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Newly discovered multicomponent virus is the first of its kind to infect animals

Source: Cell Press
Date: 08/25/16
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For the first time, a multicomponent virus–which contains different segments of genetic material in separate particles, rather than a single strand of genetic material–has been found that is capable of infecting animals, an international team led by the U.S. Army reports August 25 in Cell Host & Microbe. The Guaico Culex virus (GCXV), a type of Jingmenvirus, was isolated from mosquitoes, and opens up a new avenue of research into potentially infectious agents. The virus does not appear to infect mammals.

“Until now, multicomponent viruses were thought to infect only plants and fungi, as a result of relatively inefficient transmission,” says first author Jason Ladner, a staff scientist from the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID). “Our finding that these viruses are present in mosquitoes is going to challenge us to re-evaluate some of our assumptions about them.”

Multicomponent viruses use a method of transmission that’s different from other viruses known to infect animals. Instead of being contained in a single viral particle, their genomes are segmented and encapsulated among multiple particles. A yellow fever virus, for example, has all its genetic material packaged into a single particle. Therefore, one particle is enough to infect a cell. But in order for a multicomponent virus to establish an infection, the cell has to get infected with at least one particle of each type.

The research is part of a global effort to monitor and prepare for outbreaks of unknown viral diseases. Mosquitoes and other insects can act as vectors for viral diseases, carrying them from place to place and transmitting them to human hosts via bites. Although the new virus does not appear to be a human pathogen, or even a mammalian one, the investigators say this work is a good exercise to help hone the tools and expertise needed to characterize novel infectious agents.

In the study, the USAMRIID researchers worked with several other teams, including groups from the University of Texas Medical Branch and the New York State Department of Health, to isolate mosquitoes from different regions around the world. The newly discovered virus is named Guaico Culex after the Guaico region of Trinidad in which the mosquitoes that contained it were found.

Guaico Culex was isolated by growing material obtained from the mosquitoes in cell culture. “This method has been useful particularly in finding new arboviruses, which are transmitted by mosquitoes and other arthropods to mammals,” Ladner says. To identify arboviruses, cultures of mammalian cells are used. “We were also interested in viruses that may be found within mosquitoes but don’t necessarily grow on mammalian cells, so we used cultures of insect cells, enabling us to find this new virus.”

Deep sequencing indicated that Guaico Culex belongs to a group of segmented viruses called Jingmenviruses, which were first discovered in 2014. In collaboration with a group at the University of Wisconsin-Madison, the USAMRIID researchers also showed for the first time evidence of a Jingmenvirus in the blood of a non-human primate, in this case a Ugandan red colobus monkey. This finding is also published in the current Cell Host & Microbe paper.

Experts believe that the most likely infectious viruses to make the jump to humans are those that are already circulating in other mammals, especially non-human primates. Phylogenetic analysis indicated that this monkey virus shared a segmented common ancestor with Guaico Culex. However, researchers don’t yet know if all Jingmenviruses are multicomponent like the Guaico Culex virus. It is also not known whether the Jingmenvirus isolated from the monkey had a pathogenic effect.

“One of the things we’re focused on at USAMRIID is rapid identification of pathogens from both clinical and environmental samples as well as characterization of novel viruses,” says Gustavo Palacios, Director of the Center for Genome Sciences at USAMRIID and the study’s senior author. “We’re trying to make sure that we’re not blindsided when the next virus comes around. With all of the diversity seen in these emerging viruses, we never know what the next one will be to have an impact on human health.”

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Feed a virus, starve a bacterial infection?

Source: Cell Press
Date: 09/08/16
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A new study puts some old folk wisdom to “feed a cold and starve a fever” to the test. In mouse models of disease, Yale researchers looked at the effects of providing nutrients during infection and found opposing effects depending on whether the infections were bacterial or viral. Mice with bacterial infections that were fed died, while those with viral infections who were fed lived. The paper appears September 8 in Cell.

