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NEUROLOGY

Widespread Connections Among Neurons Help The Brain Distinguish Smells

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Can you tell the smell of a rose from the scent of a lilac? If so, you have your brain’s piriform cortex to thank. Compared to many parts of the brain, the piriform cortex — which lets animals and humans process information about smells — looks like a messy jumble of connections between cells called neurons. Now, Salk Institute researchers have illuminated how the randomness of the piriform cortex is actually critical to how the brain distinguishes between similar odors.

“The standard paradigm is that information in the brain is encoded by which cells are active, but that’s not true for the olfactory system,” says Charles Stevens, Distinguished Professor Emeritus in Salk’s Molecular Neurobiology Laboratory and coauthor of the new work.

“In the olfactory system, it turns out it’s not a matter of which cells are active, but how many cells are active and how active they are.”

Aside from better understanding how smells are processed, the new research, published in the Journal of Comparative Neurologyon July 17, 2018, could also lead to greater insight into how some parts of the brain organize information.

When odorant molecules — the signature of any given smell — bind to the receptors in a person’s nose, the signal is transmitted to the olfactory bulb, and from there to the piriform cortex. In other sensory systems — like the visual system — information maintains a strict order as it moves through the brain. Particular parts of the eye, for instance, always transmit information to specific parts of the visual cortex. But researchers have long known that this order is missing in the piriform cortex.

“We haven’t been able to discern any order in the piriform cortex connections in any species,” says coauthor Shyam Srinivasan, an assistant project scientist at the University of California San Diego’s Kavli Institute for Brain and Mind.

“Any given odor lights up about 10 percent of neurons that seem to be scattered all over the piriform cortex.”

To start working out the details of how the piriform cortex encodes odor information — and whether its connections are truly random — Stevens and Srinivasan analyzed the piriform cortices of nine mice using a variety of staining and microscopy techniques that let them visualize different cell types in the brain region. Their first goal: to quantify the number and density of cells in the piriform cortex.

“This was really like a survey,” explains Srinivasan.

“We counted the cells in different representative areas and averaged them across the whole region.”

The mouse piriform cortex, they concluded, has around half a million neurons in it, divided equally between the larger, less dense posterior piriform and the smaller, more dense anterior piriform.

Using this initial information on density and neuron number, as well as knowledge from previous studies on the number of neurons in the olfactory bulb and how many neuronal connections — or synapses — connect the olfactory bulb to the piriform cortex, the pair of researchers was able to draw a surprising finding: each neuron in the olfactory bulb is connected to nearly every single neuron in the piriform cortex.

“Every cell in the piriform is getting information from essentially every odor receptor there is,” says Stevens.

“There’s not one ‘coffee smell’ neuron but a whole bunch of coffee cell neurons all over the place.”

Rather than a single receptor detecting one odor and lighting up one cluster of telltale neurons, he explains, each odor has a fingerprint that’s based more on the strength of the connections — while the smell of coffee may activate nearly the same neurons in the piriform cortex as the smell of chocolate, they’ll activate each neuron to a different degree.

“One advantage to this system is that it can encode very complex information,” says Srinivasan.

“It also makes it very robust to noise.”

If one neuron sends a “noisy” signal — stronger or weaker activation than it should — the noise gets cancelled out by the many other neurons sending simultaneous, more accurate signals.

The researchers would like to repeat the work in other animals to see where similarities and differences lie. They also are interested in looking into other areas of the brain that have long been assumed to be dominated by seemingly random connections to see if they’re organized in the same way.

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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