Posts tagged C. elegans
Articles and news from the latest research reports.
Glowing Worms Illuminate Roots of Behavior
A research team at Worcester Polytechnic Institute (WPI) and The Rockefeller University in New York has developed a novel system to image brain activity in multiple awake and unconstrained worms. The technology, which makes it possible to study the genetics and neural circuitry associated with animal behavior, can also be used as a high-throughput screening tool for drug development targeting autism, anxiety, depression, schizophrenia, and other brain disorders.
Image: Neurons in the worms (marked by arrows) glow as the animals sense attractive odors.
The team details their technology and early results in the paper “High-throughput imaging of neuronal activity in Caenorhabditis elegans,” published on-line in advance of print by the journal Proceedings of the National Academy of Sciences.
"One of our major objectives is to understand the neural signals that direct behavior—how sensory information is processed through a network of neurons leading to specific decisions and responses," said Dirk Albrecht, PhD, assistant professor of biomedical engineering at WPI and senior author of the paper. Albrecht led the research team both at WPI and at Rockefeller, where he served previously as a postdoctoral researcher in the lab of Cori Bargmann, PhD, a Howard Hughes Medical Institute Investigator and a co-author of the new paper.
To study neuronal activity, Albrecht’s lab uses the tiny worm Caenorhabditis elegans (C. elegans), a nematode found in many environments around the world. A typical adult C. elegans is just 1 millimeter long and has 969 cells, of which 302 are neurons. Despite its small size, the worm is a complex organism able to do all of the things animals must do to survive. It can move, eat, mate, and process environmental cues that help it forage for food or react to threats. As a bonus for researchers, C.elegans is transparent. By using various imaging technologies, including optical microscopes, one can literally see into the worm and watch physiological processes in real time.
Numerous studies have been done by “worm labs” around the world exploring various neurological processes in C. elegans. These have typically been done using one worm at a time, with the animal’s body fixed in place on a slide. In their new paper, Albrecht’s team details how they imaged, recorded, and analyzed specific neurons in multiple animals as they wormed their way around a custom-designed microfluidic array, called an arena, where they were exposed to favorable or hostile sensory cues.
Specifically, the team engineered a strain of worms with neurons near the head that would glow when they sensed food odors. In experiments involving up to 23 worms at a time, Albrecht’s team infused pulses of attractive or repulsive odors into the arena and watched how the worms reacted. In general, the worms moved towards the positive odors and away from the negative odors, but the behaviors did not always follow this pattern. “We were able to show that the sensory neurons responded to the odors similarly in all the animals, but their behavioral responses differed significantly,” Albrecht said. “These animals are genetically identical, and they were raised together in the same environment, so where do their different choices come from?”
In addition to watching the head neurons light up as they picked up odor cues, the new system can trace signaling through “interneurons.” These are pathways that connect external sensors to the rest of the network (the “worm brain”) and send signals to muscle cells that adjust the worm’s movement based on the cues. Numerous brain disorders in people are believed to arise when neural networks malfunction. In some cases the malfunction is dramatic overreaction to a routine stimulus, while in others it is a lack of appropriate reactions to important cues. Since C. elegans and humans share many of the same genes, discovering genetic causes for differing neuronal responses in worms could be applicable to human physiology. Experimental compounds designed to modulate the action of nerve cells and neuronal networks could be tested first on worms using Albrecht’s new system. The compounds would be infused in the worm arena, along with other stimuli, and the reaction of the worms’ nervous systems could be imaged and analyzed.
"The basis of our work is to combine biomedical engineering and neuroscience to answer some of these fundamental questions and hopefully gain insight that would be beneficial for understanding and eventually treating human disorders," Albrecht said.
(Source: wpi.edu)
Insulin plays a role in mediating worms’ perceptions and behaviors
Using salt-sniffing roundworms, Salk scientists help explain how the nervous system processes sensory information
In the past few years, as imaging tools and techniques have improved, scientists have been working tirelessly to build a detailed map of neural connections in the human brain—with the ultimate hope of understanding how the mind works.
But determining how cells in the brain are physically connected is only the first clue for decoding our perceptions and behaviors. We also need to know the precise routes that information takes in the brain in a given context. Now, publishing their results September 8, 2013, in the journal Nature Neuroscience, researchers at the Salk Institute for Biological Studies have shown a striking example of the flexibility in neural circuitry and its influence on behaviors in worms, depending on the animals’ environment.
