allows researchers to easily observe individual axons in the wing under a fluorescent microscope without dissection. These characteristics fulfill their first requirement.

This setup also easily allows researchers to sever some of the axons without injuring others by simply snipping a piece from the edge of the wing. Axons whose cell bodies were cut off succumb to WD, while axons with cell bodies were closer to the fly’s body are unharmed. This method of inducing WD in only some of the GFP-labeled neurons fulfills the second requirement.

GFP axon being degradedThree GFP-labeled axons: two healthy, one damaged and undergoing Wallerian degeneration (white arrow).

Finally, because the entire procedure can be performed in the fly’s wing, the fly itself is generally unharmed. This fulfills the final requirement, which is important for speeding up the screening process. Usually, after random mutations are induced in a population of flies, a fly line for each mutation has to be maintained until it can be tested. But if the original fly can live through the testing process, researchers can first determine if fly’s mutation is useful and then allow the fly to mate and create a stock if it is. This characteristic not only reduces the time needed for the screen by weeks, but it also significantly reduces the amount of labor required.

So how can this help us humans? This technique can speed up the process for discovering new genes involved in Wallerian degeneration. After a gene is identified in flies, researchers will know where to look in mammals and can begin studying the gene’s function (this has already happened once, with the Sarm gene). Figuring out how these genes function will provide a target for slowing axon death, which may in turn slow the progression of neurodegenerative diseases. And it all starts with a fruit fly’s wing.


  • Neukomm L.J., Burdett, T.C., M. A. Gonzalez, S. Zuchner & M. R. Freeman (2014). Rapid in vivo forward genetic approach for identifying axon death genes in Drosophila, Proceedings of the National Academy of Sciences, 111 (27) 9965-9970. DOI:

Breaking Research: Glycogen build-up in the brain contributes to aging

young vs old brainTotal brain volume decreases as we age. Image modified from brainpowerrelease.

Why is the aging process accompanied by progressive cognitive decline such as impaired memory, decreased focus, and slowed reaction time? Although we don’t fully know what causes it, researchers have found that aging visibly affects the brain, most strikingly as a decrease in total brain volume due to progressive loss of neurons. As we age, it is thought that neurons are irreversibly damaged by cumulative mistakes in building proteins, copying DNA, and other processes.

Sometimes, these mistakes can cause abnormal proteins and other molecules to clump together and form dense deposits inside neurons. In many neurodegenerative diseases such as Alzheimer’s or Lafora’s disease, an excess of deposits is associated with rapid neuron death. Yet although the (albeit much less severe) accumulation of deposits in the brain is a normal part of aging, its role in cognitive decline has been historically ignored. In a new study published in Aging Cell by the Milán and Guinovart labs, researchers investigate why these deposits appear during the normal aging process and what effect they have on neuronal function.

glycogen moleculeGlycogen is a storage molecule made up of thousands of branching glucose units. Image by Mikael Häggström.

Previous research has shown that the deposits present in aged human brains (which are referred to as either corpora amylacea or polyglucosan bodies; I’m just going to call them PGBs) are primarily made up of glycogen molecules, along with some other proteins. Glycogen is an important energy storage molecule in animal cells (second only to fats) and each glycogen molecule is composed of thousands of glucose units. But what causes the glycogen to aggregate and form deposits in a normal aging brain?

PGBs in mouse brainTop: brain (hippocampus) slice of aged normal mouse, stained with PAS, scale bar 200um. Bottom: Zoomed in on black box, arrow points to PGBs. Modified from Sinadinos et al, 2014.

The authors analyzed PGBs in the brains of aged mice to answer this question. They first studied the composition of the mouse PGBs and confirmed that they were similar to the PGBs found in aged human brains, down to the types of proteins bound up among the glycogen molecules. Next, they created a knock-out mouse line that was missing the glycogen synthase gene, which synthesizes glycogen by attaching glucose molecules together. The authors couldn’t find PGBs in the aged brains of these mutant mice, thus demonstrating that the process of synthesizing glycogen contributed to PGB formation. This finding is admittedly unsurprising: if the cells can’t make glycogen, it’s not there to clump together.

