Researchers Make Surprising Discovery About How Neurons Talk to Each Other 08-21

Researchers at the University of Pittsburgh have uncovered the mechanism by which neurons keep up with the demands of repeatedly sending signals to other neurons. The new findings, made in fruit flies and mice, challenge the existing dogma about how neurons that release the chemical signal dopamine communicate, and may have important implications for many dopamine-related diseases, including schizophrenia, Parkinson’s disease and addiction.

The research conducted at Pitt and Columbia University was published online today in the journal Neuron.

Neurons communicate with one another by releasing chemicals called neurotransmitters, such as dopamine and glutamate, into the small space between two neurons that is known as a synapse. Inside neurons, neurotransmitters awaiting release are housed in small sacs called synaptic vesicles.

“Our findings demonstrate, for the first time, that neurons can change how much dopamine they release as a function of their overall activity. When this mechanism doesn’t work properly, it could lead to profound effects on health,” explained the study’s senior author Zachary Freyberg, M.D., Ph.D., who recently joined Pitt as an assistant professor of psychiatry and cell biology. Freyberg initiated the research while at Columbia University.

When the researchers triggered the dopamine neurons to fire, the neurons’ vesicles began to release dopamine as expected. But then the team noticed something surprising: additional content was loaded into the vesicles before they had the opportunity to empty. Subsequent experiments showed that this activity-induced vesicle loading was due to an increase in acidity levels inside the vesicles.

“Our findings were completely unexpected,” said Freyberg. “They contradict the existing dogma that a finite amount of chemical signal is loaded into a vesicle at any given time, and that vesicle acidity is fixed.”

The team then demonstrated that the increase in acidity was driven by a transport channel in the cell’s surface, which allowed an influx of negatively charged glutamate ions to enter the neuron, thus increasing its acidity. Genetically removing the transporter in fruit flies and mice made the animals less responsive to amphetamine, a drug that exerts its effect by stimulating dopamine release from neurons.

“In this case, glutamate is not acting as a neurotransmitter. Instead it is functioning primarily as a source of negative charge, which is being used by these vesicles in a really clever way to manipulate vesicle acidity and therefore change their dopamine content,” Freyberg said. “This calls into question the whole textbook model of vesicles as having fixed amounts of single neurotransmitters. It appears that these vesicles contain both dopamine and glutamate, and dynamically modify their content to match the conditions of the cell as needed.”

In the future, the team plans to look more closely at how increases in vesicle acidification affect health. A number of brain diseases are characterized by abnormal dopamine neuron signaling and altered levels of the neurotransmitter.

“Since we have demonstrated that the balance between glutamate and dopamine is important for controlling the amount of dopamine that a neuron releases, it stands to reason that an imbalance between the two neurotransmitters could be contributing to symptoms in these diseases,” said Freyberg.

This article has been republished from materials provided by UPMC. Note: material may have been edited for length and content. For further information, please contact the cited source.

 

View at the original source

              

Call for Applications: Raman–Charpak Fellowship 2016 for Indian and French Students Department of Science and Technology, Govt of India 04-06

Call for Applications: Raman–Charpak Fellowship 2016 for Indian and French Students.

Department of Science and Technology, Govt of India

Sector:  Cultural Development Education Inclusion

Last date:  Tuesday, May 31, 2016

Country:  France  India

Detailed Description

The Department of Science and Technology (DST), Government of India and the Service for Science and Technology (SST), French Embassy in India, Ministry of Foreign Affairs & International Development, Government of France have jointly announced a call for applications for Raman–Charpak Fellowship 2016 with an aim to facilitate the exchange of doctoral students between the two countries, in order to broaden the scope and depth of future engagements in science, technology and innovation.

Research Fields

• Atmospheric and Earth Sciences

• Chemical Sciences

• Engineering Sciences

• Life and Medical Sciences

• Material Sciences

• Mathematical and Computational Sciences

• Physical Sciences

• Environmental Sciences

Benefits

• For Indian Fellow: Fellowship Support of 1500 Euros per month for daily expenses, local travel, accommodation charges plus Social Security charges.

• For French Fellow: Fellowship support Rs. 40,000 per month for daily expenses, local travel, etc. plus accommodation charges not exceeding Rs. 45,000 per month

Eligibility Criteria

• Applicants from India must be Indian citizens residing in India and have registered for a PhD in a recognized university or research institution in India.

• Applicants from France must be residing in France and have registered for a PhD in a recognized university or research institution in France.