The roundworm Caenorhabditis elegans has exactly 302 neurons—far less than the estimated 100 billion neurons a person has—and we already know how each of them is connected. That, in addition to how easily the tiny creature’s cells can be manipulated, allows researchers to ask what sort of information passes through the circuits—in molecular-and circuit-level detail—and what are the behavioral consequences of this information flow.
Even with a comprehensive map of the worm’s neuronal connections in hand, however, scientists still don’t know how the animal can interact with its environment in thousands of different ways. That’s one big question that Sreekanth Chalasani, an assistant professor in Salk’s Molecular Neurobiology Laboratory and Sarah Leinwand, a doctoral student at the University of California, San Diego, sought to answer.
In C. elegans, thanks to studies performed more than 20 years ago, many sensory neurons were identified to have distinct roles such as sensing temperature, pheromones, salt and odors. To know what these cells did, scientists had zapped them one-by-one with a laser and measured the worms’ behaviors. These studies implicated one neuron in the detection of increased salt in the worm’s surroundings.
In the new study, rather than ablating individual sensory neurons, Leinwand and Chalasani imaged worms that expressed genetically encoded calcium indicators in their neurons, which caused the cells to light up when active. Surprisingly, after exposure to an attractive but high concentration of salt, the worms’ olfactory sensory neuron lit up.
"We were extremely surprised to see that with these new tools, these new calcium sensors, we could discover that there was more than one type of neuron involved in processing sensory cues that people had thought were only sensed by single neurons," says Leinwand.
Using additional genetic manipulations and behavioral assays, the researchers showed that the olfactory neuron—while still important for sensing odorants—was crucial for the worm’s movement toward salt within a certain concentration range. Unexpectedly, this neuron’s response to salt also required the previously identified salt-sensing neuron. In fact, the olfactory neuron was not directly sensing salt but instead was being activated by the salt sensory neuron, they found.
What information was the salt-sensing neuron sending to the olfactory neuron? Neurons communicate with each other by sending chemical and electrical signals through close contacts with their neighbors. By testing worms whose signaling molecules had been genetically knocked out, Chalasani and Leinwand could see which were playing a role in transmission when the worm was stimulated by higher salt. From these experiments, they saw that a neuropeptide, a small protein present in neurons, was being released by the salt-sensing neuron to shape the animal’s behavior.
Identifying the neuropeptide (or neuropeptides) responsible for the context-dependent signaling was the most challenging part of the study, because the worm has 115 genes that code for some 250 neuropeptides, Chalasani says. Luckily, there are only four different molecular machines that process all of these peptides; by using genetic knockouts of each of the four, Leinwand and Chalasani were quickly able to narrow the list down to about 40 genes which coded for insulin neuropeptides.
One by one, the team tracked olfactory neuron responses to high salt in worms missing each gene, finding that worms lacking the gene for an insulin neuropeptide known as INS-6 did not respond to increases in salt. Putting this peptide back restored the animal’s normal responses to high salt.
"It was rewarding to see that, while there might be more than one peptide signal, the contributions from INS-6 are certainly significant," Leinwand says. She and Chalasani also found the specific receptor on the receiving end of the olfactory neurons.
That insulin was the main signaling molecule recruiting the olfactory neuron into a salt-sensing circuit was a big surprise.
"Traditionally, neuropeptides have been thought to modulate neuronal function over many seconds to many minutes," Chalasani says. "But in this particular instance, it looks like the insulin is acting in less than a second to transfer information from the salt-sensing neuron to the neuron which normally responds to odor."
Similar neuropeptide communication may also create flexible neural circuits that mediate the diverse behaviors that other animals and people perform in their environments. Insulin has many roles in people—it has been implicated in aging and metabolism, for example—but so far it has only been shown to function on a slower, minute time-scale.
Chalasani and Leinwand plan to investigate whether there are other fast neural circuit switches in worms—and if so, whether those switches act through neuropeptide signaling or some other mechanism. They’re also interested in how the circuit switch changes as the animal ages. “You would expect that as the animal is aging, some of this communication becomes less efficient,” Chalasani says.
