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.
How do cells “move through walls”? An invading cell in the roundworm C. elegans is initially blocked from moving forward by a thick basement membrane. This time series of images shows the basement membrane (blue) separating to create a passage for the cell (red) to move.
Image by Elliott Hagedorn and David Sherwood, Duke University.
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.
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.”
The room is so lovely with the window panels down. Love the natural light.
Spent the morning pouring blood and water agar into the vessels. One step closer… Got new Daphnia from Shian. She said they sometimes crash for no apparent reason, including if there are no adults. Since I only had a few juveniles, I guess that is what happened. Fed them with 4ml algae.
Email from John at SABC about the nematode plate I left at Murdoch. He was excited about at least one live nematode he found on the plate. I need to ask him about the contamination on my plates and start a liquid culture. I prepared 2.5L of luria broth in preparation for a large culture of E. coli to feed the liquid culture of C. elegans. I may need to get the seed nematodes from John as mine aren’t happy.
Brought the Homo sapiens vessel into the gallery. Will bring several more tomorrow.
Ionat & Oron are coming for a squiz tomorrow. Wanted to have the Candida box frame finished but the glue is too stinky. Will finish on the weekend. Will have the labels and handles onto the tables by then though. Will also bring Daphnia, Drosophila, Physarum, Hydra & Arabidopsis in tomorrow.
Spill Hazard Kit almost finished - need hand disinfectant and am waiting on the First Aid Kit.
Spent an hour with Megan just sitting on the couches talking about possible layouts, but lovely to just sit with rosehip tea and baklava. Thanks Megs
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.”
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.“
Analysis of worm neurons suggests how a single stimulus can trigger different responses
Even worms have free will. If offered a delicious smell, for example, a roundworm will usually stop its wandering to investigate the source, but sometimes it won’t. Just as with humans, the same stimulus does not always provoke the same response, even from the same individual. New research at Rockefeller University, published online in
Cell, offers a new neurological explanation for this
variability, derived by studying a simple three-cell network within the
(Image caption: Worm brain: All the neurons within this microscopic roundworm are highlighted, with the large cluster at one end representing the brain.
Coelomocytes, a type of immune cell, appear as dots along the body)
“We found that the collective state of the three neurons at the exact moment an odor arrives determines the likelihood that the worm will
move toward the smell. So, in essence, what the worm is thinking about
at the time determines how it responds,” says study author Cori Bargmann, Torsten N. Wiesel Professor, head of the Lulu and Anthony Wang Laboratory of Neural Circuits and Behavior.
“It goes to show that nervous systems aren’t passively waiting for
signals from outside, they have their own internal patterns of activity
that are as important as any external signal when it comes to generating
The researchers went a step deeper to tease out the dynamics within
the network. By changing the activity of the neurons individually and in
combination, first author Andrew Gordus, a research associate in the
lab, and his colleagues could pinpoint each neuron’s role in generating
variability in both brain activity and the behavior associated with it.
The human brain has 86 billion neurons and 100 trillion synapses, or
connections, among them. The brain of the microscopic roundworm Caenorhabditis elegans,
by comparison, has 302 neurons and 7,000 synapses. So while the worm’s
brain cannot replicate the complexity of the human brain, scientists can
use it to address tricky neurological questions that would be nearly
impossible to broach in our own brains.
Worms spend their time wandering, looking for decomposing matter to
eat. And when they smell it, they usually stop making random turns and
travel straight toward the source. This change in behavior is initially
triggered by a sensory neuron that perceives the smell and feeds that
information to the network the researchers studied. As the worms pick up
the alluring fruity smell of isoamyl alcohol, the neurons in the
network transition into a low activity state that allows them to
approach the odor. But sometimes the neurons remain highly active, and
the worm continues to wander around – even though its sensory neuron has
detected the odor.
By recording the activity of these neurons, Gordus and colleagues
found that there were three persistent states among the three neurons:
All were off, all were on, or only one, called AIB, was on. If all were
off, then, when the odor signal arrived, they stayed off. If all were
on, they often, but not always, shut off. And, in the third and most
telling scenario, if AIB alone was active when the odor arrived,
everything shut off. “This means that for AIB, context matters. If it’s
on alone, its activity will drop when odor is added, but if it’s on with
the rest of the network, it has difficulty dropping its activity with
the others,” Gordus says.
AIB is the first neuron in the network to receive the signal, which
it then relays to the other two network members, known as RIM and AVA;
AVA sends out the final instruction to the muscles. When the researchers
shut off RIM and AVA individually and together, they found AIB’s
response to the odor signal improved. This suggests that input from
these two neurons competes with the sensory signal as it feeds down
through the network.
Scaled up to account for the more nuanced behaviors of humans, the
research may suggest ways in which our brains process competing
motivations. “For humans, a hungry state might lead to you walk across
the street to a delicious smelling restaurant. However, a competing
aversion to the cold might lead you to stay indoors,” he says.
In the worm experiments, the competition between neurons was
influenced by the state of the network. There is plenty of evidence
suggesting network states have a similar impact on animals with much
larger and more complex brains, including us, says Bargmann, who is also
a Howard Hughes Medical Institute investigator. “In a mammalian nervous
system, millions of neurons are active all the time. Traditionally, we
think of them as acting individually, but that is changing. Our
understanding has evolved toward seeing important functions in terms of
collective activity states within the brain.”