• Have a Master’s degree (in science, technology or medicine) from a recognized University/Institute.

• Age: Maximum 30 years as on 1st April, 2016.

• Students once supported by CEFIPRA, also in the framework of CEFIPRA projects, and students who have a permanent position in institutions/universities are not eligible.

• Pre-authorization or prior consent from his/her Institute / University to apply for a foreign fellowship program [No objection certificate from Head of the Institution] (Not applicable for French candidates).

• A letter of recommendation from the Ph.D. supervisor in his/her native lab.

• A letter of recommendation and agreement from the proposed host supervisor in the fellowship lab (Foreign Research Institute / University).

How to Apply

Applicants must apply online via given website.

For more information, please visit Raman–Charpak Fellowship (link is external).


View at the original source

Parental controls Neural drivers identified in research on mice 05-17

Parental controls

Neural drivers identified in research on mice

It could be that the key to being a better parent is all in your head, Harvard researchers say.

In a study in mice, Catherine Dulac, the Higgins Professor of Molecular and Cellular Biology and a Howard Hughes investigator, has pinpointed galanin neurons in the brain’s medial preoptic area (MPOA) that appear to regulate parental behavior. If similar neurons are at work in humans, it could offer clues to the treatment of conditions such as postpartum depression. The study is described in a May 15 paper published in Nature.

“If you look across different animal species, there are some species in which the father contributes to caring for the young — sometimes the work is divided equally, sometimes the father does most of the work — and there are species in which the father does nothing,” Dulac said. “The essential question is: Where is that variability coming from? We may be tempted to say that the mom has the neurons required to engage in parental behavior, and dads don’t — this paper shows that’s wrong.”

It’s long been known, Dulac said, that mice have highly stereotypical reactions to offspring. Among sexually experienced mice, both males and females build nests and groom and huddle with pups. Virgin females exhibit the same maternal behavior, while virgin males typically attack and kill pups.

Using genetic tools, graduate student Herbert Wu and other researchers in Dulac’s lab were able to activate galanin neurons in virgin males, and the results were startling.

Rather than attacking pups, the males immediately began to groom them. Other tests that killed the neurons resulted in parents that ignored the pups altogether or virgin females that behaved like males, attacking the pups.

Dulac and colleagues began exploring the roots of parenting behavior after making a surprising observation in the lab. Female mice lacking a functioning vomeronasal organ — which contains olfactory neurons responsible for certain innate behavior — suddenly behaved almost exactly like male mice.

“We came to the conclusion that what the VNO was doing in the female was repressing male-like behavior,” Dulac said. “If there is a repression of that behavior in females … we wondered if there might be a parallel system — if there are neurons in males that might drive female-like behavior, which normally are repressed.”

While the discovery of galanin neurons in the medial preoptic area suggests the answer is yes, it also raised other questions — particularly why the neurons would be present in males if they aren’t used.

What researchers found, Dulac said, is that those neurons, in fact, are used, but only after the male has mated, and they don’t become fully active until three weeks — the exact gestation period of mice pups — after mating occurs.

“The dad won’t kill the pups after three weeks, because they may very well be his own offspring,” Dulac said. “Even if you remove males immediately after mating and segregate them from females, it’s very striking — half of them will behave paternally after three weeks. Simply mating seems to trigger some sort of clock, and that leads to paternal behavior.”

Though it’s not yet clear whether similar neural pathways exist in humans, researchers say galanin neurons are concentrated in a brain region responsible for many innate behaviors, such as feeding and sleep, and that other neurons in the region have been shown to be conserved from mice across many mammal species, including humans.

“I would be extremely surprised if these neurons did not exist in humans,” Dulac said. “What does that mean? It says that mothers can do it, and fathers can do it. What is really interesting, I think, is you now have an instinctive behavior — and a very important social behavior — and we have access to how it’s being regulated.”

Understanding how parental behavior is regulated, Dulac said, opens the door to a greater understanding of how that behavior can break down.

“It is known that postpartum depression has a very close association with stress levels, particularly among first-time mothers,” Dulac said. “One interesting hypothesis is that these galanin neurons in the MPOA have stress hormone receptors that can inhibit their function. These are the type of questions we can now address directly, because we know which neurons are controlling parental behavior.”

Areas that demand further study, Dulac said, include understanding how galanin neurons are connected to brain centers involved in motivation, stress, and reward; how — and whether — genes associated with the neurons are expressed differently in males and females; and what is happening in male brains in the three weeks after mating.

