Posts tagged olfaction
Articles and news from the latest research reports.
Are Male Brains Wired to Ignore Food for Sex?
Choosing between two good things can be tough. When animals must decide between feeding and mating, it can get even trickier. In a discovery that might ring true even for some humans, researchers have shown that male brains – at least in nematodes – will suppress the ability to locate food in order to instead focus on finding a mate.
(Image caption: C. elegans male (top) and hermaphrodite (bottom))
The results, which appear today in the journal Current Biology, may point to how subtle changes in the brain’s circuitry dictate differences in behavior between males and females.
“While we know that human behavior is influenced by numerous factors, including cultural and social norms, these findings point to basic biological mechanisms that may not only help explain some differences in behavior between males and females, but why different sexes may be more susceptible to certain neurological disorders,” said Douglas Portman, Ph.D., an associate professor in the Department of Biomedical Genetics and Center for Neural Development and Disease at the University of Rochester and lead author of the study.
The findings were made in experiments involving C. elegans, a microscopic roundworm that has long been used by researchers to understand fundamental mechanisms in biology. Many of the discoveries made using C. elegans apply throughout the animal kingdom and this research has led to a broader understanding of human biology. In fact, three Nobel Prizes in medicine and chemistry have been awarded for discoveries involving C. elegans.
C. elegans is particularly useful in the study of the nervous system and scientists understand in great detail the development, function, and multiple connections of its entire neural network.
The study published today focuses on the activity of a single pair of neurons found in C. elegans – called AWA – that control smell. Smell, along with taste and touch, are critical sensory factors that dictate how C. elegans understands and navigates its environment, including finding food, avoiding danger, and locating a mate.
There are two sexes of C. elegans, males and hermaphrodites. Though the hermaphrodites are able to self-fertilize, they are also mating partners for males, and are considered to be modified females.
It has been previously observed that males and hermaphrodites act differently when exposed to food. If placed at a food source, the hermaphrodites tend to stay there. Males, however, will leave food source and “wander” – scientist believe they do this because they are in search of a mate.
The Rochester researchers discovered that the sensory mechanisms – called chemoreceptors – of the AWA neurons were regulated by the sexual identity of these cells, which, in turn, controls the expression of a receptor called ODR-10. These receptors bind to a chemical scent that is given off by food and other substances.
In hermaphrodites, more of the ODR-10 receptors are produced, making the worms more sensitive – and thereby attracted – to the presence of food. In males, fewer of these receptors are active, essentially suppressing their ability – and perhaps desire – to find food. However, when males were deprived of food, they produced dramatically higher levels of this receptor, allowing them to temporarily focus on finding food.
To confirm the role of these genetic differences between the sexes on behavior, the researchers designed a series of experiments in which they observed the activity of C. elegans when placed in a petri-dish and confronted with the option to either feed or go in search of a mate. The hermaphrodites were place in the center of the dish at a food source and, as expected, they stayed put.
The males were placed in their own individual food sources at the periphery of the dish. As a further obstacle between the males and their potential mates, an additional ring of food surrounded the hermaphrodites in the center of the dish. The males in the experiment consisted of two categories, one group with a normal genetic profile and another group that had been engineered by the researchers to overexpress the ODR-10 receptor, essentially making them more sensitive to the smell of food.
The researchers found that the normal worms left their food source and eventually made their way to the center of the dish where they mated with the hermaphrodites. The genetically engineered males were less successful at finding a mate, presumably because they were more interested in feeding. By examining the genetic profile of the resulting offspring, the scientists observed that the normal males out-produced the genetically engineered males by 10 to one.
In separate experiments, the researchers were also able to modify the behavior of the hermaphrodites by suppressing the ODR-10 receptors, causing them to act like males and abandon their food source.
“These findings show that by tuning the properties of a single cell, we can change behavior,” said Portman. “This adds to a growing body of evidence that sex-specific regulation of gene expression may play an important role in neural plasticity and, consequently, influence differences in behaviors – and in disease susceptibility – between the sexes.”
(Source: urmc.rochester.edu)
Decreased ability to identify odors can predict death
For older adults, being unable to identify scents is a strong predictor of death within five years, according to a study published October 1, 2014, in the journal PLOS ONE. Thirty-nine percent of study subjects who failed a simple smelling test died during that period, compared to 19 percent of those with moderate smell loss and just 10 percent of those with a healthy sense of smell.
The hazards of smell loss were “strikingly robust,” the researchers note, above and beyond most chronic diseases. Olfactory dysfunction was better at predicting mortality than a diagnosis of heart failure, cancer or lung disease. Only severe liver damage was a more powerful predictor of death. For those already at high risk, lacking a sense of smell more than doubled the probability of death.
"We think loss of the sense of smell is like the canary in the coal mine," said the study’s lead author Jayant M. Pinto, MD, an associate professor of surgery at the University of Chicago who specializes in the genetics and treatment of olfactory and sinus disease. "It doesn’t directly cause death, but it’s a harbinger, an early warning that something has gone badly wrong, that damage has been done. Our findings could provide a useful clinical test, a quick and inexpensive way to identify patients most at risk."
The study was part of the National Social Life, Health and Aging Project (NSHAP), the first in-home study of social relationships and health in a large, nationally representative sample of men and women ages 57 to 85.
In the first wave of NSHAP, conducted in 2005-06, professional survey teams from the independent research organization NORC at the University of Chicago used a well-validated test — adapted by Martha K. McClintock, PhD, the study’s senior author — for this field survey of 3,005 participants. It measured their ability to identify five distinct common odors.
