In order to function properly, the human brain requires the ability not only to store but also to forget: Through memory loss, unnecessary information is deleted and the nervous system retains its plasticity. A disruption of this process can lead to serious mental disorders. Basel scientists have now discovered a molecular mechanism that actively regulates the process of forgetting. The renowned scientific journal “Cell” has published their results.
The human brain is build in such a way, that only necessary information is stored permanently - the rest is forgotten over time. However, so far it was not clear if this process was active or passive. Scientists from the transfaculty research platform Molecular and Cognitive Neurosciences (MCN) at the University of Basel have now found a molecule that actively regulates memory loss. The so-called musashi protein is responsible for the structure and function of the synaptic connections of the brain, the place where information is communicated from one neuron to the next.
Using olfactory conditioning, the researchers Attila Stetak and Nils Hadziselimovic first studied the learning abilities of genetically modified ringworms (C. elegans) that were lacking the musashi protein. The experiments showed that the worms exhibited the same learning skills as unmodified animals. However, with extended duration of the experiment, the scientists discovered that the mutants were able to remember the new information much better. In other words: The genetically modified worms lacking the musashi protein were less forgetful.
Forgetting is no coincidence Further experiments showed that the protein inhibits the synthesis of molecules responsible for the stabilization of synaptic connections. This stabilization seems to play an important role in the process of learning and forgetting. The researchers identified two parallel mechanisms: One the one hand, the protein adducin stimulates the growth of synapses and therefore also helps to retain memory; on the other hand, the musashi protein actively inhibits the stabilization of these synapses and thus facilitates memory loss. Therefore, it is the balance between these two proteins that is crucial for the retention of memories.
Forgetting is thus not a passive but rather an active process and a disruption of this process may result in serious mental disorders. The musashi protein also has interesting implications for the development of drugs trying to prevent abnormal memory loss that occurs in diseases such as Alzheimer’s. Further studies on the therapeutic possibilities of this discovery will be done.
Catherine Aaron and
Gabrielle Beaudry were 17 when they knocked on the door of the
laboratory of Alex Parker, a neuroscience researcher at the University
of Montreal Hospital Research Centre (CRCHUM). While students at Collège
Jean-de-Brébeuf in Montreal, they were looking for a mentor for an
after-school research project. Two and half years later, the results of
this scientific adventure were published today in the Journal of Agricultural and Food Chemistry.
“We wanted to test the effect of a natural product on a
neurodegenerative disease such as Alzheimer’s. Professor Parker had
already discovered that sugar prevents the occurrence of amyotrophic
lateral sclerosis (ALS) in an animal model of the disease, the C. elegans worm. That’s how we got the idea of maple syrup, a natural sugar produced in Quebec,” said Beaudry.
Supervised by PhD student Martine Therrien and Alex Parker, Aaron and
Beaudry added maple syrup to the diet of these barely 1 mm-long
nematodes. “We just gave them a supplement of maple syrup at various
concentrations and compared with a control group that had a normal
diet,” said Aaron. “After twelve days, we counted under the microscope
the worms that were moving and those that were paralyzed. The worms that
had consumed the highest dose of syrup were much less likely to be
In the pantheon of animal models upon which basic scientific research relies, no species stands taller (metaphorically speaking) than Caenorhabditis elegans, a tiny worm (just one millimeter in length) that is broadly used to study fundamental molecular, cellular and developmental processes in animals.
Nobel laureate Sidney Brenner was among the first to promote the nematode’s utility as a model organism in the early 1960s for a variety of reasons: It is simple. Its entire neural system consists of exactly 302 neurons. It’s easy and cheap to grow in large numbers – and you can freeze the worms, and then thaw them out for later use. And it’s transparent, making it all the easier to peer at the worm’s internal workings.
C. elegans was the first organism to have its genome completely sequenced in 1998. An adult hermaphrodite worm contains 20,470 protein-coding genes, only slightly less than the estimated total for a human being.
In recent years, scientists have begun creating systemic catalogs of how these genes function and interact, not just in C. elegans but in other model organisms as well. Some of this research is being done by researchers Karen Oegema, PhD, a professor of cellular and molecular medicine and head of the Laboratory of Mitotic Mechanisms in the Ludwig Institute for Cancer Research at UC San Diego and her colleague, Rebecca Green, PhD.