Capturing brain activity with sculpted light
Researchers in Vienna develop new imaging technique to study the function of entire nervous systems. Scientists at the Campus Vienna Biocenter (Austria) have found a way to overcome some of the limitations of light microscopy. Applying the new technique, they can record the activity of a worm’s brain with high temporal and spatial resolution, ultimately linking brain anatomy to brain function. The journal Nature Methods publishes the details in its current issue.
A major aim of today’s neuroscience is to understand how an organism’s nervous system processes sensory input and generates behavior. To achieve this goal, scientists must obtain detailed maps of how the nerve cells are wired up in the brain, as well as information on how these networks interact in real time.
The organism many neuroscientists turn to in order to study brain function is a tiny, transparent worm found in rotting soil. The simple nematode C. elegans is equipped with just 302 neurons that are connected by roughly 8000 synapses. It is the only animal for which a complete nervous system has been anatomically mapped.
Researchers have so far focused on studying the activity of single neurons and small networks in the worm, but have not been able to establish a functional map of the entire nervous system. This is mainly due to limitations in the imaging-techniques they employ: the activity of single cells can be resolved with high precision, but simultaneously looking at the function of all neurons that comprise entire brains has been a major challenge. Thus, there was always a trade-off between spatial or temporal accuracy and the size of brain regions that could be studied.
Scientists at Vienna’s Research Institute of Molecular Pathology (IMP), the Max Perutz Laboratories (MFPL), and the Research Platform Quantum Phenomena & Nanoscale Biological Systems (QuNaBioS) of the University of Vienna have now closed this gap and developed a high speed imaging technique with single neuron resolution that bypasses these limitations. In a paper published online in Nature Methods, the teams of Alipasha Vaziri and Manuel Zimmer describe the technique which is based on their ability to “sculpt” the three-dimensional distribution of light in the sample. With this new kind of microscopy, they are able to record the activity of 70% of the nerve cells in a worm’s head with high spatial and temporal resolution.
“Previously, we would have to scan the focused light by the microscope in all three dimensions”, says quantum physicist Robert Prevedel. “That takes far too long to record the activity of all neurons at the same time. The trick we invented tinkers with the light waves in a way that allows us to generate “discs” of light in the sample. Therefore, we only have to scan in one dimension to get the information we need. We end up with three-dimensional videos that show the simultaneous activities of a large number of neurons and how they change over time.” Robert Prevedel is a Senior Postdoc in the lab of Alipasha Vaziri, who is an IMP-MFPL Group Leader and is heading the Research Platform Quantum Phenomena & Nanoscale Biological Systems (QuNaBioS) of the University of Vienna, where the new technique was developed.
However, the new microscopic method is only half the story. Visualising the neurons requires tagging them with a fluorescent protein that lights up when it binds to calcium, signaling the nerve cells’ activity. “The neurons in a worm’s head are so densely packed that we could not distinguish them on our first images”, explains neurobiologist Tina Schrödel, co-first author of the study. “Our solution was to insert the calcium sensor into the nuclei rather than the entire cells, thereby sharpening the image so we could identify single neurons.” Tina Schrödel is a Doctoral Student in the lab of the IMP Group Leader Manuel Zimmer.
The new technique that came about by a close collaboration of physicists and neurobiologists has great potentials beyond studies in worms, according to the researchers. It will open up the way for experiments that were not possible before. One of the questions that will be addressed is how the brain processes sensory information to “plan” specific movements and then executes them. This ambitious project will require further refinement of both the microscopy methods and computational methods in order to study freely moving animals. The team in Vienna is set to achieve this goal in the coming two years.
Biologists Uncover Details of How We Squelch Defective Neurons
Biologists at the University of California, San Diego have identified a new component of the cellular mechanism by which humans and animals automatically check the quality of their nerve cells to assure they’re working properly during development.
In a paper published in this week’s issue of the journal Neuron, the scientists report the discovery in the laboratory roundworm C. elegans of a “quality check” system for neurons that uses two proteins to squelch the signals from defective neurons and marks them for either repair or destruction.