“We were surprised at how profound the effects of feeding were, both positive and negative,” says senior author Ruslan Medzhitov, David W. Wallace Professor of Immunobiology and a Howard Hughes Medical Institute investigator at Yale School of Medicine. “Anorexia–not eating–is a common behavior during sickness that is seen in people and all kinds of animals. Our findings show that it has a strong protective effect with certain infections, but not with others.”

In the first series of experiments, the investigators infected mice with the bacterium Listeria monocytogenes, which commonly causes food poisoning. The mice stopped eating, and they eventually recovered. But when the mice were force fed, they died. The researchers then broke the food down by component and found fatal reactions when the mice were given glucose, but not when they were fed proteins or fats. Giving mice the chemical 2-DG, which prevents glucose metabolism, was enough to rescue even mice who were fed glucose and allowed them to survive the infection.

When the researchers did similar studies in mice with viral infections, they found the opposite effect. Mice infected with the flu virus A/WSN/33 survived when they were force fed glucose, but died when they were denied food or given 2-DG.

Further research showed that different areas of the brain were affected depending on which type of infection the mice died from, indicating that the animals’ metabolic needs differ depending on which part of the immune system had been activated.

“Almost everything we know about infection is based on immune response studies and looking at how the immune system eliminates pathogens,” Medzhitov says. “But that’s not the only way we defend ourselves. There are also cases where we change and adapt so that microbes don’t cause harm. Our study manipulated the ability of these mice to tolerate and survive infection without doing anything that had an effect on the pathogens themselves.”

Medzhitov’s Lab is now looking at the effects of another common sickness behavior–changes in sleep patterns–on how the immune system fights infection. His team is also doing follow-up studies on the pathways involved in food preference, which may explain the cravings that people have for certain foods when they’re sick.

But he says their findings may have more immediate implications as well, for the design of clinical trials evaluating the benefits of providing nutrients to patients with sepsis. “Sepsis is a critical problem in hospital ICUs that defies most modern medical approaches,” he says. “A number of studies have looked at nutrition in patients with sepsis, and the results have been mixed. But these studies didn’t segregate patients based on whether their sepsis was bacterial or viral. The implication is that patients should be stratified by the cause of their sepsis, and trials should be designed based on that.”

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Twin study finds that gut microbiomes run in families

Source: Cell Press
Date: 05/11/16
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A genome-wide association analysis of over 1,000 twins in the UK supports that some parts of our microbiomes are inherited and shaped–not through a spread of microbes from parent to child, but through our genes. The results, revealing new examples of heritable bacterial species–including those related to diet preference, metabolism, and immune defense–appear May 11 in Cell Host & Microbe‘s special issue on the “Genetics and Epigenetics of Host-Microbe Interactions.”

“We set out to find out about human genes that are implicated in the regulation of the gut microbiome, and we found some that are,” says senior author Ruth Ley, an Associate Professor in the Department of Microbiology at Cornell University and the study’s senior author. One connection they were able to make was between the LCT gene, which is involved in making the enzyme that helps the body digest dairy, and a type of microorganism called Bifidobacterium, which is commonly used in probiotics. They also found links between specific gut bacteria blood pressure and self/non-self recognition.

“Based on our research, we identified more than a dozen microbes with known links to health that are heritable,” says Ley, also director of the Department of Microbiome Science at the Max Planck Institute for Developmental Biology in Tübingen, Germany. “These microorganisms are environmentally acquired, but the genome also plays a part–by determining which microorganisms are more dominant than others.”

The investigators analyzed the gut microbiomes of 1,126 pairs of twins who were part of the TwinsUK Study. This multiyear research effort, which includes a total of 12,000 twins, is looking at a number of diseases and conditions. By including data from both identical and fraternal twins who were raised together, the study seeks to account for both environmental and genetic contributions.

The twins in the current study had already had their genomes analyzed, and 1.3 million small genetic variations (also known as single-nucleotide polymorphisms or SNPs) were known for each participant. The investigators used the genome-wide association approach to look for connections between genetic variations between twin pairs and certain bacterial types that were present and stable in the study subjects.

