Novel study identifies an area of the mosquito brain that mixes taste and smell
A new study by Johns Hopkins researchers suggests that a specialized area of the mosquito brain mixes tastes with smells to create unique and preferred flavors. The findings advance the possibility, they say, of identifying a substance that makes “human flavor” repulsive to the malaria-bearing species of the mosquitoes, so instead of feasting on us, they keep the disease to themselves, potentially saving an estimated 450,000 lives a year worldwide.
A report on the research appeared online on Oct. 3 in the journal Nature Communications. Malaria is an infectious parasite disease of humans and animals transmitted by the bite of the female Anopheles gambiaemosquito. In 2015, experts estimate it affected 214 million people, mostly in Africa, despite decades of mosquito eradication and control efforts. There is no malaria vaccine, and although the disease is curable in early stages, treatment is costly and difficult to deliver in places where it is endemic.
“All mosquitoes, including the one that transmits malaria, use their sense of smell to find a host for a blood meal. Our goal is to let the mosquitoes tell us what smells they find repulsive and use those to keep them from biting us,” says Christopher Potter, Ph.D., assistant professor of neuroscience at the Johns Hopkins University School of Medicine.
Because smell is essential to mosquito survival, each mosquito has three pairs of “noses” for sensing odors: two antennae, two maxillary palps and two labella. The maxillary palps are thick, fuzzy appendages that protrude from the lower region of the mosquito’s head, more or less parallel to its proboscis, the long, flexible sheath that keeps its “feeding needle” under wraps until needed. At the very tip of the proboscis are the labella, two small regions that contain both “gustatory” neurons that pick up tastes and olfactory neurons for recognizing odorants.
To better understand how An. gambiae mosquitoes that cause malaria receive and process olfactory information from so many sensory regions, Potter’s team wanted to see where olfactory neurons from those regions go to in the brain.
They used a powerful genetic technique — never before accomplished in mosquitoes, according to Potter — to make certain neurons “glow” green. The green glowing label was designed to appear specifically in neurons that receive complex odors through proteins called odorant receptors (ORs), since OR neurons are known to help distinguish humans from other warm-blooded animals in Aedes aegypti mosquitoes, which carry the Zika virus.
“This is the first time researchers managed to specifically target sensory neurons in mosquitoes. Previously, we had to use flies as a proxy for all insects, but now we can directly study the sense of smell in the insects that spread malaria,” says Olena Riabinina, Ph.D., the lead author of the study and a postdoctoral fellow now at the Imperial College London. “We were pleasantly surprised by how well our genetic technique worked and how easy it is now to see the smell-detecting neurons. The ease of identification will definitely simplify our task of studying these neurons in the future.”
As expected, Potter says, the OR neurons from the antennae and maxillary palps went to symmetrical areas of the brain called antennal lobes, just as they do in flies. But Potter was quite surprised when he saw that the OR neurons from the labella went to the so-called subesophageal zone, which, he says, had never before been associated with the sense of smell in any fly or insect; it had only been associated with the sense of taste.
“That finding suggests that perhaps mosquitoes don’t just like our smell, but also our flavor,” says Potter. “It’s likely that the odorants coming off our skin are picked up by the labella and influence the preferred taste of our skin, especially when the mosquito is looking for a place to bite.”
Potter says the finding potentially offers researchers one more way to repel mosquitoes. The antennae and maxillary palps are more specialized for picking up long-range signals, while the labella come into direct contact with our skin. In fact, Potter says, before injecting their needlelike proboscis, mosquitoes use the labella to probe about on a victim’s skin. “We don’t really know why they do that, but we suspect that they’re looking for sensory cues that hint at easy access to a blood vessel,” he says. “This suggests that a combination of repellants could keep mosquitoes from biting us in two ways. One could target the antennal neurons and reduce the likelihood that they come too close, while another could target the labellar neurons and make the mosquitoes turn away in disgust — before sucking our blood — if they got close enough to land on us.”
The two-part genetic system Potter devised to generate the glowing neurons will make it much easier for his and other laboratories to mix and match genetically altered mosquitoes to generate new traits, he says. His group has already created a strain of An. gambiaemosquitoes whose OR neurons glow green upon activation. Scientists can thus see which neurons light up in response to a specific smell.
“Using this method, we hope to find an odorant that is safe and pleasant-smelling for us but strongly repellant to mosquitoes at very low concentrations,” says Potter.
His group was also able to compare the brains of male and female mosquitoes. Since only females use their sense of smell to find humans and males feed only on nectar, it was previously thought that males had just a rudimentary sense of smell. The Potter group found instead that males have the same level of complexity in their brains to detect odors as females but have fewer olfactory neurons. “It appears that males might just have a scaled-down version of a female’s sense of smell. So they can still smell everything a female smells, just not as well,” Potter says.
His group plans to study other types of neurons to better understand how signals from the mosquitoes’ three types of olfactory receptors interact to influence their behavior. For example, why is lactic acid not attractive on its own but highly attractive when mixed with carbon dioxide?
“We’d like to figure out what regions and neurons in the brain lead to this combined effect,” says Potter. “If we can identify them, perhaps we could also stop them from working.”
Mini midbrains provide next generation platforms to investigate human brain biology, diseases and therapeutics
Scientists in Singapore have made a big leap on research on the ‘mini-brain’. These advanced mini versions of the human midbrain will help researchers develop treatments and conduct other studies into Parkinson’s Disease (PD) and ageing-related brain diseases.