“To be able to see, talk and walk, nerve cells in our body need to communicate with their right partner cells,” explains Zhiping Wang, the lead author in the team of researchers headed by Yishi Jin, a professor of neurobiology in UC San Diego’s Division of Biological Sciences and a professor of cellular and molecular medicine in its School of Medicine. “The communication is mediated by long fibers emitting from neurons called axons, which transmit electric and chemical signals from one cell to the other, just like cables connecting computers in a local wired network. In developing neurons, the journey of axons to their target cells is guided by a set of signals. These signals are detected by ‘mini-receivers’—proteins called guidance receptors—on axons and translated into ‘proceed,’ ‘stop,’ ‘turn left’ or ‘turn right.’ Thus, the quality of these receivers is very important for the axons to interpret the guiding signals.”
Jin, who is also an Investigator of the Howard Hughes Medical Institute, says defective protein products and environmental stress, such as hyperthermia, can sometimes jeopardize the health and development of cells. “This may be one reason why pregnant women are advised by doctors to avoid saunas and hot tubs,” she adds.
The scientists discovered the quality check system in roundworms, and presumably other animals including humans, consists of two parts: a protein-cleaning machine containing a protein called EBAX-1, and a well-known protein assembly helper called heat-shock protein 90 known as “hsp90.”
“Hsp90 facilitates the assembly of guidance receivers during the production and also fixes flawed products whenever they are detected,” says Andrew Chisholm, a professor of neurobiology and cell and developmental biology, who also helped lead the study. “The EBAX-containing protein-cleaning machine is in charge of destroying any irreparable products so that they don’t hang around and affect the performance of functional receivers. The EBAX-1 protein plays as a defectiveness detector in this machine and a connector to Hsp90. It captures defective products and presents them for either repair or destruction.”
A human neurodevelopmental disorder called “horizontal gaze palsy with progressive scoliosis” is associated with the defective production of one of the protein guidance receivers. This team of researchers showed that the defective human protein can interact with EBAX proteins. The authors hope that by investigating the action of EBAX-1 protein, their findings will provide clues to develop remedies or drugs to retreat human disorders in the future.
Worms May Shed Light on Human Ability to Handle Chronic Stress
New research at Rutgers University may help shed light on how and why nervous system changes occur and what causes some people to suffer from life-threatening anxiety disorders while others are better able to cope.
Maureen Barr, a professor in the Department of Genetics, and a team of researchers, found that the architectural structure of the six sensory brain cells in the roundworm, responsible for receiving information, undergo major changes and become much more elaborate when the worm is put into a high stress environment.
Scientists have known for some time that changes in the tree-like dendrite structures that connect neurons in the human brain and enable our thought processes to work properly can occur under extreme stress, alter brain cell development and result in anxiety disorders like depression and Post Traumatic Stress Disorder affecting millions of Americans each year.
What scientists don’t understand for sure, Barr says, is the cause behind these molecular changes in the brain.
“This type of research provides us necessary clues that ultimately could lead to the development of drugs to help those suffering with severe anxiety disorders,” Barr says.
In the study published today in Current Biology, scientists at Rutgers have identified six sensory nerve cells in the tiny, transparent roundworm, known as the C. elegans and an enzyme called KPC-1/furin which triggers a chemical reaction in humans that is needed for essential life functions like blood-clotting.
While the enzyme also appears to play a role in the growth of tumors and the activation of several types of virus and diseases in humans, in the roundworm the enzyme enables its simple neurons to morph into new elaborately branched shapes when placed under adverse conditions.
Normally, this one-millimeter long worm develops from an embryo through four larval stages before molting into a reproductive adult. Put it under stressful conditions of overcrowding, starvation and high temperature and the worm transforms into an alternative larval stage known as the dauer that becomes so stress-resistant it can survive almost anything – including the Space Shuttle Columbia disaster in 2003 of which they were the only living things to survive.
“These worms that normally have a short life cycle turn into super worms when they go into the dauer stage and can live for months, although they are no longer able to reproduce,” Barr says.
What is so interesting to Barr is that when a perceived threat is over, these tiny creatures and their IL2 neurons transform back to a normal lifespan and reproductive state like nothing had ever happened. Under a microscope, the complicated looking tree-like connectors that receive information are pruned back and the worm appears as it did before the trauma occurred.
This type of neural reaction differs in humans who can suffer from extreme anxiety months or even years after the traumatic event even though they are no longer in a threatening situation.
The ultimate goal, Barr says, is to determine how and why the nervous system responds to stress. By identifying molecular pathways that regulate neuronal remodeling, scientists may apply this knowledge to develop future therapeutics.