“The overall numbers in this study were still small for genome-wide association analysis, but they help validate some of the findings we’ve seen in smaller studies,” Ley says. The analysis confirmed earlier findings that several other types of bacteria are also heritable, but specific genes connected to those differences were not found. “This type of study opens up many questions but doesn’t give us a lot of answers yet,” Ley says. “It gives us lots of ideas to study.”

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Mapping the routes to drug resistance in cancer

Source: Cell Press
Date: 04/11/16
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When a freeway shuts down because of an accident or construction, drivers find another road to take them where they’re going. Likewise, when a targeted therapy blocks a pathway that enables tumors to grow, the cells usually manage to get around that obstacle. The result is drug resistance. Researchers have now found a way to map those alternate routes by studying individual cancer cells, suggesting approaches for developing more effective combination therapies. The results are published April 11 in Cancer Cell.

“Because technology now allows us to see the alternate pathways that cancer cells use to drive growth, it will enable us to identify ways to cut off multiple roads at the same time,” says James Heath, one of the paper’s corresponding authors, at the NanoSystems Biology Cancer Center in the Division of Chemistry and Chemical Engineering at the California Institute of Technology.

In the study, the investigators primarily looked at glioblastoma, the most deadly form of brain cancer. Although therapies tailored based on genetic alterations in these tumors have been developed, their benefit is usually short-lived. Combination therapies, which target multiple alterations at the same time, may offer a better way to fight this disease.

“Figuring out why resistance to targeted therapies develops has been the focus of our research for a long time,” says Paul Mischel, the paper’s co-corresponding author, at the Ludwig Institute for Cancer Research at the University of California, San Diego. “In this study, we looked at a drug that should work and found out why it doesn’t.”

The technology the team used is called single-cell phosphoproteomics. This tool enables investigators to peer into the inner workings of individual cancer cells and see their signaling. Using patient tissues obtained directly from operating rooms, the researchers found that the cells began to adapt to and resist therapies that target the growth pathway called mTOR in as little as 48 hours. Analysis showed that these cells were remapping their routes and finding ways to evade the drug’s effect long before any changes could be detected at the clinical level.

The investigators say that this approach could eventually be used to find better combination therapies for glioblastoma, but obstacles remain. “Although the technology used to analyze the cells is relatively simple and inexpensive–just glass and plastic–trials will be difficult to design,” says Heath. “For this type of personalized treatment, we won’t know what drugs to give patients until after their tumors are analyzed. Every trial will essentially have a sample size of one.”

Mischel adds that there are additional challenges in developing drugs for glioblastoma because they must be able to cross the blood-brain barrier.

In the paper, the researchers also described that single-cell phosphoproteomics could be used to study how melanoma cells develop resistance to a class of drugs called BRAF inhibitors. The single-cell-analysis approach could likely be employed to develop personalized treatment for many other types of cancer as well.

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Mouse study suggests autism is not just a disease of the brain

Source: Cell Press
Date: 06/09/16
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Autism spectrum disorders (ASDs) are characterized by impaired social interactions and repetitive behaviors, often accompanied by abnormal reactions to sensory stimuli. ASD is generally thought to be caused by deficits in brain development, but a study in mice, published June 9 in Cell, now suggests that at least some aspects of the disorder–including how touch is perceived, anxiety, and social abnormalities–are linked to defects in another area of the nervous system, the peripheral nerves found throughout the limbs, digits, and other parts of the body that communicate sensory information to the brain.

“An underlying assumption has been that ASD is solely a disease of the brain, but we’ve found that may not always be the case,” says senior author David Ginty, a Professor of Neurobiology at Harvard Medical School and a Howard Hughes Medical Institute Investigator. “Advances in mouse genetics have made it possible for us to study genes linked to ASD by altering them only in certain types of nerve cells and studying the effects.”

In the new study, the researchers examined the effects of gene mutations known to be associated with ASD in humans. In particular, they focused on Mecp2, which causes Rett syndrome, a disorder that is often associated with ASD, and Gabrb3, which also is implicated in ASD. They looked at two other genes connected to ASD-like behaviors as well.

These genes are believed to be essential for the normal function of nerve cells, and previous studies have linked these mutations to problems with synaptic function–how neurons communicate with each other.