Rather than studying individual cells, Oegema, Green and co-workers look at the effect of gene inhibitions in the structure of a complex tissue. Sometimes, it results in an eye-popping picture. The image above reveals the architecture of C. elegans’ reproductive tissue – its gonads. Red fluorescent markers highlight cell boundaries; green markers indicate DNA.
Researchers at MIT and the University of Vienna have created an imaging system that reveals neural activity throughout the brains of living animals. This technique, the first that can generate 3-D movies of entire brains at the millisecond timescale, could help scientists discover how neuronal networks process sensory information and generate behavior.
The team used the new system to simultaneously image the activity of every neuron in the worm Caenorhabditis elegans, as well as the entire brain of a zebrafish larva, offering a more complete picture of nervous system activity than has been previously possible.
“Looking at the activity of just one neuron in the brain doesn’t tell you how that information is being computed; for that, you need to know what upstream neurons are doing. And to understand what the activity of a given neuron means, you have to be able to see what downstream neurons are doing,” says Ed Boyden, an associate professor of biological engineering and brain and cognitive sciences at MIT and one of the leaders of the research team. “In short, if you want to understand how information is being integrated from sensation all the way to action, you have to see the entire brain.”
The new approach, described May 18 in Nature Methods, could also help neuroscientists learn more about the biological basis of brain disorders. “We don’t really know, for any brain disorder, the exact set of cells involved,” Boyden says. “The ability to survey activity throughout a nervous system may help pinpoint the cells or networks that are involved with a brain disorder, leading to new ideas for therapies.”
Boyden’s team developed the brain-mapping method with researchers in the lab of Alipasha Vaziri of the University of Vienna and the Research Institute of Molecular Pathology in Vienna. The paper’s lead authors are Young-Gyu Yoon, a graduate student at MIT, and Robert Prevedel, a postdoc at the University of Vienna.
High-speed 3-D imaging
Neurons encode information — sensory data, motor plans, emotional states, and thoughts — using electrical impulses called action potentials, which provoke calcium ions to stream into each cell as it fires. By engineering fluorescent proteins to glow when they bind calcium, scientists can visualize this electrical firing of neurons. However, until now there has been no way to image this neural activity over a large volume, in three dimensions, and at high speed.
Scanning the brain with a laser beam can produce 3-D images of neural activity, but it takes a long time to capture an image because each point must be scanned individually. The MIT team wanted to achieve similar 3-D imaging but accelerate the process so they could see neuronal firing, which takes only milliseconds, as it occurs.
The new method is based on a widely used technology known as light-field imaging, which creates 3-D images by measuring the angles of incoming rays of light. Ramesh Raskar, an associate professor of media arts and sciences at MIT and an author of this paper, has worked extensively on developing this type of 3-D imaging. Microscopes that perform light-field imaging have been developed previously by multiple groups. In the new paper, the MIT and Austrian researchers optimized the light-field microscope, and applied it, for the first time, to imaging neural activity.
With this kind of microscope, the light emitted by the sample being imaged is sent through an array of lenses that refracts the light in different directions. Each point of the sample generates about 400 different points of light, which can then be recombined using a computer algorithm to recreate the 3-D structure.
“If you have one light-emitting molecule in your sample, rather than just refocusing it into a single point on the camera the way regular microscopes do, these tiny lenses will project its light onto many points. From that, you can infer the three-dimensional position of where the molecule was,” says Boyden, who is a member of MIT’s Media Lab and McGovern Institute for Brain Research.
Prevedel built the microscope, and Yoon devised the computational strategies that reconstruct the 3-D images.
Aravinthan Samuel, a professor of physics at Harvard University, says this approach seems to be an “extremely promising” way to speed up 3-D imaging of living, moving animals, and to correlate their neuronal activity with their behavior. “What’s very impressive about it is that it is such an elegantly simple implementation,” says Samuel, who was not part of the research team. “I could imagine many labs adopting this.”
Neurons in action
The researchers used this technique to image neural activity in the worm C. elegans, the only organism for which the entire neural wiring diagram is known. This 1-millimeter worm has 302 neurons, each of which the researchers imaged as the worm performed natural behaviors, such as crawling. They also observed the neuronal response to sensory stimuli, such as smells.