(Source: news.rutgers.edu)
Scientists develop worm EEG to test the effects of drugs
Scientists from the University of Southampton have developed a device which records the brain activity of worms to help test the effects of drugs.
NeuroChip is a microfluidic electrophysiological device, which can trap the microscopic worm Caenorhadbitis elegans and record the activity of discrete neural circuits in its ‘brain’ - a worm equivalent of the EEG.
C. elegans have been enormously important in providing insight into fundamental signalling processes in the nervous system and this device opens the way for a new analysis. Prior to this development, electrophysiological recordings that resolve the activity of excitatory and inhibitory nerve cells in the nervous system of the worm required a high level of technical expertise - single microscopic (1mm long) worms have to be trapped on the end of a glass tube, a microelectrode, in order to make the recording. The worms are very mobile as well as being small and this can be a challenging procedure.
The microfluidic invention consists of a reservoir through which worms can be fed, one after the other, into a narrow fluid-filled channel. The channel tapers at one end and this captures the worm by the front end. The worm is then in the correct orientation for recording the activity of the nervous system in the anterior of its body. The device incorporates metal electrodes, which are connected to an amplifier to make the recording. The design of the trapping channel has been optimised by PhD student Chunxiao Hu, so that the quality of the worm ‘EEG’ recording is sufficient to resolve the activity of components of the neural circuit in the worm’s nervous system.
This device has been used to detect the effects of drugs and is highly suitable for high throughput screens (which allow researchers to quickly conduct millions of chemical, genetic or pharmacological tests) in neurotoxicology and for generic screening for neuroactive drugs. It has more power to resolve discrete effects on excitatory, inhibitory or modulatory transmission than previously possible with behavioural screens.
Lindy Holden-Dye, Professor of Neuroscience at the University of Southampton and lead author of the paper, says: “We are particularly interested in using this as a sensitive new tool for screening compounds for neurotoxicity. It will allow us to precisely quantify sub-lethal effects on neural network activity. It can also provide an information rich platform by reporting the effects of compounds on a diverse array of neurotransmitter pathways, which are implicated in mammalian toxicology. “
The research, which is published in the latest issue of the journal PLOS One, is a joint project between the University’s Centre for Biological Sciences and the Hybrid Biodevices Group.
Mathematicians help to unlock brain function
Mathematicians from Queen Mary, University of London will bring researchers one-step closer to understanding how the structure of the brain relates to its function in two recently published studies.
Publishing in Physical Review Letters the researchers from the Complex Networks group at Queen Mary’s School of Mathematical Sciences describe how different areas in the brain can have an association despite a lack of direct interaction.
The team, in collaboration with researchers in Barcelona, Pamplona and Paris, combined two different human brain networks - one that maps all the physical connections among brain areas known as the backbone network, and another that reports the activity of different regions as blood flow changes, known as the functional network. They showed that the presence of symmetrical neurons within the backbone network might be responsible for the synchronised activity of physically distant brain regions.
Lead author Vincenzo Nicosia, said “We don’t fully understand how the human brain works. So far the focus has been more on the analysis of the function of single, localised regions. However, there isn’t a complete model that brings the whole functionality of the brain together. Hopefully, our research will help neuroscientists to develop a more accurate map of the brain and investigate its functioning beyond single areas.”
The research adds to the recent findings published in Proceedings of the National Academy of Sciences in which the QM researchers along with the Department of Psychiatry at University of Cambridge analysed the development of the brain of a small worm called Caenorhabditis elegans. In this paper, the team examined the number of links formed in the brain during the worm’s lifespan, and observed an unexpected abrupt change in the pattern of growth, corresponding with the time of egg hatching.
“The research is important as it’s the first time that a sharp transition in the growth of a neural network has ever been observed,” added Dr Nicosia.
“Although we don’t know which biological factors are responsible for the change in the growth pattern, we were able to reproduce the pattern using a simple economical model of synaptic formation. This result can pave the way to a deeper understanding of how neural networks grow in more complex organisms.”
(Source: qmul.ac.uk)
Tiny worm sheds light on giant mystery about neurons
Scientists have identified a gene that keeps our nerve fibers from clogging up. Researchers in Ken Miller’s laboratory at the Oklahoma Medical Research Foundation (OMRF) found that the unc-16 gene of the roundworm Caenorhabditis elegans encodes a gatekeeper that restricts flow of cellular organelles from the cell body to the axon, a long, narrow extension that neurons use for signaling. Organelles clogging the axon could interfere with neuronal signaling or cause the axon to degenerate, leading to neurodegenerative disorders. This research, published in the May 2013 Genetics Society of America’s journal GENETICS, adds an unexpected twist to our understanding of trafficking within neurons.