“Although we know about several genes associated with ASD, a challenge and a major goal has been to find where in the nervous system the problems occur,” Ginty says. “By engineering mice that have these mutations only in their peripheral sensory neurons, which detect light touch stimuli acting on the skin, we’ve shown that mutations there are both necessary and sufficient for creating mice with an abnormal hypersensitivity to touch.”

The investigators measured how the mice reacted to touch stimuli, such as a light puff of air on their backs, and tested whether they could discriminate between objects with different textures. Mice with ASD gene mutations in only their sensory neurons exhibited heightened sensitivity to touch stimuli and were unable to discriminate between textures. The transmission of neural impulses between the touch-sensitive neurons in the skin and the spinal cord neurons that relay touch signals to the brain was also abnormal. Together, these results show that mice with ASD-associated gene mutations have deficits in tactile perception.

The investigators next examined anxiety and social interactions in the mice using established tests looking at how much mice avoided being out in the open and how much they interacted with mice they’d never seen before. Surprisingly, the animals with ASD gene mutations only in peripheral sensory neurons showed heightened anxiety and interacted less with other mice. “How closely these behaviors mimic anxiety seen in ASD in humans is up for debate,” Ginty says, “but in our field, these are well-established measures of what we consider to be anxiety-like behavior and social interaction deficits.”

“A key aspect of this work is that we’ve shown that a tactile, somatosensory dysfunction contributes to behavioral deficits, something that hasn’t been seen before,” Ginty says. “In this case, that deficit is anxiety and problems with social interactions.” How problems with processing the sense of touch lead to anxiety and social problems isn’t clear at this point, however.

“Based on our findings, we think mice with these ASD-associated gene mutations have a major defect in the ‘volume switch’ in their peripheral sensory neurons,” says first author Lauren Orefice, a postdoctoral fellow in Ginty’s lab. Essentially, she says, the volume is turned up all the way in these neurons, leading the animals to feel touch at an exaggerated, heightened level.

“We think it works the same way in humans with ASD,” Ginty adds.

“The sense of touch is important for mediating our interactions with the environment, and for how we navigate the world around us,” Orefice says. “An abnormal sense of touch is only one aspect of ASD, and while we don’t claim this explains all the pathologies seen in people, defects in touch processing may help to explain some of the behaviors observed in patients with ASD.”

The investigators are now looking for approaches that might turn the “volume” back down to normal levels in the peripheral sensory neurons, including both genetic and pharmaceutical approaches.

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HIV infection prematurely ages humans by an average of 5 years

Source: Cell Press
Date: 04/21/16
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Thanks to combination antiretroviral therapy, many people with HIV can be expected to live decades after being infected. Yet doctors have observed that these patients often show signs of premature aging. Now a study published April 21 in Molecular Cell has applied a highly accurate biomarker to measure just how much HIV infection ages people at the biological level–an average of almost 5 years.

“The medical issues in treating people with HIV have changed,” says Howard Fox, a Professor in the Department of Pharmacology and Experimental Neuroscience at the University of Nebraska Medical Center and one of the authors of the new study. “We’re no longer as worried about infections that come from being immunocompromised. Now we worry about diseases related to aging, like cardiovascular disease, neurocognitive impairment, and liver problems.”

The tool used in the new study looks at epigenetic changes in people’s cells. Epigenetic changes affect the DNA, but not the DNA sequence. Once they occur, they are passed down from one generation of cell to the next, influencing how genes are expressed. The particular epigenetic change used as a biomarker in this research was methylation, the process by which small chemical groups are attached to DNA. Methylation of DNA can impact how genes get translated into proteins.

“What we’ve seen in previous studies is that as we age, methylation across the entire genome changes,” says Trey Ideker, a Professor of Genetics in the Department of Medicine at the University of California San Diego and the study’s other corresponding author. “Some people call it entropy or genetic drift. Although we’re not sure of the exact mechanism by which these epigenetic changes lead to symptoms of aging, it’s a trend that we can measure inside people’s cells.”