The hilariously named C. instagram shows C. elegans worms eating E. coli, which they gorge on before clumping together in these patterns. Meredith Wright caught the phenomenon using her smartphone—hence the name of the photo. “I’ve since shared the photo on social networking sites and have had friends who’ve never been interested in biology ask me more about my work because of this photo,” she explains. “To me, this image represents the simple pleasure of finding something beautiful when you don’t expect to, and it shows how easy it is to connect science with new audiences by simply clicking ‘share.’”
(Image caption: This image shows a single sensory neuron in the roundworm Caenorhabditis elegans.
Salk researchers demonstrated how a neural circuit uses prior
experience to modify future behaviors. The work reveals new details on the function of two chemical signals critical to animal–and
human–behavior: dopamine (responsible for reward and risk-taking) and CREB (needed for learning). Credit: Salk Institute for Biological Studies)
If you had 10 chances to roll a die, would you rather be guaranteed
to receive $5 for every roll ($50 total) or take the risk of winning
$100 if you only roll a six?
Most animals, from roundworms to humans, prefer the more predictable
situation when it comes to securing resources for survival, such as
food. Now, Salk scientists have discovered the basis for how animals
balance learning and risk-taking behavior to get to a more predictable
environment. The research reveals new details on the function of two
chemical signals critical to human behavior: dopamine–responsible for
reward and risk-taking–and CREB–needed for learning.
“Previous research has shown that certain neurons respond to changes in
light to determine variability in their environment, but that’s not the
only mechanism,” says senior author Sreekanth Chalasani, an assistant professor in Salk’s Molecular Neurobiology Laboratory. “We discovered a new mechanism that evaluates environmental variability, a skill crucial to animals’ survival.”
By studying roundworms (Caenorhabditis elegans), Salk
researchers charted how this new circuit uses information from the
animal’s senses to figure out how predictable the environment and prompt
the worm to move to a new location if needed. The work was detailed
April 9, 2015 in Neuron.
The circuit, made up of 16 of the 302 neurons in the worm’s brain,
likely has parallels in more complex animal brains, researchers say, and
could be a starting point to understanding–and fixing–certain
psychiatric or behavioral disorders.
“What was surprising is the degree to which variability in animal
behavior can be explained by variability in their past sensory
experience and not just noise,” says Tatyana Sharpee,
associate professor and co-senior author of the paper. “We can now
predict future animal behaviors based on past sensory experience,
independent of the influence of genetic factors.”
The team discovered that two pairs of neurons in this learning circuit
act as gatekeepers. One pair responds to large increases of the presence
of food and the other pair responds to large decreases of the presence
of food. When either of these high-threshold neurons detect a large
change in an environment (for example, the smell of a lot of food to no
food) they induce other neurons to release the neurotransmitter
Dumping dopamine onto a brain–human or otherwise–makes one more willing
to take risks. It’s no different in the roundworm: stimulated by large
varieties in its environment, dopamine surges in the worm’s system and
activates four other neurons in the learning circuit, giving them a
greater response range. This prompts the worm to search more actively in
a wider area (risk-taking) until it hits a more consistent environment.
The amount of dopamine in its system serves as its memory of the past
experience: about 30 minutes or so and it forgets information gathered
in the time before that.
While it’s been known that the presence of dopamine is tied to
risk-taking behavior, how exactly dopamine does this hasn’t been well
understood. With this new work, scientists now have a fundamental model
of how dopamine signaling leads the worm to take more risks and explore
“The connection between dopamine and risk is conserved across animals
and is already known, but we showed mechanistically how it works,” says
Chalasani, who is also holder of the Helen McLoraine Developmental Chair in Neurobiology.
“We hope this work will lead to better therapies for neurodegenerative
and behavioral diseases and other disorders where dopamine signaling is
Interestingly, the scientists found that the high-threshold neurons also
lead to increased signaling from a protein called CREB, known in humans
and other animals to be essential to learning and retaining new
memories. The researchers showed that not only are the presence of CREB
important to learning, but the amount of CREB protein determines how
quickly an animal learns. This surprising connection could lead to new
avenues of research for brain enhancements, adds Chalasani.
How did researchers test all of this in worms exactly? They began by
placing worms in dishes that contained either a large or a small patch
of edible bacteria. Worms in the smaller patches tended to reach the
edges more frequently, experiencing large changes in variability (edges
have large amounts of food compared to the center). Worms on the large
patch, however, reached the edge less frequently, thereby experiencing a
general stable environment (mainly an area with constant food).
Using genetics, imaging, behavioral analysis and other techniques,
researchers found that when worms are on small patches, the two pairs of
high-threshold neurons respond to the greater variation and signal
leading to increased dopamine. When worms in these smaller patches (and
higher dopamine) were taken out and put into a new dish, they explored a
larger area, taking more of a risk. Worms from the larger patches,
however, produced less dopamine and were more cautious, exploring just a
small space when placed in a new area.
Additionally, when the protein CREB was present in larger amounts, the
team found that the worms took far less time to learn about their food
variability. “Normally the worms took about 30 minutes or so to explore
and learn about food, but as you keep increasing the CREB protein they
learn it faster,” says Chalasani. “So dopamine stores the memory of what
these worms learn while CREB regulates how quickly they learn.”