Proteins equivalent to UNC-16 are present in the neurons of all animals, including humans And are known to interact with proteins associated with neurodegenerative disorders in humans (Hereditary Spastic Paraplegia) and mice (Legs at Odd Angles). However, the underlying cause of these disorders is not well understood.
"Our UNC-16 study provides the first insights into a previously unrecognized trafficking system that protects axons from invasion by organelles from the cell soma," Dr. Miller said. "A breakdown in this gatekeeper may be the underlying cause of this group of disorders," he added.
The use of the model organism C. elegans, a tiny, translucent roundworm with only 300 neurons, enabled the discovery because the researchers were able to apply complex genetic techniques and imaging methods in living organisms, which would be impossible in larger animals. Dr. Miller’s team tagged organelles with fluorescent proteins and then used time-lapse imaging to follow the movements of the organelles. In normal axons, organelles exited the cell body and entered the initial segment of the axon, but did not move beyond that. In axons of unc-16 mutants, the organelles hitched a ride on tiny motors that carried them deep into the axon, where they accumulated.
Dr. Miller acknowledges there are still a lot of unanswered questions. His lab is currently investigating how UNC-16 performs its crucial gatekeeper function by looking for other mutant worms with similar phenotypes. A Commentary on the article, also published in this issue of GENETICS, calls the work “provocative”, and highlights several important questions prompted by this pioneering study.
"This research once again shows how studies of simple model organisms can bring insight into complex neurodegenerative diseases in humans," said Mark Johnston, Editor-in-Chief of the journal GENETICS. “This kind of basic research is necessary if we are to understand diseases that can’t easily be studied in more complex animals.”
(Source: eurekalert.org)
Turning back the clock on regeneration in neurons
When minor wounds heal, the fine nerve endings that sense touch, or control sweating, are usually able to regrow. Like many processes in the body, the ability to regenerate new tissues changes throughout the lifecycle, typically diminishing with age. To investigate the molecular details of regeneration, the nervous system of the worm, C. Elegans, is ideal because its entire blueprint—the connectome—is available. The close-knit cadre of researchers who study C. elegans are the true veterinarians of neuroscience in that they command nearly every tool in the field to study this microcosm of biology. Publishing today in Science, a group of these researchers has uncovered a genetic circuit that regulates the regrowth of axons after they are experimentally cut with a laser. While the integrity of these mechanisms insures stability in the adult nervous system, manipulation of them could allow insults to the system to be restored to normal function.
(C. Elegans neuron. Credit: Technion-Israel Institute of Technology)
In order to develop properly in the first place, the expression of the genes controlling tissue construction proceeds in a choreographed rhythm, with each having its proper time and place. Once the organism has developed, many of these genes are decommissioned, or their cycles of expression dephased. Sometimes two components that act together in the larval stage, oppose each other in the adult. Two players in this genetic tit-for-tat, lin-41 and let-7, have previously been found to act as timers during these transitions. The researchers in the study described here, stumbled upon this particular circuit while they were looking at the effect of yet another gene, alg-1, on axon regeneration. Specifically, they had found that worms with a mutant form of alg-1, could regenerate certain axons up to 2.5 times longer than the axons of normal adult worms.
One particular sensory neuron, the AVM (anterior ventral microtubule) neuron, has a clearly defined axon that can regrow in larva, in not in adults. This strangely-named neuron has an even stranger subcellular feature. Its dendrites, in addition to the axon, are filled with a unique kind of microtubule, one that is composed of 15 protofilaments. Most mammals use a microtubule form-factor specifically made from 13 protofilaments, but many invertebrates use anywhere from 10 to 15. The avm neuron is also unique in that is one of just a few neurons that migrates to an asymmetric position in the body of the worm—it has no counterpart on the opposite side.
