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NEUROLOGY

How Our Brains Become Addicted To Alcohol

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The study links molecular changes in the brain to behaviors that are central in addiction, such as choosing a drug over alternative rewards. The researchers have developed a method in which rats learn to get an alcohol solution by pressing a lever. In order to better capture how addiction makes the individual choose alcohol over other rewards, the researchers offered the rats an alternative to alcohol — sweetened water. When the animals could choose between alcohol and sweetened water, the majority stopped making an effort to get alcohol and chose the sweetened solution instead. But 15 percent of the rats continued to choose alcohol, even when they could obtain another reward. This proportion is similar to the percentage of humans with alcohol addiction.

The behavior of rats that chose alcohol had several similarities to the diagnostic criteria that are used for alcohol addiction in humans, for instance, continued use despite negative consequences. This was shown by the observation that they continued to press the lever to get alcohol, even if they got an unpleasant electric shock in the paw.

“We have to understand that a core feature of addiction is that you know it is going to harm you, potentially even kill you, and nevertheless something has gone wrong with the motivational control and you keep doing it,” says Markus Heilig, professor at the Department of Clinical and Experimental Medicine and director of the Centre for Social and Affective Neuroscience.

To investigate the mechanism behind the addiction-like behaviors in the rats, the researchers measured the expression of hundreds of genes in five areas of the brain. The largest differences they found were in the amygdala, which is important for emotional reactions. In the rats that chose alcohol over sweetened water, one gene, in particular, was expressed at much lower levels. This gene is the blueprint for the protein GAT-3, a transport protein (or ‘transporter’) that helps maintain low levels of the inhibitory signal substance GABA around the nerve cells. This discovery is in line with previous studies that identified changes in GABA signaling in the amygdala as rats developed alcohol dependence.

The researchers investigated the role of reduced transport protein by knocking out GAT-3 in rats that initially clearly preferred sweetened water over alcohol. After the knockdown, the rats were once more presented with the choice between alcohol and sugar.

“Decreasing the expression of the transporter had a striking effect on the behavior of these rats. Animals that had preferred the sweet taste over alcohol reversed their preference and started choosing alcohol,” says Eric Augier, the lead investigator in the project.

Ultimately, the significance of animal findings like this is determined by the degree to which they reflect what happens in humans. To determine if this is the case, the research team collaborated with investigators at the University of Texas at Austin and analysed GAT-3 levels in brain tissue from deceased humans. In individuals with documented alcohol addiction, GAT-3 levels in the amygdala region were lower than in control individuals.

“This is one of those relatively rare times where we find an interesting change in our animal models and we find the same change in the brains of human alcoholics,” said Dayne Mayfield, a research scientist at the University of Texas at Austin’s Waggoner Center for Alcohol and Addiction Research and co-author of the new study.

“It’s a very good indication that our animal model is correct. And if our animal model is correct, we can screen therapeutics with it and have increased confidence in the findings.”

The discovery has the potential to help improve treatment of alcohol dependence. Baclofen, a medication that has long been used to treat increased muscular tension in certain neurological states, has also been studied for the treatment of alcohol dependence. Results have been promising, but the mechanism has been unclear.

“One of the things baclofen does is to suppress GABA release. We are currently working with a drug company to try to develop a second-generation molecule as a candidate for alcoholism medication that targets this signaling pathway,” says Markus Heilig.

The study was carried out by researchers at Linköping University in collaboration with researchers from the University of Gothenburg, and the University of Texas. The research was funded by the Swedish Research Council.

NEUROLOGY

Focused Delivery For Brain Cancers

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A person’s brainstem controls some of the body’s most important functions, including heart beat, respiration, blood pressure and swallowing. Tumor growth in this part of the brain is therefore twice as devastating. Not only can such a growth disrupt vital functions, but operating in this area is so risky, many medical professionals refuse to consider it as an option.

New, interdisciplinary research in Washington University in St. Louis has shown a way to target drug delivery to just that area of the brain using noninvasive measures, bolstered by a novel technology: focused ultrasound.