The downside to light field microscopy, Boyden says, is that the resolution is not as good as that of techniques that slowly scan a sample. The current resolution is high enough to see activity of individual neurons, but the researchers are now working on improving it so the microscope could also be used to image parts of neurons, such as the long dendrites that branch out from neurons’ main bodies. They also hope to speed up the computing process, which currently takes a few minutes to analyze one second of imaging data.
The researchers also plan to combine this technique with optogenetics, which enables neuronal firing to be controlled by shining light on cells engineered to express light-sensitive proteins. By stimulating a neuron with light and observing the results elsewhere in the brain, scientists could determine which neurons are participating in particular tasks.
EDIT: Wow tumblr, thanks for eating my whole description.
My C. elegans recently outgrew his little vial, so these are some pictures of me transferring my fat happy baby into a bigger container. c: He’s actually a lot more docile and confident than I expected, and he was totally cool with being handled. EATS LIKE A MONSTER AND DOESN’T AFRAID OF ANYTHING. So I think after another moult or two I’ll start handling him once a week for a few minutes to get him more accustomed to it, and see how he does. He might make a better “hand” tarantula than I anticipated! He’s grown so much, too. I seriously can’t get over it. I’ve only had him for less than 5 months, and he was under 0.25" when I got him. I’M SO PROUD.
In this image, courtesy of Arshad Desai, a one-cell C. elegans embryo is shown undergoing mitosis. Microtubules are depicted red, chromosomes in blue, centromeres in green.
Add, subtract, divide equals life
Centromeres are regions of DNA and proteins on each chromosome that both link together sister chromatids and ensure accurate chromosome segregation and distribution during cell division or mitosis. When centromeres don’t work right, the result can be catastrophic. Indeed, aberrant division and chromosomal instability are hallmarks of cancer cells, especially the most aggressive types.
Yet despite their existential importance – “Chromosome segregation is the key event of cell division and fundamental to understanding life,” said Arshad Desai, PhD, professor of Cellular and Molecular Medicine at UC San Diego – centromeres remain imperfectly understood more than a century after German biologist Walther Flemming first described them.
In a letter published today in the advance online edition of the journal Nature, Desai, who is also an investigator at the Ludwig Institute for Cancer Research at UC San Diego, and colleagues fill in some critical details, describing the germline transcription process that defines centromeres in Caenorhabditis elegans, a nematode whose similar molecular mechanisms make it a model for human biology.
“How does a chromosomal region know it is a centromere and how is that information maintained. That’s the topic of our paper,” said Desai.
The work goes beyond simply advancing basic scientific understanding. Current cancer drugs like taxol and vinca alkaloids work by perturbing cell division. The problem is that these drugs can be toxic in non-dividing cells, such as neurons. A better understanding of how centromeres form and function could lead to more finely tuned or different ways for perturbing cell division.
Perhaps more significantly, said Desai, understanding centromeres will help in designing artificial chromosomes. “We currently rely on viruses for stable delivery of genetic information,” Desai said. “But this has the disadvantage that viruses integrate at random into genomes, which can negatively impact the patient.”
An artificial chromosome, with all of the genetic information tucked into the appropriate places, would preclude the need for viral vectors. And, said Desai, “the major limitation to designing true artificial chromosomes is our lack of understanding of centromeres.”
Scientists at the Max Planck Institute for Biology of Ageing in Cologne have found that a naturally occurring molecule has the ability to enhance defense mechanisms against neurodegenerative diseases. Feeding this particular metabolite to the small round worm Caenorhabditis elegans, helps clear toxic protein aggregates in the body and extends life span.
During ageing, proteins in the human body tend to aggregate. At a certain point, protein aggregation becomes toxic, overloads the cell, and thus prevents it from maintaining normal function. Damage can occur, particularly in neurons, and may result in neurodegenerative diseases like Alzheimer’s, Parkinson’s or Huntington’s disease. By studying model organisms like Caenorhabditis elegans, scientists have begun to uncover the mechanisms underlying neurodegeneration, and thus define possible targets for both therapy and prevention of those diseases. “Although we cannot measure dementia in worms“, explains Martin Denzel of the Max Planck Institute for Biology of Ageing, “we can observe proteins that we also know from human diseases like Alzheimer’s to be toxic by measuring effects on neuromuscular function. This gives us insight into how Alzheimer actually progresses on the molecular level“.