Well here’s the interesting part! Not only couldn’t the authors find glycogen deposits, but they also didn’t see accumulation of any of other protein associated with PGBs. One of the proteins they tested was alpha-synuclein, the aggregate-prone protein involved in Parkinson’s disease. In the normal mice, alpha-synclein accumulated along with the PGBs, but there was no accumulation in the mutant mice. Thus, glycogen synthesis seemed to be a prerequisite for the formation of other protein deposits. This finding could have implications for possible treatments to slow aging—if we can interfere with glycogen synthesis, could we stop the accumulation of other damage-causing proteins and reduce the detrimental effects on the brain?

To answer that question, we’d need to first confirm that the PGBs are actually involved in the decline of neuronal function during aging. This leads me to the authors’ next set of experiments, for which they turned to Drosophila melanogaster. Because fruit flies have shorter lifespans, it’s easier to study how PGBs affect them over their entire lives. In addition, fly researchers have developed a vast array of genetic tools for their animal model, which the authors used to knock-out the glycogen synthase gene again, but this time only in the brain and only during adulthood. This allowed the researchers to study how PGB formation affects brain function without altering the development and general health of the fly (a very difficult feat in mice).

As expected, the authors found that the mutant flies had reduced levels of glycogen in the brain. But remarkably, they also found that the mutants lived significantly longer than the normal flies. And this was quality life—the aged mutant flies could climb better and faster than normal flies of the same age. Based on these results, the authors concluded that glycogen synthesis impairs neuronal function and survival with age.

The findings from this paper is a step in the right direction for figuring out why cognitive decline is associated with aging. Before this can be useful for humans, however, there are a lot of questions to answer. How and why does glycogen synthesis cause PGB formation as we age? Will interfering with this process in adulthood extend quality life and cognitive function (and can it be done safely)?  Finally, the finding that glycogen synthesis may be required for other protein deposits was completely unexpected. Future work in this field may therefore provide insights into neurodegenerative diseases associated with protein aggregation, such as Alzheimer’s disease (beta-amyloid), Parkinson’s disease (alpha-synuclein), and Lafora’s disease (glycogen!).
For more research on aging, click the “aging” tag in the right column.

For another post about how to reduce aging-related protein aggregation, check out this post about the possible use of lithium.



  • Sinadinos C., Laura Boulan, Estel Solsona, Maria F. Tevy, Mercedes Marquez, Jordi Duran, Carmen Lopez-Iglesias, Joaquim Calbó, Ester Blasco, Marti Pumarola, Marco Milán & Joan J. Guinovart (2014). Neuronal glycogen synthesis contributes to physiological aging, Aging Cell, n/a-n/a. DOI:

General References:

Breaking Research: Lithium may protect against Alzheimer’s and other aging-related diseases

As human life expectancy continues to increase at a steady rate in most countries worldwide, the prevalence of aging-related diseases is also increasing. One such example is Alzheimer’s disease (AD), the most common cause of dementia in the aging population. There is currently no cure for AD, and the only treatments that exist temporarily cover up the symptoms without actually slowing the disease itself.

Alzheimer’s disease can be identified by the abnormal accumulation of a protein called amyloid beta (Aβ) in the brain. Aβ is a byproduct of an important cellular process, and is usually cleared away by the cell’s garbage recycling processes. It’s normal for some leftovers to be missed, however, and over time Aβ builds up as we age. But in large enough concentrations—such as in older patients with AD—accumulation leads to the formation of aggregated deposits of Aβ. These deposits damage neurons and cause neurodegeneration (progressive neuron death).

healthy vs Alzheimer's neuronsThe left side shows healthy neurons. The right side shows damaged neurons and Aβ deposits as seen in Alzheimer’s disease patients. Image modified from

Eventually, this widespread brain tissue damage leads to imbalances in the levels of neurotransmitters, which are chemicals that neurons use to communicate. This imbalance is thought to cause the symptoms of AD, including problems with memory, thinking, or changes in behavior. Current treatments simply alter the amount of these neurotransmitters without doing anything to slow or prevent Aβ aggregation and neuron death. Therefore, research aimed at developing a drug that can interfere with Aβ accumulation is important for treating this disease.

Recent findings in lithium research holds hope for such a treatment. Although lithium is most widely used as a treatment for bipolar disorder, some preliminary research suggests that it might also be able to slow or prevent the symptoms of Alzheimer’s disease in humans if prescribed early enough. However, the results have been mixed and even sometimes contradictory. This is largely due to the fact that lithium’s actions in the brain are not understood, so figuring out how lithium might be helping AD patients is essential before it could be considered as a treatment. A recent paper published in Frontiers of Aging Neuroscience by the Partridge lab has begun to do just that by studying how lithium can reduce Aβ accumulation in a fruit fly model of Alzheimer’s disease.