The 137 patients included in the analysis were enrolled in CHARTER (the CNS Antiretroviral Therapy Effects Research study), a long-term study aimed at monitoring HIV-infected individuals who are being treated with combination antiretroviral therapy. Subjects who were chosen didn’t have other health conditions that could skew the results. 44 HIV-negative control subjects were also included in the initial analysis. An independent group of 48 subjects, both HIV positive and negative, was used to confirm the findings.

In addition to the discovery that HIV infection led to an average advance in biological aging of 4.9 years, the researchers note that such a change correlates with an increased risk of mortality of 19%.

“We set out to look at the effects of HIV infection on methylation, and I was surprised that we found such a strong aging effect,” Ideker says.

“Another thing that was surprising was that there was no difference between the methylation patterns in those people who were recently infected [less than five years] and those with chronic infection [more than 12 years],” Fox adds.

The investigators say it’s possible drugs could eventually be developed to target the kinds of epigenetic changes observed in the study. But the more immediate implications are much simpler: they note that people infected with HIV should be aware that they’re of greater risk for age-related diseases and work to diminish those risks by making healthy lifestyle choices regarding exercise, diet, and drug, alcohol, and tobacco use.

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Inflammation from mosquito bites may enhance viral infection

Source: Cell Press
Date: 06/21/16
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The itchy, red welts that appear after being bitten by a mosquito may help any viruses the insect is carrying pass on to a new host. A mouse study published June 21 in Immunity suggests that the swelling and irritation that make mosquito bites so unpleasant may provide a mechanism by which viruses like Zika are able to replicate and spread.

“Before we did this study, little was known about the events and processes that occur at mosquito bite sites,” says Clive McKimmie, a Research Fellow at the University of Leeds and the paper’s senior author. “Our findings suggest that the inflammatory response at these sites helps viruses to replicate, enhancing their ability to cause disease.”

In the new research, the investigators used mouse models to study the bites of the Aedes aegypti mosquito, the species that spreads infections such as Zika, dengue, and chikungunya.

When a mosquito bites, it injects saliva into the skin. The saliva triggers an immune response, in which white blood cells called neutrophils and myeloid cells rush to the site. In this study, the team injected mice with viruses into the skin with or without the presence of a mosquito bite at the injection site and compared the reaction. They found that instead of helping, some of these immune cells get infected and inadvertently replicate virus.

In the absence of mosquito bites and their accompanying inflammation, the viruses failed to replicate well. But the presence of mosquito bites at the infection site resulted in an order of magnitude higher levels of virus. Further studies showed that the influx of white blood cells was required for enhanced replication of the viruses.

According to McKimmie, previous studies that have used in vivo models to study the course of mosquito-borne infections haven’t looked at the bite as a necessary component. “We think the bite itself is affecting the systemic course and clinical outcome of the infection,” he says. “If you want an in vivo model that replicates the most relevant parts of infection, you should include this inflammatory aspect.”

“This was a big surprise we didn’t expect,” he adds. “These viruses are not known for infecting immune cells. And sure enough, when we stopped these immune cells from coming in, the bite did not enhance the infection anymore.”

Although this research is still early work done in mice, McKimmie says the finding suggests new approaches for combating viruses that lead to health problems in humans. “We’re quite keen to see if using topical creams to suppress bite inflammation will enable you to stop a virus from making someone as sick as it otherwise would do,” he says.

He notes that if it’s proven effective, this approach could work against future virus outbreaks that we don’t know about yet. “Nobody expected Zika, and before that nobody expected chikungunya,” he says. “There are estimated to be hundreds of other mosquito-borne viruses out there and it’s hard to predict what’s going to start the next outbreak.”

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Diabetic mice on fasting-mimicking diet repair insulin-producing pancreas cells

Source: Cell Press
Date: 02/23/17
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Research in mice and human cells suggests that a fasting-mimicking diet may reprogram pancreas cells that are unable to produce insulin and enable them to repair themselves and start making it. The work, published February 23 in Cell, provides an alternative approach to replacing damaged insulin-producing beta cells.

