Linking insulin to learning: Important insights in research with worms

Recent work by Harvard researchers demonstrates how the signaling pathway of insulin and insulinlike peptides plays a critical role in helping to regulate learning and memory.

The research, led by Yun Zhang, associate professor of organismic and evolutionary biology, is described in a Feb. 6 paper in Neuron.

“People think of insulin and diabetes, but many metabolic syndromes are associated with some types of cognitive defects and behavioral disorders, like depression or dementia,” Zhang said. “That suggests that insulin and insulinlike peptides may play an important role in neural function, but it’s been very difficult to nail down the underlying mechanism, because these peptides do not have to function through synapses that connect different neurons in the brain.”

To get at that mechanism, Zhang and colleagues turned to an organism whose genome and nervous system are well described and highly accessible by genetics: C. elegans.

Using genetic tools, researchers altered the transparent worms by removing their ability to create individual insulinlike compounds. These new “mutant” worms were then tested to see whether they would learn to avoid eating a particular type of bacteria that is known to infect the worms. Tests showed that although some worms did learn to steer clear of the bacteria, others didn’t — suggesting that removing a specific insulinlike compound halted the worms’ ability to learn.

Researchers were surprised to find, however, that it wasn’t just removing the molecules that could make the animals lose the ability to learn — some peptides were found to inhibit learning.

“We hadn’t predicted that we would find both positive and negative regulators from these peptides,” Zhang said. “Why does the animal need this bidirectional regulation of learning? One possibility is that learning depends on context. There are certain things you want to learn — for example, the worms in these experiments wanted to learn that they shouldn’t eat this type of infectious bacteria. That’s a positive regulation of the learning. But if they needed to eat, even if it is a bad food, to survive, they would need a way to suppress this type of learning.”

Even more surprising for Zhang and her colleagues was evidence that the various insulinlike molecules could regulate each other.

“Many animals, including humans, have multiple insulinlike molecules, and it appears that these molecules can act like a network,” she said. “Each of them may play a slightly different role in the nervous system, and they function together to coordinate the signaling related to learning and memory. By changing the way the molecules interact, the brain can fine-tune learning in a host of different ways.”

Cellular renewal process may underlie benefits of omega fatty acids

A search for genes that change their levels of expression in response to nutrient deprivation has uncovered potential clues to the mechanism underlying the health benefits of omega fatty acids. In the Feb. 15 issue of Genes & Development, Massachusetts General Hospital (MGH) researchers describe finding that feeding omega-6 fatty acids to C. elegans roundworms or adding them to cultured human cells activates a cellular renewal process called autophagy, which may be deficient in several important diseases of aging. A process by which defective or worn-out cellular components and molecules are broken down for removal or recycling, autophagy is also activated in metabolically stressful situations, allowing cells to survive by self-digesting nonessential components.

"Enhanced autophagy implies improved clearance of old or damaged cellular components and a more efficient immune response," says Eyleen O’Rourke, PhD, of MGH Molecular Biology, lead author of the report. "It has been suggested that autophagy can extend lifespan by maintaining cellular function, and in humans a breakdown in autophagic function may involved in diseases including inflammatory bowel disease, Parkinson’s disease, and in a more complex way in cancer and metabolic syndrome."

O’Rourke is a research fellow in the laboratory of MGH investigator Gary Ruvkun, PhD, whose team investigates the development, longevity and metabolism of C.elegans. Ruvkun and other researchers have discovered that simple mutations in genetic pathways conserved throughout evolution can double or triple the lifespan of C. elegans and that similar mutations in the corresponding mammalian pathways also regulate lifespan. Many of these mutations also make animals resistant to starvation, suggesting that common molecular mechanisms may underlie both response to nutrient deprivation and the regulation of lifespan.

To find these mechanisms O’Rourke searched genomic databases covering many types of animals for shared genes that respond to fasting by changing their expression. She found that expression of the C. elegans gene lipl-4 increases up to seven times in worms not given access to nutrients. A transgenic strain that constantly expresses elevated levels of lipl-4, even when given full access to food, was found to have increased levels of arachidonic acid (AA), an omega-6, and eicosapentanoic acid (EPA), an omega-3 fatty acid and to resist the effects of starvation.

(Image: The Herman Lab, Kansas State University)

With Identical Neurons, Two Worm Species Live Very Different Lives

Two species of worms have the same set of 20 neurons that control their foregut (a digestive organ located, naturally, near the front end of the worm). The way those neurons are wired, though, completely changes their behavior.

Caenorhabditis elegans eats bacteria, while its worm cousin Pristionchus pacificus, while able to subsist on bacteria, also eats other worms. While C. elegans uses a grinder to break up bacteria, P. pacificus develops teeth-like denticles to puncture its prey.

"These species are separated by 200 to 300 million years, but have the same cells," researcher Ralf Sommer told New Scientist. However, they found the synapses were wired vastly differently, leading to a substantial change in the way information flows through their neural system.

In P. pacificus, neural signals pass through more cells before reaching the muscles. That suggests that it’s perfuming more complex motor functions, according to the European Molecular Biology Lab’s Detlev Arendt.

