Category Archives: Medical Sciences

Neuron responsible for alcoholism found

Scientists have pinpointed a population of neurons in the brain that influences whether one drink leads to two, which could ultimately lead to a cure for alcoholism and other addictions.

A study, published in the Journal of Neuroscience by researchers at the Texas A&M Health Science Center College of Medicine, finds that alcohol consumption alters the structure and function of neurons in the dorsomedial striatum, a part of the brain known to be important in goal-driven behaviors. The findings could be an important step toward creation of a drug to combat alcoholism.

“Alcoholism is a very common disease,” said Jun Wang, M.D., Ph.D., the lead author on the paper and an assistant professor in the Department of Neuroscience and Experimental Therapeutics at the Texas A&M College of Medicine, “but the mechanism is not understood very well.”

Now, Wang and his team have helped come a little closer to that understanding. Using an animal model, the researchers determined that alcohol actually changes the physical structure of medium spiny neurons, the main type of cell in the striatum. These neurons can be thought of like a tree, with many branches, and many small protrusions, or spines, coming off of them. They each have one of two types of dopamine receptors, D1 or D2, and so can be thought of as either D1 or D2 neurons. D1 neurons are informally called part of a “go” pathway in the brain, while D2 neurons are in the “no-go” pathway. In other words, when D2 neurons are activated, they discourage action — telling you to wait, to stop, to do nothing.

Although it is well known that the neurotransmitter dopamine is involved in addiction, this study goes further, showing that the dopamine D1 receptor also plays an important role in addiction. The team found that periodic consumption of large amounts of alcohol acts on D1 neurons, making them much more excitable, which means that they activate with less stimulation.

“If these neurons are excited, you will want to drink alcohol,” Wang said. “You’ll have a craving.” That is to say, when neurons with D1 receptors are activated, they compel you to perform an action — reaching for another bottle of tequila, in this case. This then creates a cycle, where drinking causes easier activation, and activation causes more drinking.

These changes in activation of D1 neurons might be related to the physical changes happening at the sub-cellular level in brains that have been exposed to alcohol. They have longer branching and more of the mature, mushroom-shaped spines — the type that stores long-term memories — than their abstaining counterparts.

Conversely, the placebo group, the ones not exposed to alcohol, tended to have more of the immature versions of the mushroom-shaped spines in D1 neurons of their brains. The total number of spines didn’t change in the two groups, but the ratio between mature and immature was dramatically different between the alcohol group and the placebo group. This has important implications for memory and learning in drug addiction.

“When you drink alcohol, long-term memory is enhanced, in a way,” Wang said. “But this memory process is not useful — in fact, it underlies addiction since it affects the ‘go’ neurons.” Because there was no difference in the number of each type of spine in the D2 (no-go) neurons of alcohol-consuming and control models, the researchers realized there was a specific relationship between D1 neurons and alcohol consumption.

“We’re now able to study the brain at the neuron-specific and even spine-specific level,” Wang said.

How do you determine which neuron, which type of neurons or which group of neurons is responsible for a specific disease? That’s what the next part of the study tried to answer.

The alcohol-consuming animal models with the increased mature spines in D1 neurons also showed an increased preference to drink large quantities of alcohol when given the choice.

“Even though they’re small, D1 receptors are essential for alcohol consumption,” Wang said.

Furthermore, and perhaps most excitingly, when those same animal models were given a drug to at least partially block the D1 receptor, they showed much-reduced desire to drink alcohol. However, a drug that inhibited the D2 dopamine receptors had no effect. “If we suppress this activity, we’re able to suppress alcohol consumption,” Wang said. “This is the major finding. Perhaps in the future, researchers can use these findings to develop a specific treatment targeting these neurons.”

The study, which was co-authored with researchers from the University of California San Francisco, was supported by a grant from the National Institute on Alcohol Abuse and Alcoholism (NIAAA).

“My ultimate goal is to understand how the addicted brain works,” Wang said, “and once we do, one day, we’ll be able to suppress the craving for another round of drinks and ultimately, stop the cycle of alcoholism.”




Imaging techniques set new standard for super-resolution in live cells

Scientists can now watch dynamic biological processes with unprecedented clarity in living cells using new imaging techniques developed by researchers at the Howard Hughes Medical Institute’s Janelia Research Campus. The new methods dramatically improve on the spatial resolution provided by structured illumination microscopy, one of the best imaging methods for seeing inside living cells.

The vibrant videos produced with the new technology show the movement and interactions of proteins as cells remodel their structural supports or reorganize their membranes to take up molecules from outside the cell. Janelia group leader Eric Betzig, postdoctoral fellow Dong Li and their colleagues have added the two new technologies — both variations on SIM — to the set of tools available for super-resolution imaging. Super-resolution optical microscopy produces images whose spatial resolution surpasses a theoretical limit imposed by the wavelength of light, offering extraordinary visual detail of structures inside cells. But until now, super-resolution methods have been impractical for use in imaging living cells.


“These methods set a new standard for how far you can push the speed and non-invasiveness of super-resolution imaging,” Betzig says of the techniques his team described in the August 28, 2015, issue of the journal Science. “This will bring super-resolution to live-cell imaging for real.”

In traditional SIM, the sample under the lens is observed while it is illuminated by a pattern of light (more like a bar code than the light from a lamp). Several different light patterns are applied, and the resulting moiré patterns are captured from several angles each time by a digital camera. Computer software then extracts the information in the moiré images and translates it into a three-dimensional, high-resolution reconstruction. The final reconstruction has twice the spatial resolution that can be obtained with traditional light microscopy.