“Our conclusion is that by pushing the mice into an extreme state and then bringing them back–by starving them and then feeding them again–the cells in the pancreas are triggered to use some kind of developmental reprogramming that rebuilds the part of the organ that’s no longer functioning,” says senior author Valter Longo of the University of Southern California School of Gerontology and Director of the USC Longevity Institute.

Longo originally developed the fasting-mimicking diet as a way to reduce stress and protect from toxicity in people undergoing chemotherapy. It involves consuming a very limited number of high-fat calories for five days and then returning to a normal diet. Measurement of four biomarkers associated with a water-only diet suggested that the diet has the same physiological effects on the body as more extreme fasting.

Studies since then have suggested that the diet may be a way to “reboot” the body by inducing it to slow down aging and regenerating new cells. Researchers have found that the expression of three key genes drops during the fasting-mimicking diet. These genes–IGF1, TOR, and PKA–are associated with stress and aging.

In the latest study, the researchers hypothesize that the downregulation of these three genes reprograms the cells so that they return to an embryonic-like state, in which they have the potential to give rise to a number of different cell types. “During starvation, the cells go into standby mode,” Longo says. “Then, when you begin refeeding the mice, you see these embryonic-like cells begin to give rise to beta cells.”

The researchers used two different mouse models of diabetes to study the effects of the diet. One was mice with a gene mutation that causes insulin resistance and loss of insulin secretion. The other was mice that were treated with a chemical to destroy their beta cells. Both models were given three cycles of the diet.

“Medically, these findings have the potential to be very important because we’ve shown–at least in mouse models–that you can use diet to reverse the symptoms of diabetes,” Longo says. “Scientifically, the findings are perhaps even more important because we’ve shown that you can use diet to reprogram cells without having to make any genetic alterations.” In addition to looking at mouse models of diabetes, the researchers also showed that exposure of human pancreatic islet cells–both from healthy donors and from patients with Type 1 diabetes–to fasting-mimicking diet in a dish stimulated insulin production.

Much research is needed before the findings can be validated in humans, but Longo says these clinical trials are already being planned. In Science Translational Medicine (DOI: 10.1126/scitranslmed.aai8700) on February 15, his team published a related, randomized Phase II study in 100 people that showed that when humans were exposed to three rounds of the fasting-mimicking diet, their IGF1 levels decreased and their fasting glucose levels improved, among other findings.

Longo says the findings also have implications for diseases beyond diabetes. “We want to start looking system by system to see how widely acting this process is on different types of cells,” he says. “The amazing thing is that this system has probably always been there. Now that we’ve discovered it, we can find ways to work with it and utilize it for benefits to human health.”

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Antibody Combination Puts HIV on the Ropes

Source: Rockefeller University, Newswire
Date: 01/25/17
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Without antiretroviral drug treatment, the majority of people infected with HIV ultimately develop AIDS, as the virus changes and evolves beyond the body’s ability to control it. But a small group of infected individuals—called elite controllers—possess immune systems capable of defeating the virus. They accomplish this by manufacturing broadly neutralizing antibodies, which can take down multiple forms of HIV.

Now a study using antibodies from one of these elite controllers has shown that a combination of three such antibodies can completely suppress the virus in HIV-infected mice. The findings, from the laboratory of Michel C. Nussenzweig, who is Zanvil A. Cohn and Ralph M. Steinman Professor at The Rockefeller University and head of the Laboratory of Molecular Immunology, are being reported in Science Translational Medicine.

“Some people with HIV produce these antibodies, but most of the time the virus eventually escapes them through mutations in the antibody’s corresponding epitope,” says postdoctoral fellow Natalia Freund, the study’s first author. The epitope is the part of the virus that antibodies recognize and attach themselves to, and this ability to mutate makes HIV particularly tricky to tame. It ensures that once the virus is in their bodies, people remain infected forever, and this may be the biggest roadblock in developing immune therapies to overcome the virus.

Tug of war

“Think of the relationship between the antibodies and the virus as an arms race that goes on and on,” Freund says. “By mutating, some of the virus may escape the antibodies and continue growing. Years later, the body may produce new broadly neutralizing antibodies against the escaped virus, which in turn may mutate and escape yet again.”