The paper can be found in the January 17 issue of Cell.

The nematode worm (scientific name C. elegans) is a simple-minded animal: it has exactly 302 neurons (compare that to a human’s roughly 100 billion). The pattern of connections between these neurons was painstakingly mapped out decades ago using electron microscopy, but it turns out that knowledge of the connections is not sufficient to understand (or even replicate) the information processor they represent. For example, some connections are inhibitory while others are excitatory, but this map doesn’t say which is which.

In order to learn how one neuron affects another, we need to see what happens when the first neuron is activated. NEMALOAD (“nematode upload”) is a project to integrate a number of recent technologies that should make this feasible, at least in C. elegans, and using this capability to replicate the information processing structure that governs the worm’s behavior in a digital model.

Sophisticated worms
One cell does it all: Sensory input to motor output in extraordinary neuron

It’s one of the basic tenets of biological research — by studying simple “model” systems, researchers hope to gain insight into the workings of more complex organisms.

Caenorhabditis elegans — a tiny, translucent worm with just 302 neurons — has long been studied to understand how a nervous system is capable of translating sensory input into motion and behavior.

New research by the laboratory of Professor Aravi Samuel in the Harvard Physics Department and the Center for Brain Sciences, however, is uncovering surprising sophistication in the individual neurons of the worm’s “simple” nervous system.

Quan Wen, a postdoctoral fellow in the Samuel lab who spearheaded the research, has shown that a single type of neuron in the C. elegans nerve cord (the worm equivalent of the spinal cord) packs both sensory and motor capabilities. The locomotory systems of most creatures, including humans, use different neurons to gather sensory information about animal movement or to send signals to muscle cells. C. elegans encodes an entire sensorimotor loop into one particularly sophisticated type of motor neuron. The work is described in the journal Neuron.

“This type of circuit is completely new — this is not the way people think about any motor circuit,” Samuel said.

The discovery arose from researchers asking a simple question: How does C. elegans organize its movements?

“What sent us down this road was a phenomenon that we’ve observed in the lab,” Samuel explained. “If we place the worms in a wet environment, they will swim. On surfaces, however, they crawl. The question was how the animal ‘knew’ to do each. The answer had to be feedback: Something is telling the worm that it’s in a low-viscous environment here, and a high-viscous environment there.

“The general name for this is ‘proprioceptive feedback,’ ” Samuel continued. “It’s that process that allows your brain to understand what each of your legs is doing and coordinate your ability to walk, it gives you an awareness of your body posture. The real puzzle in this case, however, was that C. elegans has so few neurons … we didn’t understand how proprioceptive feedback could come back into the system.”

(Image credit: snickclunk)

UC Santa Barbara Scientists Learn How to Unlock the Destiny of a Cell: A Gift for the Tin Man?

Scientists have discovered that breaking a biological signaling system in an embryo allows them to change the destiny of a cell. The findings could lead to new ways of making replacement organs.

The discovery was made in the laboratory of Joel H. Rothman, a professor in the Department of Molecular, Cellular, and Developmental Biology at UC Santa Barbara. The studies were reported in the interdisciplinary journal Genes and Development, and were carried out by Ph.D student Nareg Djabrayan, in collaboration with Rothman and two other members of the laboratory, Ph.D student Erica Sommermann and postdoctoral fellow Nathaniel Dudley.

"At some point along the way toward becoming part of a complete individual, cells become destined to choose a particular identity and long-term profession," Rothman noted. "Once a cell chooses who it will be, it locks onto that identity for the remainder of its life."

A cell that is destined to become a heart cell functions exclusively in the heart until it dies, and never chooses later to change jobs by becoming, for example, a brain cell. “If Oz’s wizard possessed the powers he claimed, and had a spare brain lying around, he could switch it to a heart as a gift for the Tin Man. And he could reverse the trick for the Scarecrow,” Rothman said.

Similarly, the researchers have found a way to unlock cells’ destinies and lead them to take on a new profession.

Neurotransmitters Linked to Mating Behavior Are Shared by Mammals and Worms

When it comes to sex, animals of all shapes and sizes tend to behave in predictable ways. There may be a chemical reason for that. New research from Rockefeller University has shown that chemicals in the brain — neuropeptides known as vasopressin and oxytocin — play a role in coordinating mating and reproductive behavior in animals ranging from humans to fish to invertebrates.

"Our research shows that molecules similar to vasopressin and oxytocin have an ancient and evolutionarily conserved role in controlling a critical social behavior, mating," says Cori Bargmann, Torsten N. Wiesel Professor and head of the Lulu and Anthony Wang Laboratory of Neural Circuits and Behavior. "This work suggests that these molecules encode the same kind of information in the brains of very different animals."

Bargmann, whose laboratory studies the relationship between genes, neural circuits and behavior in the C. elegans roundworm, says vasopressin and oxytocin have been implicated in a variety of reproductive and social behaviors in humans and other mammals, including pair bonding, maternal bonding and aggressive and affiliative behaviors. Mice that lack oxytocin may develop social amnesia, and humans who sniff oxytocin through an inhaler change their cooperative behavior in computer games, behaving as though they “trust” other players more.