The research comes from the lab of Hong Chen, assistant professor of biomedical engineering in the School of Engineering & Applied Science and assistant professor of radiation oncology at Washington University School of Medicine. Chen has developed a novel way in which ultrasound and its contrast agent — consisting of tiny bubbles — can be paired with intranasal administration, to direct a drug to the brainstem.

The research, which also included faculty from the Mallinckrodt Institute of Radiology and the Department of Pediatrics at the School of Medicine, along with the Department of Energy, Environmental & Chemical Engineering in the School of Engineering & Applied Science, was published online this week and will be in the Sept. 28 issue of the Journal of Controlled Release.

This technique may bring medicine one step closer to curing brain-based diseases such as diffuse intrinsic pontine gliomas (DIPG), a childhood brain cancer with a five-year survival rate of a scant two percent, a dismal prognosis that has remained unchanged over the past 40 years. (To add perspective, the most common childhood cancer, acute lymphoblastic leukemia, has a five-year survival rate of nearly 90 percent).

“Each year in the United States, there are no more than 300 cases,” Chen said.

“All pediatric diseases are rare; luckily, this is even more rare. But we cannot count numbers in this way, because for kids that have this disease and their families, it is devastating.”

Chen’s technique combines Focused UltraSound with IntraNasal delivery, (FUSIN). The intranasal delivery takes advantage of a unique property of the olfactory and trigeminal nerves: they can carry nanoparticles directly to the brain, bypassing the blood brain barrier, an obstacle to drug delivery in the brain.

This unique capability of intranasal delivery was demonstrated last year by co-authors Ramesh Raliya, research scientist, and Pratim Biswas, assistant vice chancellor and chair of the Department of Energy, Environmental & Chemical Engineering and the Lucy & Stanley Lopata Professor, in their 2017 publication in Scientific Reports.

“At the beginning, I couldn’t even believe this could work,” Hong said of delivering drugs to the brain intranasally.

“I thought our brains are fully protected. But these nerves actually directly connect with the brain and provide direct access to the brain.”

While nasal brain drug delivery is a huge step forward, it isn’t yet possible to target a drug to a specific area. Chen’s targeted ultrasound technique is addressing that problem.

When doing an ultrasound scan, the contrast agent used to highlight images is composed of microbubbles. Once injected into the bloodstream, the microbubbles behave like red blood cells, traversing the body as the heart pumps.

Once they reach the site where the ultrasound wave is focused, they do something unusual.

“They start to expand and contract,” Chen said.

As they do so, they act as a pump to the surrounding blood vessels as well as the perivascular space — the space surrounding the blood vessels.

“Consider the blood vessels like a river,” Chen said.

“The conventional way to deliver drugs is to dump them in the river.”

In other parts of the body, the banks of the river are a bit “leaky,” Chen said, allowing the drugs to seep into the surrounding tissue. But the blood brain barrier, which forms a protective layer around blood vessels in the brain, prevents this leakage, particularly in the brains of young patients, such as those with with DIPG.

“We will deliver the drug from the nose to directly outside the river,” Chen said, “in the perivascular space.”

Then, once ultrasound is applied at the brain stem, the microbubbles will begin to expand and contract. The oscillating microbubbles push and pull, pumping the drug toward the brainstem. This technique also addresses the problem of drug toxicity — the drugs will go directly to the brain instead of circulating through the whole body. In collaboration with Yongjian Liu, an associate professor of radiology, and Yuan-Chuan Tai, an associate professor of radiology, Chen used positron emission tomography (PET scan) to verify that there was minimal accumulation of intranasal-administered nanoparticles in major organs, including lungs, liver, spleen, kidney and heart.

So far, Chen’s lab has had success using their technique in mice for the delivery of gold nanoclusters made by the team led by Liu.

“The next step is to demonstrate the therapeutic efficacy of FUSIN in the delivery of chemotherapy drugs for the treatment of DIPG,” said Dezhuang Ye, lead author of the paper, who is Chen’s graduate student from the Department of Mechanical Engineering & Materials Science.