“Parental behavior is many things,” Dulac said. “It’s grooming, it’s building a nest, it’s protecting the pups — the male is able to do all of those. What this says is that in the male brain, they have the neurons to be paternal, but somehow those neurons are repressed. But we can now say, yes, dads can do it.”

View at the original source

Researchers Grow Human 'Mini Brains' 09-01

Researchers Grow Human 'Mini Brains'

Researchers have used stem cells to grow pea-sized structures that resemble the developing human brain, an advance that offers a way to model brain maladies that are otherwise hard to study.

The human brain is one of the most elaborate natural structures known to science. These new lab-grown "mini brains" are imperfect, and a long way off from matching the real thing.

Still, the structures, which are about four millimeters in diameter, share some of the crucial three-dimensional architecture of a developing human brain. The different brain parts interact in a normal manner, though they aren't necessarily in the proper places.

Enlarge Image

Credit: Madeline A. Lancaster

A cross-section showing development of different brain regions.

"It would be like a car with the engine on the roof, the gear box in the trunk and an exhaust pipe that points to the front," said Jürgen Knoblich at the Institute of Molecular Biotechnology of the Austrian Academy of Sciences and leader of the research team. "You can still use such a car to study how an engine works."

The experiment was reported Wednesday in the journal Nature.

The advance is expected to allow researchers to investigate human brain disease in a lab—something that currently is a big challenge. Brain disorders such as Alzheimer's typically are studied in rats, mice and other animals, but these are inadequate proxies mainly because the human brain is much more complex.

By contrast, the new approach should enable scientists to study neurological disorders by examining brain tissue derived from actual patients.

Jürgen Knoblich created versions of developing brains in the lab.

In the Nature paper, Dr. Knoblich and his colleagues described how they used their technique to study brain tissue created from a patient suffering from microcephaly, a genetic disorder that leads to a smaller brain. His team's research builds on several experiments published by other researchers since 2008, which showed how stem cells could be manipulated to create not just nerve cells, but more elaborate neuron-based structures as well.

At a lab in Austria, Dr. Knoblich did experiments with human embryonic stem cells, which are derived from an embryo. He experimented with stem cells that were obtained by reprogramming mature tissue, such a person's skin cells, into an embryonic-like state. Both types of stem cells are "pluripotent"—they can be changed into all other cell types in the body.

The researchers added chemicals known as growth factors to the stem cells, which created tissues that would go on to form the central nervous system. The tissues were put in a gel-like substance resembling the environment of a developing human embryo.

That mix was then put into a spinning bioreactor, a vessel that helps cells develop and grow. After 20 to 30 days, the neural cells organized themselves into tiny structures, called cerebral organoids.

These structures had defined brain regions, including a dorsal cortex—which makes up the largest part of our brain—and the choroid plexus, where cerebrospinal fluid is produced. The neurons were active and fired.

"That was the big surprise—it was self-organizing," said Dr. Knoblich, who added that his team made hundreds of the "mini brains."

But within the structures, the various bits were in a jumble and the shape and overall spatial organization didn't fully match that of a real brain. Plus, key pieces—such as the cerebellum, an area involved in motor control—were missing.

After the organoids achieved a size of four millimeters in diameter, they stopped growing, probably because they lacked a circulatory system, the researchers said. At that stage, they resembled the developing brain of a nine-week-old human embryo.

"Despite these compelling data, the realization of a 'brain in a dish' remains out of reach," wrote Oliver Brustle of the University of Bonn, in an article that accompanied the study. Dr. Brustle, who wasn't involved in the study, added: Although parts of the organoids' exteriors "clearly bear a resemblance to the developing cerebral cortex, it remains unclear whether they can advance to the complex six-tiered architecture of their natural counterpart."

Nonetheless, even imperfect brain tissue has uses, such as the work by Dr. Knoblich's team to study a patient suffering from microcephaly, the malady that leads to a small brain size and which has been difficult to model in mice.

The researchers first reprogrammed the patient's skin cells into stem cells, then grew those into mini brains. As expected, the mini brains grew to a lesser-than-normal size.

By examining the mini brains in the lab, Dr. Knoblich's team was able to pinpoint some ways in which the disease develops. In such patients, it seems, stem cells get transformed into neurons prematurely—at the expense of a proper buildup of stem cells. That is why the brains of such patients end up being smaller than normal, the scientists theorized.

View at the original source