(Let-7 microRNA. Credit: Wikipedia commons)
The AVM neuron shows clear expression not only the alg-1 gene, but also another factor regulated by alg-1 known as let-7. The researchers were able to show that let-7 is responsible for inhibiting adult regrowth in the AVM neuron. Inhibiting let-7 directly, or alternatively, increasing the level of its reciprocal inhibitor, lin-41, completely restored the regeneration capabilities of the larval axons. From this they conclude that cyclic interactions between let-7 and lin-41 are a general strategy used not only in determining cell fate in development, but also in controlling axon regeneration.
Expression of let-7 was controlled by using a version of the gene which is temperature-sensitive. The particular allele used has normal activity at 15 degrees C, but can be completely turned off at 20 degrees C. The actual product of the let-7 gene is ultimately not a protein, but one of a class of newly-discovered regulators known as microRNAs. The full functionality of microRNAs has yet to be completely defined, but they seem to be able to regulate proteins, DNA, and mRNA.
The researchers were also partial to speculation as to why the organism appears to take pains to inhibit regrowth in the adult. Axotomy by laser may not have been a primary selection criteria during the evolution of the worm, but some ability for tissue repair would be important in the life of a worm. In the greater scheme of things, it would seem that loss of certain capabilities in the adult, may be a small price to pay for the greater stability of connections that may come along with it.
We recently reported on a study in mice, which demonstrated that mature brains continue to remodel their fine structure throughout the entire life of the organism. Mammalian axons have the further complication that while myelination is required to conduct signals over appreciable distances, it can also be an impediment to regrowth. For axons that have been compromised by trauma, or through developmental fault, turning back the clock on a few genes may be only part of the puzzle.
(Source: medicalxpress.com)
Worming Our Way to New Treatments for Alzheimer’s Disease
According to a 2012 World Health Organization report, over 35 million people worldwide currently have dementia, a number that is expected to double by 2030 (66 million) and triple by 2050 (115 million). Alzheimer’s disease, the most common form of dementia, has no cure and there are currently only a handful of approved treatments that slow, but do not prevent, the progression of symptoms.
New drug development, no matter the disease, is a slow, expensive, and risky process. Thus, innovative techniques to study and assess the possibilities of already-existing drugs for different diseases can be used to alleviate the traditional burdens of cost and time. Detailed in their new article in Biological Psychiatry, researchers from the University of Washington, led by Dr. Brian Kraemer, have developed an exciting new approach to screening potential new treatments for Alzheimer’s disease using C. elegans, a small transparent worm.
Their focus was on tau, a protein involved in maintaining brain cell structure. In Alzheimer’s disease and related disorders, tau protein becomes abnormally modified and forms clumps of protein called aggregates. These aggregates are a hallmark of the dying nerve cells in Alzheimer’s disease and other related disorders. Diseases with abnormal tau are called tauopathies.
Dr. Kraemer’s lab previously developed a worm model for tauopathy by expressing human tau in C. elegans nerve cells. This model has behavioral abnormalities, accumulates abnormal tau protein, and exhibits loss of nerve cells—all of which are general features of Alzheimer’s disease.
Using their worm model for this study, they screened a library of 1,120 drugs approved for human use and tested each at three different concentrations to identify compounds that suppress the effects of abnormal tau aggregation.
“We have identified six compounds capable of reliably alleviating tau induced behavioral abnormalities in our C. elegans model for tauopathy. In a human cultured cell model for abnormal tau protein, we have also seen that azaperone treatment can decrease the amount of abnormal tau,” said Kraemer.
Azaperone, an antipsychotic drug, normally binds to certain dopamine receptors found in nerve cells. They demonstrated that removing those receptors in either C. elegans or human cells has the same effect as azaperone treatment, indicating that azaperone and related drugs should alter abnormal tau accumulation. Other antipsychotic drugs also have a similar effect to azaperone.
Tests of these compounds for anti-tau properties are now underway in existing mouse models of Alzheimer’s disease.
“This study is an exemplary instance of how a simple C. elegans model system may be used to rapidly screen drugs for diseases and evaluate mechanism of action,” said Drs. Sangeetha Iyer and Jonathan Pierce-Shimomura, authors of a commentary that accompanies this article.
Dr. John Krystal, Editor of Biological Psychiatry, agrees and added: “Studying the worm, C. elegans, has already provided us with fundamental insights into how the brain develops. The new approach described by McCormick and colleagues suggests that this animal model may be a powerful new approach to studying novel treatments that prevent its decline.”
(Source: elsevier.com)