The authors created a model for AD by introducing a mutated form of human Aβ protein known to cause AD in some families (called Arctic Aβ42) into adult fruit flies. Flies with the Arctic Aβ42 mutation displayed progressive neuron dysfunction and shortened lifespan, which mimicked the symptoms of AD in human patients. They had previously shown that lithium treatment was able to reduce the amount of Aβ (and thus also its toxic effects on neurons) in these flies. But how did it work?  In this study, they treated these mutant flies with lithium again to answer this question.

What they found was surprising. Lithium didn’t just reduce the amount of Aβ protein in the brain, it reduced the amount of all proteins.  It worked by suppressing the activity of the “translation machinery”, which refers to the system that actually assembles and produces proteins from the instructions in the genetic code. So lithium actually reduced the production of all proteins through a mechanism that wasn’t specific to Aβ.

What does this mean for the possibility of using lithium to treat Alzheimer’s disease? The fact that lithium’s effects are more general is actually pretty good news not just for AD, but for all research into the aging process. It is currently thought that normal aging is caused by the accumulation of damaged or mutated proteins that haven’t been cleaned up, and research aimed at increasing lifespan has focused on either improving the cell’s recycling processes or reducing protein production. In fact, lithium treatment has been shown to increase life expectancy in animal models, including fruit flies (and possibly even in humans!).

So if lithium can increase lifespan in animals without Alzheimer’s disease, can it reverse the lifespan reduction in the AD model flies? Yes! The authors found that lithium treatment also improved the life expectancy of their mutant flies compared to ones that did not get a lithium treatment. This result provides further hope that lithium could one day be used to actually slow the progression of AD and give patients more years of quality life.

The findings in this paper are not just promising for Alzheimer’s disease, but also for other aging-related diseases caused by abnormal accumulation of protein in the brain, such as Parkinson’s disease and Huntington’s disease. Lithium also has the advantage of already being an approved drug for treating patients with bipolar disease, so some information on side-effects and dosages already exists. Of course, this doesn’t mean doctors should begin prescribing lithium for AD patients right away; the dosage requirements will likely be different and older adults may experience other side-effects. But research in this field has definitely leapt forward, and we may see a cure for aging-related diseases in our (extended?) lifetime.


  • Sofola-Adesakin O., Jorge I. Castillo-Quan, Charalampos Rallis, Luke S. Tain, Ivana Bjedov, Iain Rogers, Li Li, Pedro Martinez, Mobina Khericha, Melissa Cabecinha, Jürg Bähler & Linda Partridge(2014). Lithium suppresses Aβ pathology by inhibiting translation in an adult Drosophila model of Alzheimer’s disease, Frontiers in Aging Neuroscience, 6 DOI:

General References:

Breaking Research: A method by which invading bacteria avoid detection could also be our key to defeating them

Have you ever wondered how our body recognizes when it’s being invaded by harmful bacteria? Nearly all forms of life—from single-celled organisms all the way to humans—have an “innate” immune system, which has evolved to recognize cellular components shared by broad groups of pathogens. One such example is peptidoglycan, a molecule found on the cell walls of virtually all bacteria. Peptidoglycan forms a sort of “load-bearing mesh” required for the bacteria to maintain their shape and is therefore an essential part of their structure. As a result, our immune systems have evolved to recognize peptidoglycan as a danger signal and will trigger an immune response when it is detected.

But just as our innate immune system has evolved to recognize invaders bearing peptidoglycan, bacteria have also evolved to escape detection. In a recent paper published in eLife by the Filipe lab, researchers used fruit flies to study how some bacteria can remain undetected by its host. Understanding how bacteria avoid detection will help us develop new ways to defeat them by preventing them from evading our immune system. This could reduce the need for antibiotics, which is particularly important now that antibiotic-resistant bacteria are becoming painfully common (in 2014, the World Health Organization declared antibiotic resistance a major threat to public health).