Betzig was one of three scientists awarded the 2014 Nobel Prize in Chemistry for the development of super-resolved fluorescence microscopy. He says SIM has not received as much attention as other super-resolution methods largely because those other methods offer more dramatic gains in spatial resolution. But he notes that SIM has always offered two advantages over alternative super-resolution methods, including photoactivated localization microscopy (PALM), which he developed in 2006 with Janelia colleague Harald Hess.

Both PALM and stimulated emission depletion (STED) microscopy, the other super-resolution technique recognized with the 2014 Nobel Prize, illuminate samples with so much light that fluorescently labeled proteins fade and the sample is quickly damaged, making prolonged imaging impossible. SIM, however, is different. “I fell in love with SIM because of its speed and the fact that it took so much less light than the other methods,” Betzig says.

Betzig began working with SIM shortly after the death in 2011 of one of its pioneers, Mats Gustafsson, who was a group leader at Janelia. Betzig was already convinced that SIM had the potential to generate significant insights into the inner workings of cells, and he suspected that improving the technique’s spatial resolution would go a long way toward increasing its use by biologists.

Gustafsson and graduate student Hesper Rego had achieved higher-resolution SIM with a variation called saturated depletion non-linear SIM, but that method trades improvements in spatial resolution for harsher conditions and a loss of speed. Betzig saw a way around that trade-off.

Saturated depletion enhances the resolution of SIM images by taking advantage of fluorescent protein labels that can be switched on and off with light. To generate an image, all of the fluorescent labels in a protein are switched on, then a wave of light is used to deactivate most of them. After exposure to the deactivating light, only molecules at the darkest regions of the light wave continue to fluoresce. These provide higher frequency information and sharpen the resulting image. An image is captured and the cycle is repeated 25 times or more to generate data for the final image. The principle is very similar to the way super-resolution in achieved in STED or a related method called RESOLFT, Betzig says.

The method is not suited to live imaging, he says, because it takes too long to switch the photoactivatable molecules on and off. What’s more, the repeated light exposure damages cells and their fluorescent labels. “The problem with this approach is that you first turn on all the molecules, then you immediately turn off almost all the molecules. The molecules you’ve turned off don’t contribute anything to the image, but you’ve just fried them twice. You’re stressing the molecules, and it takes a lot of time, which you don’t have, because the cell is moving.”

The solution was simple, Betzig says: “Don’t turn on all of the molecules. There’s no need to do that.” Instead, the new method, called patterned photoactivation non-linear SIM, begins by switching on just a subset of fluorescent labels in a sample with a pattern of light. “The patterning of that gives you some high resolution information already,” he explains. A new pattern of light is used to deactivate molecules, and additional information is read out of their deactivation. The combined effect of those patterns leads to final images with 62-nanometer resolution — better than standard SIM and a three-fold improvement over the limits imposed by the wavelength of light.

“We can do it and we can do it fast,” he says. That’s important, he says, because for imaging dynamic processes, an increase in spatial resolution is meaningless without a corresponding increase in speed. “If something in the cell is moving at a micron a second and I have one micron resolution, I can take that image in a second. But if I have 1/10-micron resolution, I have to take the data in a tenth of a second, or else it will smear out,” he explains.

Patterned photoactivation non-linear SIM captures the 25 images that go into a final reconstruction in about one-third of a second. Because it does so efficiently, using low intensity light and gleaning information from every photon emitted from a sample’s fluorescent labels, labels are preserved so that the microscope can image longer, letting scientists watch more action unfold.

The team used patterned photoactivation non-linear SIM to produce videos showing structural proteins break down and reassemble themselves as cells move and change shape, as well as the dynamics of tiny pits on cell surfaces called caveolae.

Betzig’s team also reports in the Science paper that they can boost the spatial resolution of SIM to 84 nanometers by imaging with a commercially available microscope objective with an ultra-high numerical aperture. The aperture restricts light exposure to a very small fraction of a sample, limiting damage to cells and fluorescent molecules, and the method can be used to image multiple colors at the same time, so scientists can simultaneously track several different proteins.

Using the high numerical aperture approach, Betzig’s team was able to watch the movements and interactions of several structural proteins during the formation of focal adhesions, physical links between the interior and exterior of a cell. They also followed the growth and internalization of clathrin-coated pits, structures that facilitate the intake of molecules from outside of the cell. Their quantitative analysis answered several questions about the pits’ distribution and the relationship between pits’ size and lifespan that could not be addressed with previous imaging methods.

Finally, by combining the high numerical-aperture approach with patterned photoactivatable non-linear SIM, Betzig and his colleagues could follow two proteins at a time with higher resolution than the high numerical aperture approach offered on its own.

Betzig’s team is continuing to develop their SIM technologies, and say further improvements are likely. They are also eager to work with biologists to continue to explore potential applications and refine their techniques’ usability.

For now, scientists who want to experiment with the new SIM methods can arrange to do so through Janelia’s Advanced Imaging Center, which provides access to cutting-edge microscopy technology at no cost. Eventually, Betzig says, it should be fairly straightforward to make the SIM technologies accessible and affordable to other labs. “Most of the magic is in the software, not the hardware,” he says.





Smart phone not a smart choice when facing depression

A team of researchers, that included the dean of Michigan State University’s College of Communication Arts and Sciences, found that people who substitute electronic interaction for the real-life human kind find little if any satisfaction.

In a paper published in the journal Computers in Human Behavior, the researchers argue that relying on a mobile phone to ease one’s woes just doesn’t work.



Using a mobile phone for temporary relief from negative emotions could worsen psychological conditions and spiral into unregulated and problematic use of mobile phones, or PUMP, said MSU’s Prabu David.

“The research bears out that despite all the advances we’ve made, there is still a place for meaningful, face-to-face interaction,” he said. “The mobile phone can do a range of things that