“What we’ve shown in this study is that after several rounds of escape from these particular antibodies, the virus seems to run out of options,” she adds. “In this particular case, HIV eventually loses this arms race.”

An elite controller’s immune system can defeat the virus by coming up with new broadly neutralizing antibodies, and also by producing cytotoxic T cells—immune cells that can recognize and destroy infected cells to immobilize the virus. The patient whose HIV response created antibodies for the study has been working with the Rockefeller team for 10 years, contributing his blood serum for their research. He was infected at least three decades ago, and has developed three different types of broadly neutralizing antibodies that bind to three different sites on the virus.

The remarkable thing about his antibodies is that they seem to complement one another’s activity, completely shutting down HIV.

The investigators gave the three antibodies, called BG18, NC37, and BG1, to HIV-infected mice whose immune systems had been modified to more closely resemble those of humans. They found that the trio rendered the virus undetectable in two-thirds of the mice three weeks after it was administered.

“This study validates the approach of using three different antibodies to control HIV infection,” Freund concludes, “pointing the way toward a potential new treatment for people infected with HIV.”

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Mouse studies offer new insights about cocaine’s effect on the brain

Source: Rockefeller University, Newswire
Date: 02/15/17
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Cocaine is one of the most addictive substances known to man, and for good reason: By acting on levels of the “feel-good” chemical dopamine, it produces a tremendous sensation of euphoria.

Now the laboratory of Rockefeller University Professor and Nobel Laureate Paul Greengard has shown for the first time in mice how a protein called WAVE1 regulates the brain’s response to cocaine. Their discovery, which was published recently in the journal Proceedings of the National Academy of Sciences, offers fundamental insights into the brain’s inner workings—and could lead to better interventions for treating addiction to cocaine and other drugs.

Cocaine and the brain

Researchers have long used cocaine as a model to study how certain messages are transmitted in the brain. And Greengard’s group, which investigates the molecular basis of communication between nerve cells in the brains of mammals, has studied WAVE1, a protein involved in cell signaling, for more than a decade. But their PNAS study reveals something new about the way in which WAVE1 and dopamine interact.

“We knew about the connection between WAVE1 and dopamine many years ago, but until now no one knew the mechanism of how cocaine stimulates WAVE1 and how WAVE1 regulates cocaine’s actions,” says Yong Kim, a Research Assistant Professor in Greengard’s lab and the senior author of the new study.

No WAVE1, no reward

In the new work, the team observed that WAVE1 became active in the brain of mice exposed to cocaine, and that this cocaine effect on WAVE1 could be prevented by blocking dopamine receptors. The research also provides new clues about how WAVE1 influences changes in the brain’s synapses— the junctions between nerves through which impulses pass—in response to cocaine exposure.

Specifically, the investigators looked at changes in an area of the brain called the nucleus accumbens, a key component of the neural reward system that is known to play a critical part in addiction—and in which dopamine is heavily involved. When these synapses form, they allow the signals from dopamine and another neurotransmitter called glutamate to be transmitted.

To investigate the interaction between WAVE1 and dopamine more specifically, the team looked at mice that had WAVE1 selectively removed in nerve cells. These nerve cells also contained one of the subtypes of dopamine receptor (called D1). They found a significant decrease in the preference for cocaine in these mice, compared with those producing normal WAVE1 levels.  This suggested that the dopamine signals were not being transmitted.

However, this effect was not seen when WAVE1 was removed from nerve cells containing a different dopamine receptor subtype (called D2). Those results suggest previously unknown details about how cocaine works.

Addiction intervention

“It’s well known that cocaine increases the signaling of dopamine in the brain,” Kim says. “Understanding more about the mechanism of cocaine action is providing new insight into the neurobiology of addiction. Our eventual goal is to use these findings to find a way to develop a drug to treat addiction.”

However, Kim says there are limitations to the current work, largely because the mice were injected with cocaine by the researchers. Future studies will need a system in which the mice can self-administer the cocaine by pushing a lever and injecting themselves, a model that more closely mimics human addiction behavior.