Gram-negative and -positive bacteriaThe difference between Gram-negative and Gram-positive bacteria. Image source

So how do bacteria with peptidoglycan conceal themselves from our immune system? Previous work has categorized bacteria into two groups based on the way they cover up their peptidoglycan mesh: Gram-negative bacteria, which have a full membrane surrounding the peptidoglycan molecules, and Gram-positive bacteria, which have the mesh directly outside the cell wall. Instead of a full membrane, Gram-positive bacteria have layers of molecules that stick out of the cell wall and block access to the peptidoglycan. Because of this, it has long been thought that the immune system can only detect peptidoglycan when fragments have been snipped off of the bacterial walls (when bacteria need to grow and divide, they must break down their mesh and then rebuild it).

But now, researchers have uncovered a new twist to this story. Recent findings have suggested that under certain conditions, the immune system can actually recognize peptidoglycan while it’s still a part of the bacterial cell wall. So the authors of this paper asked: Have bacteria evolved other methods to prevent this from happening?

To answer this question, they infected fruit flies with Staphylococcus aureus (S. aureus), a Gram-positive strain of bacteria related to MRSA. They observed how well the fruit fly hosts were able to defend against the invaders, and then mutated parts of the bacteria to determine how each manipulation affected the hosts’ ability to survive. The authors learned that S. aureus releases a molecule called Atl, which they found was responsible for trimming off pieces of peptidoglycan that stick up above the bacteria’s protective layer. When the bacteria couldn’t release Atl, the flies were much more likely to survive the infection because their immune system could more easily recognize the intruders and fight them off.

How can this help us humans?  The mammalian innate immune system is similar to that of flies, and also recognizes peptidoglycan as a trigger for activating an immune response. Thus, if bacteria that infect humans use the same evasive maneuvers, it could be possible to develop a drug that targets and disables Atl and other peptidoglycan-snipping molecules. This would allow our immune systems to better recognize and fight back against bacterial infections and reduce the need for antibiotics.

The authors have already done some of the work toward this goal. To find out if strains of bacteria known to endanger humans use the same avoidance mechanism, they also infected flies with MRSA, a dangerous antibiotic-resistant strain of bacteria often found in hospitals, and Streptococcus pneumoniae, which is a frequent cause of pneumonia in developed countries and a major cause of infant mortality in developing countries. That found that both of these bacteria use Atl to shave their surface and avoid recognition by the immune system. Future research may therefore lead to treatments that prevent these bacteria from going into hiding, allowing our immune system to hunt them down and do its job with ease.


  • Atilano M.L., Filipa Vaz, Maria João Catalão, Patricia Reed, Inês Ramos Grilo, Rita Gonçalves Sobral, Petros Ligoxygakis, Mariana Gomes Pinho & Sérgio Raposo Filipe (2014). Bacterial autolysins trim cell surface peptidoglycan to prevent detection by the Drosophila innate immune system, eLife, 3 DOI:

Breaking Research: WIDE AWAKE is a newly identified gene that explains how we become sleepy at night

The body’s biological clock is responsible for keeping track of time and synchronizing behavior with the environment, so that you feel alert during daylight hours and sleepy at night. This biological clock (also called the circadian clock or circadian rhythms) consists of three major parts:

  1. The central pacemaker, which oscillates with a period of about 24 hours to keep time
  2. Inputs to the clock, such as light or temperature, that synchronize it with the environment
  3. Outputs from the clock, which signal to your body to indicate when it’s time to sleep, eat, etc

Researchers have made great progress in understanding how the central pacemaker works and how environmental cues can control the clock, but how does the clock signal to the rest of the body to control rhythmic behaviors? A recent fruit fly paper published in Neuron by the Koh and Wu labs investigated this question and discovered a new gene involved in signaling that it’s time to sleep.

How does our body know when it’s time to feel sleepy or alert? The biological clock must have an output pathway for controlling sleep, but the mechanism of exactly how that happens is poorly understood. After analyzing the sleep patterns of thousands of fruit fly colonies with different genetic mutations, the authors of this paper found a group of flies that had trouble falling asleep at night. They called the mutated gene Wide Awake (wake for short) and discovered that while the gene wasn’t necessary for accurate functioning of the circadian clock itself, it was important for signaling a transition from wake to sleep at the end of the day.

The role of WAKE in LNvsDuring the day, GABA signaling from sleep circuits in the fly brain has little effect on LNvs (the wake-promoting clock cells). At dusk, increased amounts of WAKE proteins in clock cells leads to an increase in the number of GABA receptors on the membrane, thus increasing the cells’ sensitivity to GABA. This dampens LNvs activity, allowing flies to fall asleep at night.