The lab has also teamed up with Biswas to develop a new aerosol nasal delivery device to scale up the technique from a mouse to a large animal model.

Chen’s lab collaborated on this research with pediatric neuro-oncologist Joshua Rubin, MD, PhD, a professor of pediatrics at the School of Medicine who treats patients at St. Louis Children’s Hospital. Chen said the team hopes to translate the findings of this study into clinical trials for children with DIPG.

There are difficulties ahead, but Chen believes researchers will need to continue to innovate when it comes to solving such a difficult problem as treating DIPG.

A targeted inspiration

Hong Chen’s lab collaborated with Joshua Rubin, MD, PhD, a professor of pediatrics at the School of Medicine on this research. And it all started with a couple of colleagues talking one day:

“My work in this field started with a conversation with him,” Chen said.

“He said, ‘Wow, this would be a perfect technique for treating this deadly disease.’ Without him to point me in this direction, I probably wouldn’t have known this application existed.

“That’s why I consider the Washington University environment, and the School of Engineering & Applied Science, so unique. It provides you so much opportunity to work with people from different backgrounds. It allowed me to expand my research scope and to be able to work on clinically relevant questions.”

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NEUROLOGY

Secret Tunnels Discovered Between The Skull And The Brain

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Bone marrow, the spongy tissue inside most of our bones, produces red blood cells as well as immune cells that help fight off infections and heal injuries. According to a new study of mice and humans, tiny tunnels run from skull bone marrow to the lining of the brain and may provide a direct route for immune cells responding to injuries caused by stroke and other brain disorders. The study was funded in part by the National Institutes of Health and published in Nature Neuroscience.

“We always thought that immune cells from our arms and legs traveled via blood to damaged brain tissue. These findings suggest that immune cells may instead be taking a shortcut to rapidly arrive at areas of inflammation,” said Francesca Bosetti, Ph.D., program director at the NIH’s National Institute of Neurological Disorders and Stroke (NINDS), which provided funding for the study.

“Inflammation plays a critical role in many brain disorders and it is possible that the newly described channels may be important in a number of conditions. The discovery of these channels opens up many new avenues of research.”

Using state-of-the-art tools and cell-specific dyes in mice, Matthias Nahrendorf, M.D., Ph.D., professor at Harvard Medical School and Massachusetts General Hospital in Boston, and his colleagues were able to distinguish whether immune cells traveling to brain tissue damaged by stroke or meningitis, came from bone marrow in the skull or the tibia, a large legbone. In this study, the researchers focused on neutrophils, a particular type of immune cell, which are among the first to arrive at an injury site.

Results in mouse brains showed that during stroke, the skull is more likely to supply neutrophils to the injured tissue than the tibia. In contrast, following a heart attack, the skull and tibia provided similar numbers of neutrophils to the heart, which is far from both of those areas.

Dr. Nahrendorf’s group also observed that six hours after stroke, there were fewer neutrophils in the skull bone marrow than in the tibia bone marrow, suggesting that the skull marrow released many more cells to the injury site. These findings indicate that bone marrow throughout the body does not uniformly contribute immune cells to help injured or infected tissue and suggests that the injured brain and skull bone marrow may “communicate” in some way that results in a direct response from adjacent leukocytes.

Dr. Nahrendorf’s team found that differences in bone marrow activity during inflammation may be determined by stromal cell-derived factor-1 (SDF-1), a molecule that keeps immune cells in the bone marrow. When levels of SDF-1 decrease, neutrophils are released from marrow. The researchers observed levels of SDF-1 decreasing six hours after stroke, but only in the skull marrow, and not in the tibia. The results suggest that the decrease in levels of SDF-1 may be a response to local tissue damage and alert and mobilize only the bone marrow that is closest to the site of inflammation.

Next, Dr. Nahrendorf and his colleagues wanted to see how the neutrophils were arriving at the injured tissue.

“We started examining the skull very carefully, looking at it from all angles, trying to figure out how neutrophils are getting to the brain,” said Dr. Nahrendorf.