These mini midbrain versions are three-dimensional miniature tissues that are grown in the laboratory and they have certain properties of specific parts of the human brains. This is the first time that the black pigment neuromelanin has been detected in an organoid model. The study also revealed functionally active dopaminergic neurons.
The human midbrain, which is the information superhighway, controls auditory, eye movements, vision and body movements. It contains special dopaminergic neurons that produce dopamine – which carries out significant roles in executive functions, motor control, motivation, reinforcement, and reward. High levels of dopamine elevate motor activity and impulsive behaviour, whereas low levels of dopamine lead to slowed reactions and disorders like PD, which is characterised by stiffness and difficulties in initiating movements.
The Johns Hopkins University School of Medicine (JHUSOM), located in Baltimore, Maryland, U.S., is the academic medical teaching and research arm of Johns Hopkins University.
Johns Hopkins has consistently been among the nation’s top medical schools in the number of research grants awarded by the National Institutes of Health. Its major teaching hospital, the Johns Hopkins Hospital, was ranked the best hospital in the United States every year between 1991 and 2011 and again in 2013 by U.S. News and World Report.
According to the Flexner Report, Hopkins has served as the model for American medical education. It was the first medical school to require its students to have an undergraduate degree and was also the first graduate-level medical school to admit women on an equal basis as men. Mary Elizabeth Garrett, head of the Women’s Medical School Fund, was a driving force behind both of these firsts. School founder Sir William Osler became the first Professor of Medicine at Johns Hopkins and the Physician-in-Chief at Johns Hopkins Hospital. Osler was responsible for establishing the residency system of postgraduate medical training, where young physicians were required to “reside” within the hospital to better care for their patients.
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When it comes to early diagnosis of Lyme disease, the insidious tick-borne illness that afflicts about 300,000 Americans annually, finding the proverbial needle in the haystack might be a far easier challenge—until now, perhaps. An experimental method developed by federal and university researchers appears capable of detecting the stealthy culprit Lyme bacteria at the earliest time of infection, when currently available tests are often still negative.
The team suggests the approach might also be useful for early detection of other elusive bacterial infections. The collaborators—from the National Institute of Standards and Technology (NIST), Institute for Bioscience and Biotechnology Research, and Johns Hopkins School of Medicine—recently reported the successful first trial of their new method.
“Our hypothesis was that Lyme bacteria shed vesicle-like particles—or fragments—derived from the cell wall of the bacteria circulating in the serum of individuals. These particles would contain membrane proteins that can be detected to provide a unique indicator of infection,” explains NIST research chemist Larik Turko.
The challenge was to detect these bacterial membrane proteins among the far, far more plentiful proteins normally present in serum, the watery, cell-free component of blood. The researchers speculated that running serum samples through a high-speed centrifuge—a standard step in chemistry labs—might selectively concentrate the larger, heavier fragments containing the bacterial membrane proteins into pellets. In effect, they predicted, this step would separate the wheat—the sparse target proteins—from the chaff—the much more abundant human serum proteins.
The new method’s promise was demonstrated in tests on serum samples drawn from three patients with undetected Lyme disease at the time of their initial doctor visit. By customizing standard analytical techniques for determining the types and amounts of chemicals in a sample, the team detected extremely small amounts of the target protein in all three samples.
For chemistry buffs, the protein in enriched samples was present at a level of about four billionths of a millionth of a mole, the standard unit for amount of substance.
In one patient, the experimental method detected the bacteria three weeks before infection was confirmed with the standard blood tests now used. For the other two, infection was detected simultaneously by the two methods.
“The complexity of Lyme disease, combined with lack of biomarkers to measure infection, has slowed progress,” study collaborator John Aucott, head of the Johns Hopkins Lyme Disease Clinical Research Center, said in advance of a session on precision and personalized medicine this weekend at the AAAS 2016 Annual Meeting in Washington, D.C. “Now, thanks to recent advances in technology, the tiniest concentration of blood molecules can now be detected, molecules that were previously ‘invisible’ to scientists.”
The current standard blood test for Lyme disease exposes the infection only after antibodies have accumulated to detectable levels, which can take up to 4 to 6 weeks. If patients exhibit a telltale bull’s-eye rash, diagnosis and treatment can begin earlier. But the rash does not occur in 20 to 30 percent of Lyme disease patients, according to the Centers for Disease Control and Prevention.
Rather than waiting for an infected person’s immune system to produce noticeable amounts of antibodies, the team chose to home in on the bacteria itself—specifically, proteins the bug sheds when attacked by the body’s defenses.
“From many candidates, we chose one that is both easily distinguished from human serum proteins and an unambiguous indicator of the bacteria,” Turko says. “This protein, which resides on the outer surface of membranes, became the target of our search in serum samples.”
But finding that target required an important preliminary step to ensure the accuracy of their measurements: making a reference sample that contained ample amounts of the target protein. With the reference sample, the team established the unmistakable signature the bug’s outer-surface membrane protein would yield when they examined samples drawn from patients. As a result of these steps, the team could detect the copies of the target protein, even though human proteins were 10 million times more plentiful.
“We believe that this approach may be universally applicable to detection of other bacterial infections in humans,” the researchers write.