So how does this gene translate clock information into a feeling of sleepiness? The authors looked to “clock cells” to answer this question. Clock cells are a group of cells that make up the central pacemaker. In mammals, this pacemaker is located in the suprachiasmatic nucleus (SCN). In flies, the central pacemaker includes a small group of neurons called LNvs, which promote wakefulness. During the day, activity in the LNvs causes flies to be awake and active. But at dusk, the amount of WAKE protein from the wake gene in these cells increases. WAKE makes the cells more susceptible to inhibition from a chemical messenger called GABA, which dampens activity. As the wake-inducing LNvs become more sensitive to GABA, they become less active, which allows the sleep circuits in the brain to exert more control over behavior so the flies can fall asleep. On the other hands, flies with a mutation in the wake gene were not getting enough GABA signal to quiet the LNvs at night, keeping them agitated and awake.

The circadian clock in humans

The authors identified a gene that seems to be a messenger from the circadian clock to the brain, telling it that it’s time to shut down and go to sleep at night. But how can these fruit fly findings help us humans? They also found the same gene in the SCN in mammals, suggesting that it plays the same role in other species as well. The finding that wake mutants had difficulty falling asleep after lights-off is reminiscent of sleep-onset insomnia in humans. Currently, the most common treatment for insomnia are drugs the mimic the effects of GABA in the brain. However, these findings suggest that the effectiveness of this treatment is limited if wake-promoting neurons are not sensitive enough to GABA signaling. Thus, future research in this area may focus on manipulating the wake gene and its proteins to develop a better treatment for sleep disorders such as insomnia in humans.

For more information on circadian rhythm research in fruit flies, check out the related Translational Findings post.


  • Liu S., Qili Liu, Masashi Tabuchi, Yong Yang, Melissa Fowler, Rajnish Bharadwaj, Julia Zhang, Joseph Bedont, Seth Blackshaw & Thomas E. Lloyd & (2014). WIDE AWAKE Mediates the Circadian Timing of Sleep Onset, Neuron, 82 (1) 151-166. DOI:

Breaking Research: Aging can be delayed in fruit flies by activating AMPK in the gut

How can we slow or even halt the steady march of aging? In a previous post, I reviewed a paper that asked “What causes aging?” (the prevailing hypothesis is that aging is caused by accumulating cell damage). Understanding why we age is important for developing ways to interfere with the process. But there are other ways to study aging in the hopes of one day developing the mythical “elixir of life”. A recent fruit fly paper published in Cell Reports by the Walker lab instead asked, “How does caloric restriction increase lifespan?”

Scientists discovered a long time ago that caloric restriction can extend lifespan in a wide range of animal models, including rats and fruit flies. But the diet is severe and leads to side effects including reduced energy levels and sensitivity to cold. Who wants to live longer in such misery? Decreased food intake itself can’t be the cause of increased lifespan (it does seem rather counterintuitive), so what is going on?

Autophagy can be thought of as a cell's recycling mechanism

The authors found that activating a molecule called AMPK could increase lifespan just like dietary restriction, without all those miserable side effects. Normally, AMPK is activated when a cell needs more energy (such as when the animal isn’t eating enough calories). AMPK then triggers a process called macroautophagy, which means that components and molecules inside of cells are broken down and recycled for energy. This usually happens when the cell needs more energy than it is being provided, and the first things to go are old, unnecessary, and damaged cellular components. By artificially activating AMPK, the authors tricked the cells into breaking down more of this “cellular garbage”, slowing the accumulation of damage that leads to aging.

Perhaps the most exciting finding was that the authors could extend the lifespan of adult flies just by activating AMPK in the intestines. This manipulation slowed aging not just in intestinal cells, but also in brain tissue and even muscles. In fact, older flies even showed improved climbing ability. Although there is much work left to be done, these findings give hope that one day, aging can be slowed in adult humans just by swallowing a pill that activates AMPK in our gut.


  • Ulgherait M., Michael Rera, Jacqueline Graniel & David W. Walker (2014). AMPK Modulates Tissue and Organismal Aging in a Non-Cell-Autonomous Manner, Cell Reports, 8 (6) 1767-1780. DOI:
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