Now, the scientists Martin Denzel, Nadia Storm, and Max Planck Director Adam Antebi have discovered that a substance called N-acetylglucosamine apparently stimulates the body’s own defense mechanism against such toxicity. This metabolite occurs naturally in the organism. If it is additionally fed to the worm, “we can achieve very dramatic benefits“, says Denzel. “It is a broad-spectrum effect that alleviates protein toxicity in Alzheimer’s, Parkinson’s and Huntington’s disease models in the worm, and it even extends their life span.“
This molecule apparently plays a crucial role in quality control mechanisms that keep the body healthy. It helps the organism to clear toxic levels of protein aggregation, both preventing aggregates from forming and clearing already existing ones. As a result, onset of paralysis is delayed in models of neurodegeneration - How exactly the molecule achieves this effect is yet to be uncovered. “And we still don’t know whether it also works in higher animals and humans“, says Antebi. “But as we also have these metabolites in our cells, this gives good reason to suspect that similar mechanisms might work in humans.”
Rutgers scientists have uncovered biological pathways in the
roundworm that provide insight into how tiny bubbles released by cells
can have beneficial health effects, like promoting tissue repair, or may
play a diabolical role and carry disease signals for cancer or
neurodegenerative diseases like Alzheimer’s.
In a new study, published in Current Biology,
Rutgers scientists isolated and profiled cells releasing these
sub-micron sized bubbles, known as extracellular vesicles (EVs) in adult
C. elegans and identified 335 genes that provide significant
information about the biology of EVs and their relationship to human
“These EV’s are exciting but scary because we don’t know what the
mechanisms are that decide what is packaged inside them.” said Maureen
Barr, lead author and a professor in the Department of Genetics in
Rutgers’ School of Arts and Sciences. "It’s like getting a letter in
the mail and you don’t know whether it’s a letter saying that you won
the lottery or a letter containing anthrax.“
All multicellular organisms that reproduce sexually rely on eggs to support early life. Researchers at University of California, San Diego School of Medicine and Ludwig Cancer Research used the tiny roundworm C. elegans as a model to better understand how eggs enable embryonic development, using only the materials already present in them. Their study, published March 24 in Cell, uncovers the role small RNAs — a type of genetic material — and helper proteins play in fine-tuning egg development.
“Eggs differ from other growing cells, where nutrients are used to build up cell mass before division occurs,” said Arshad Desai, PhD, professor at UC San Diego School of Medicine and member of Ludwig Cancer Research’s San Diego branch. “A frog egg, for example, makes about 3,000 cells by simply dividing into smaller and smaller cells, without growth. We were interested in understanding how eggs are able to do this.”
Adding to the growing body of knowledge on small RNAs and how they influence cellular function, this study shows that small RNAs work together with an enzyme known as an Argonaute to help create the perfect C. elegans egg. The researchers based their study on earlier work showing that a specific Argonaute protein called CSR-1 affects chromosome distribution in the first division of the embryo that occurs after the egg is fertilized.
(Image caption: For the first time, sound waves are used to control brain cells. Salk scientists developed the new technique, dubbed sonogenetics, to selectively and noninvasively turn on groups of neurons in worms that could be a boon to science and medicine. Credit: Courtesy of the Salk Institute for Biological Studies)
Salk scientists have developed a new way to selectively activate
brain, heart, muscle and other cells using ultrasonic waves. The new
technique, dubbed sonogenetics, has some similarities to the burgeoning
use of light to activate cells in order to better understand the brain.
This new method–which uses the same type of waves used in medical
sonograms–may have advantages over the light-based approach–known as
optogenetics–particularly when it comes to adapting the technology to
human therapeutics. It was described September 15, 2015 in the journal Nature Communications.
“Light-based techniques are great for some uses and I think we’re going to continue to see developments on that front,” says Sreekanth Chalasani, an assistant professor in Salk’s Molecular Neurobiology Laboratory and senior author of the study. “But this is a new, additional tool to manipulate neurons and other cells in the body.”
In optogenetics, researchers add light-sensitive channel proteins to
neurons they wish to study. By shining a focused laser on the cells,
they can selectively open these channels, either activating or silencing
the target neurons. But using an optogenetics approach on cells deep in
the brain is difficult: typically, researchers have to perform surgery
to implant a fiber optic cable that can reach the cells. Plus, light is
scattered by the brain and by other tissues in the body.