“Unexpectedly, we discovered tiny channels that connected the marrow directly with the outer lining of the brain.”

With the help of advanced imaging techniques, the researchers watched neutrophils moving through the channels. Blood normally flowed through the channels from the skull’s interior to the bone marrow, but after a stroke, neutrophils were seen moving in the opposite direction to get to damaged tissue.

Dr. Nahrendorf’s team detected the channels throughout the skull as well as in the tibia, which led them to search for similar features in the human skull. Detailed imaging of human skull samples obtained from surgery uncovered the presence of the channels. The channels in the human skull were five times larger in diameter compared to those found in mice. In human and mouse skulls, the channels were found in the both in the inner and outer layers of bone.

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NEUROLOGY

Missing Immune Cells That Could Fight Lethal Brain Tumors

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Glioblastoma brain tumors can have an unusual effect on the body’s immune system, often causing a dramatic drop in the number of circulating T-cells that help drive the body’s defenses.

Where the T-cells go has been unclear, even as immunotherapies are increasingly employed to stimulate the body’s natural ability to fight invasive tumors.

Now researchers at Duke Cancer Institute have tracked the missing T-cells in glioblastoma patients. They found them in abundance in the bone marrow, locked away and unable to function because of a process the brain stimulates in response to glioblastoma, to other tumors that metastasize in the brain and even to injury.

The findings, published online Aug. 13 in the journal Nature Medicine, open a new area of exploration for adjunct cancer drugs that could free trapped T-cells from the bone marrow, potentially improving the effectiveness of existing and new immunotherapies.

“Part of the problem with all these immunotherapies — particularly for glioblastoma and other tumors that have spread to the brain — is that the immune system is shot,” said lead author Peter E. Fecci, M.D., Ph.D., director of the Brain Tumor Immunotherapy Program in Duke’s Department of Neurosurgery.

“If the goal is to activate the T-cells and the T-cells aren’t there, you’re simply delivering therapy into a black hole.”

Fecci said the research team began its search for the missing T-cells after observing that many newly diagnosed glioblastoma patients have the equivalent immune systems of people with full-blown AIDS, even before they undergo surgery, chemotherapy and radiation.

Where most people have a CD-4 “helper” T-cell count upwards of 700-1,000, a substantial proportion of untreated glioblastoma patients have counts of 200 or less, marking poor immune function that makes them susceptible to all manner of infections and potentially to progression of their cancer.

Initially, the researchers hunted for the missing T-cells in the spleen, which is known to pathologically harbor the cells in certain disease states. But the spleens were abnormally small, as were the thymus glands — another potential T-cell haven. They decided to check the bone marrow to see if production was somehow stymied and instead found hordes of T-cells.

“It’s totally bizarre — this is not seen in any disease state,” Fecci said.

“This appears to be a mechanism that the brain possesses for keeping T-cells out, but it’s being usurped by tumors to limit the immune system’s ability to attack them.”

When examining the stashed T-cells, Fecci and colleagues found that they lacked a receptor on the cell surface called S1P1, which essentially serves as a key that enables them to leave the bone marrow and lymph system. Lacking that key, they instead get locked in, unable to circulate and fight infections, let alone cancer.

Fecci said the research team is now working to learn exactly how the brain triggers the dysfunction of this S1P1 receptor. He said the current theory is that the receptor somehow is signaled to retract from the cell surface into the cell interior.

“Interestingly, when we restore this receptor to T-cells in mice, the T-cells leave the bone marrow and travel to the tumor, so we know this process is reversible,” Fecci said.

His team is collaborating with Duke scientist Robert Lefkowitz, M.D., whose 2012 Nobel Prize in Chemistry honored discovery of the class of receptors to which S1P1 belongs. They are working to develop molecules that would restore the receptors on the cells’ surface.

“We are hopeful that this finding provides a missing element that would enable more immunotherapies to be effective for more people,” Fecci said. He said the finding could also work in reverse, offering a new approach to quell auto-immune disorders by activating the T-cell sequestration.

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