#c elegans
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.
Study reveals how differences in male and female brains emerge
Nematode worms may not be from Mars or Venus, but they do have sex-specific circuits in their brains that cause the males and females to act differently. According to new research published in Nature, scientists have determined how these sexually dimorphic (occurring in either males or females) connections arise in the worm nervous system. The research was funded by the NIH’s National Institute of Neurological Disorders and Stroke (NINDS).
“For decades, there has been little focus on the impact of sex on many areas of biomedical research,” said Coryse St. Hillaire-Clarke, Ph.D., program officer on this NINDS project. “This study helps us understand how sex can influence brain connectivity.”
In nematode worms, (known as Caenorhabditis elegans or C. elegans), a small number of neurons are found exclusively in male or female brains. The remaining neurons are found in both sexes, although their connection patterns are different in male and female brains. Oliver Hobert, Ph.D., professor of biological sciences at Columbia University in New York City, and his colleagues looked at how these wiring patterns form.
Dr. Hobert’s team observed that in the worms’ juvenile state, before they reach sexual maturity, their brain connections were in a hybrid, or mixed state, comprised of both male and female arrangements. As they reached sexual maturity, however, their brains underwent a pruning process, which got rid of particular connections and led to either male or female patterns.
“We found that differences in male and female brains develop from a ground state, which contains features of both sexes. From this developmental state, distinctly male or female features eventually emerge,” said Dr. Hobert.
Next, Dr. Hobert’s team showed that sex-specific wiring in the brain results in dimorphic behavior. They discovered that PHB neurons, chemosensory brain cells that detect chemical cues in the environment such as food, predators or potential mates, work differently in males and females. In males, these neurons proved to be important in recognizing mating cues while in females, the neurons helped them avoid specific taste cues. However, early in development, PHB neurons in males also responded to signals regulating taste, suggesting that even though those neurons are found in all nematodes, in adults, their functions differ as a result of sex-specific wiring in the brain.
Dr. Hobert’s team used genetically engineered nematodes to look more carefully at individual connections between brain cells. The researchers found that swapping the sex of individual neurons changed wiring patterns and influenced behavioral differences in males and females.
Additional experiments helped to identify genes involved in regulating the pruning process during development. Dr. Hobert’s group discovered that certain transcription factors, which are molecules that help control gene activity, are present in a dimorphic state and may help establish male or female connections in the brain. In future experiments, Dr. Hobert and his colleagues plan to examine how these molecules target specific connections for pruning.
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Stress on mothers can influence biology of future generations
Biologists at the University of Iowa found that roundworm mothers subjected to heat stress passed, under certain conditions and through modifications to their genes, the legacy of that stress exposure not only to their offspring but even to their offspring’s children.
The researchers, led by Veena Prahlad, associate professor in the Department of Biology and the Aging Mind and Brain Initiative, looked at how a mother roundworm reacts when she senses danger, such as a change in temperature, which can be harmful or even fatal to the animal. In a study published last year, the biologists discovered the mother roundworm releases serotonin when she senses danger. The serotonin travels from her central nervous system to warn her unfertilized eggs, where the warning is stored, so to speak, and then passed to offspring after conception.
Examples of such genetic cascades abound, even in humans. Studies have shown that pregnant women affected by famine in the Netherlands from 1944 to 1945, known as the Dutch Hunger Winter, gave birth to children who were influenced by that episode as adults—with higher rates than average of obesity, diabetes, and schizophrenia.
In this study, the biologists wanted to find out how the memory of stress exposure was stored in the egg cell.
“Genes have ‘memories’ of past environmental conditions that, in turn, affect their expression even after these conditions have changed,” Prahlad explains. “How this ‘memory’ is established and how it persists past fertilization, embryogenesis, and after the embryo develops into adults is not clear. “This is because during embryogenesis, most organisms typically reset any changes that have been made to genes because of the genes’ past activity.”
Prahlad and her teams turned to the roundworm, a creature regularly studied by scientists, for clues. They exposed mother roundworms to unexpected stresses and found the stress memory was ingrained in the mother’s eggs through the actions of a protein called the heat shock transcription factor, or HSF1. The HSF1 protein is present in all plants and animals and is activated by changes in temperature, salinity, and other stressors.
The team found that HSF1 recruits another protein, an enzyme called a histone 3 lysine 9 (H3K9) methyltransferase. The latter normally acts during embryogenesis to silence genes and erase the memory of their prior activity.
However, Prahald’s team observed something else entirely.
“We found that HSF1 collaborates with the mechanisms that normally act to ‘reset’ the memory of gene expression during embryogenesis to, instead, establish this stress memory,” Prahlad says.
One of these newly silenced genes encodes the insulin receptor, which is central to metabolic changes with diabetes in humans, and which, when silenced, alters an animal’s physiology, metabolism, and stress resilience. Because these silencing marks persisted in offspring, their stress-response strategy was switched from one that depended on the ability to be highly responsive to stress, to relying instead on mechanisms that decreased stress responsiveness but provided long-term protection from stressful environments.
“What we found all the more remarkable was that if the mother was exposed to stress for a short period of time, only progeny that developed from her germ cells that were subjected to this stress in utero had this memory,” Prahlad says. “The progeny of these progeny (the mother’s grandchildren) had lost this memory. However, if the mother was subjected to a longer period of stress, the grandchildren generation retained this memory. Somehow the ‘dose’ of maternal stress exposure is recorded in the population.”
The researchers plan to investigate these changes further. HSF1 is not only required for stress resistance but also increased levels of both HSF1 and the silencing mark are associated with cancer and metastasis. Because HSF1 exists in many organisms, its newly discovered interaction with H3K9 methyltransferase to drive gene silencing is likely to have larger repercussions.
Appetite for survival: Brain signal alerts roundworms to changing food supply
Microscopic roundworms may hold the key to understanding what is happening in the brain when the instinct of an animal changes in order to survive. In a newly published paper in the journal Current Biology University of Rochester Medical Center researchers found that a signaling system in the brain changes to redirect the behavior of an animal when their survival is at risk because there is not enough food.
The experiments were conducted in C. elegans – a microscopic roundworm that has been used by scientists for decades to understand the basic organization and function of the central nervous system and how it impacts behavior. Researchers found C. elegans hermaphrodites (the equivalent of females in this species) produce a pheromone that allows worms to monitor how crowded their environment is and how much food there is to go around. When food becomes scarce the aversion circuit is trigged in the animal and it becomes repelled by the pheromone.
“The key thing we identified is a molecular mechanism whereby an instinctive response can be suppressed under particular environmental conditions, namely, abundant food,” said Douglas Portman, Ph.D., lead author of the study and professor of Biomedical Genetics. “Adaptively it makes sense that an animal’s instinctive response would have this kind of flexibility.”
This underlying repulsive mechanism to the pheromone is present in both hermaphrodites and males, but researchers found that in males, the mechanism is overridden by another circuit that causes males to be attracted to the pheromone. A subtlety that could provide an understanding of how the neural circuits work that cause this change in behavior.
Understanding how basic decision-making mechanisms work gives insight into the inner workings of a more complex brain. “These findings lend important insight into the mechanisms by which animals detect and integrate multiple sensory cues to make adaptive behavioral decisions. Understanding how things like this work at the molecular level, provides a framework for understanding how much more complex brains work, and how genetic and environmental insults can ‘break’ things and lead to behavioral and psychiatric disorders.”