Chalasani and his group decided to see if they could develop an approach
that instead relied on ultrasound waves for the activation. “In
contrast to light, low-frequency ultrasound can travel through the body
without any scattering,” he says. “This could be a big advantage when
you want to stimulate a region deep in the brain without affecting other
regions,” adds Stuart Ibsen, a postdoctoral fellow in the Chalasani lab
and first author of the new work.
Chalasani and his colleagues first showed that, in the nematode Caenorhabditis elegans,
microbubbles of gas outside of the worm were necessary to amplify the
low-intensity ultrasound waves. “The microbubbles grow and shrink in
tune with the ultrasound pressure waves,” Ibsen says. “These
oscillations can then propagate noninvasively into the worm.”
Next, they found a membrane ion channel, TRP-4, which can respond to
these waves. When mechanical deformations from the ultrasound hitting
gas bubbles propagate into the worm, they cause TRP-4 channels to open
up and activate the cell. Armed with that knowledge, the team tried
adding the TRP-4 channel to neurons that don’t normally have it.
With this approach, they successfully activated neurons that don’t
usually react to ultrasound.
So far, sonogenetics has only been applied to C. elegans
neurons. But TRP-4 could be added to any calcium-sensitive cell type in
any organism including humans, Chalasani says. Then, microbubbles could
be injected into the bloodstream, and distributed throughout the body–an
approach already used in some human imaging techniques. Ultrasound
could then noninvasively reach any tissue of interest, including the
brain, be amplified by the microbubbles, and activate the cells of
interest through TRP-4. And many cells in the human body, he points out,
can respond to the influxes of calcium caused by TRP-4.
“The real prize will be to see whether this could work in a mammalian
brain,” Chalasani says. His group has already begun testing the approach
in mice. “When we make the leap into therapies for humans, I think we
have a better shot with noninvasive sonogenetics approaches than with
Both optogenetics and sonogenetics approaches, he adds, hold promise in
basic research by letting scientists study the effect of cell
activation. And they also may be useful in therapeutics through the
activation of cells affected by disease. However, for either technique
to be used in humans, researchers first need to develop safe ways to
deliver the light or ultrasound-sensitive channels to target cells.
Ablation in medicine means to remove tissue by various means, such as cutting, chipping or vaporizing, to eliminate a threat to health. Cellular ablation is a more particular endeavor: Cells are selectively destroyed to better understand their lineage and function.
Researchers have some clever tools to do this. A laser, for example, can focus upon a single cell in Caenorhabditis elegans, a tiny worm and proven model organism. Or genetically coded reagents, such as enzymes or cytotoxic molecules, can be introduced into targeted cells to induce apoptosis or programmed cell death.
The problem with the latter approach, which has been used in organisms other than C. elegans, is that chemical reagents may accumulate in tissues other than the targeted cells, causing non-specific toxicity. In other words, healthy cells near the target can also die.
In a paper published online this week in the Proceedings of the National Academy of Sciences, Yishi Jin, PhD, a professor in the division of biological sciences and Howard Hughes Medical Institute investigator, and Roger Tsien, PhD, professor of pharmacology, chemistry and biochemistry Howard Hughes Medical Institute investigator, and Nobel laureate describe, with colleagues, using a tiny, light-activated molecule to effectively kill single neurons in a nematode without any apparent collateral effect.
The molecule is called a mini-singlet oxygen generator or miniSOG. It’s a radically re-engineered light-absorbing protein from the cress plant Arabidopsis thaliana that, when exposed to blue light, produces abundant quantities of singlet oxygen. The researchers in Jin’s lab targeted the expression of miniSOG to mitochondria, and observed that the expressing cells die quickly upon blue light illumination, without affecting neighboring tissues.
“We believe that singlet oxygen generated by miniSOG (genetically introduced into the mitochondria of the targeted neuron) destroys the integrity of the mitochondria, which releases toxic molecules that lead to the death of the cell,” said Jin. “The dead neuron is then cleared away by nearby cells, most likely through phagocytosis.”
While the findings may be a boon to basic research, Tsien said they are unlikely to have direct value for developing human treatments because the method requires gene therapy, which is not yet practical enough.
“Plus it needs blue light, which doesn’t penetrate very far through organisms as thick as ourselves. However, we are separately working on synthetic injectable molecules (not minSOG) that would home in on cancer cells and kill them with red or near-infrared light, which penetrate mammalian tissues much better than blue light. But even red or near-infrared would mostly have to be applied by endoscopes or during surgery.“