The modified smell tests used “Sniffin’Sticks,” odor-dispensing devices that resemble a felt-tip pen but are loaded with aromas rather than ink. Subjects were asked to identify each smell, one at a time, from a set of four choices. The five odors, in order of increasing difficulty, were peppermint, fish, orange, rose and leather.
Measuring smell with this test, they learned that:
- Almost 78 percent of those tested were classified as “normosmic,” having normal smelling; 45.5 percent correctly identified five out of five odors and 29 percent identified four out of five.
- Almost 20 percent were considered “hyposmic.” They got two or three out of five correct.
- The remaining 3.5 percent were labelled “anosmic.” They could identify just one of the five scents (2.4%), or none (1.1%).
The interviewers also assessed participants’ age, physical and mental health, social and financial resources, education, and alcohol or substance abuse through structured interviews, testing and questionnaires. As expected, performance on the scent test declined steadily with age; 64 percent of 57-year-olds correctly identified all five smells. That fell to 25 percent of 85-year-olds.
In the second wave, during 2010-11, the survey team carefully confirmed which participants were still alive. During that five-year gap, 430 (12.5%) of the original 3005 study subjects had died; 2,565 were still alive.
When the researchers adjusted for demographic variables such as age, gender, socioeconomic status (as measured by education or assets), overall health, and race, those with greater smell loss when first tested were substantially more likely to have died five years later. Even mild smell loss was associated with greater risk.
"This evolutionarily ancient special sense may signal a key mechanism that affects human longevity," noted McClintock, the David Lee Shillinglaw Distinguished Service Professor of Psychology, who has studied olfactory and pheromonal communication throughout her career.
Age-related smell loss can have a substantial impact on lifestyle and wellbeing, according to Pinto, a member of the university’s otolaryngology-head and neck surgery team. “Smells impact how foods taste. Many people with smell deficits lose the joy of eating. They make poor food choices, get less nutrition. They can’t tell when foods have spoiled or detect odors that signal danger, like a gas leak or smoke. They may not notice lapses in personal hygiene.”
"Of all human senses," Pinto said, "smell is the most undervalued and underappreciated — until it’s gone."
Precisely how smell loss contributes to mortality is unclear. “Obviously, people don’t die just because their olfactory system is damaged,” McClintock said.
The research team, which includes biopsychologists, physicians, sociologists and statisticians, is considering several hypotheses. The olfactory nerve, the only cranial nerve directly exposed to the environment, may serve as a conduit, they suggest, exposing the central nervous system to pollution, airborne toxins, pathogens or particulate matter.
McClintock noted that the olfactory system also has stem cells which self-regenerate, so “a decrease in the ability to smell may signal a decrease in the body’s ability to rebuild key components that are declining with age and lead to all-cause mortality.”
(Source: uchospitals.edu)
NIH and Italian Scientists Develop Nasal Test for Human Prion Disease
A nasal brush test can rapidly and accurately diagnose Creutzfeldt-Jakob disease (CJD), an incurable and ultimately fatal neurodegenerative disorder, according to a study by National Institutes of Health scientists and their Italian colleagues.
Up to now, a definitive CJD diagnosis requires testing brain tissue obtained after death or by biopsy in living patients. The study describing the less invasive nasal test appears in the Aug. 7 issue of the New England Journal of Medicine.
CJD is a prion disease. These diseases originate when, for reasons not fully understood, normally harmless prion protein molecules become abnormal and gather in clusters. Prion diseases affect animals and people. Human prion diseases include variant, familial and sporadic CJD. The most common form, sporadic CJD, affects an estimated 1 in one million people annually worldwide. Other prion diseases include scrapie in sheep; chronic wasting disease in deer, elk and moose; and bovine spongiform encephalopathy (BSE), or mad cow disease, in cattle. Scientists have associated the accumulation of these clusters with tissue damage that leaves sponge-like holes in the brain.
“This exciting advance, the culmination of decades of studies on prion diseases, markedly improves on available diagnostic tests for CJD that are less reliable, more difficult for patients to tolerate, and require more time to obtain results,” said Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), a component of NIH. “With additional validation, this test has potential for use in clinical and agricultural settings.”
An easy-to-use diagnostic test would let doctors clearly differentiate prion diseases from other brain diseases, according to Byron Caughey, Ph.D., the lead NIAID scientist involved in the study. Although specific CJD treatments are not available, prospects for their development and effectiveness could be enhanced by early and accurate diagnoses. Further, a test that identifies people with various forms of prion diseases could help to prevent the spread of prion diseases among and between species. For instance, it is known that human prion diseases can be transmitted via medical procedures such as blood transfusions, transplants and the contamination of surgical instruments. People also have contracted variant CJD after exposure to BSE-infected cattle.
The NIAID study involved 31 nasal samples from patients with CJD and 43 nasal samples from patients who had other neurologic diseases or no neurologic disease at all. These samples were collected primarily by Gianluigi Zanusso, M.D., Ph.D., and colleagues at the University of Verona in Italy, who developed the technique of brushing the inside of the nose to collect olfactory neurons connected to the brain. Testing in Dr. Caughey’s lab in Montana then correctly identified 30 of the 31 CJD patients (97 percent sensitivity) and correctly showed negative results for all 43 of the non-CJD patients (100 percent specificity). By comparison, tests using cerebral spinal fluid—currently used to detect sporadic CJD—were 77 percent sensitive and 100 percent specific, and the results took twice as long to obtain.
Jason Wilham, Ph.D., Christina Orrú, Ph.D., Dr. Caughey, and other members of his research group had previously developed the cerebral spinal fluid test method with Ryuichiro Atarashi, M.D., Ph.D., a former NIAID postdoctoral fellow who is now at Nagasaki University in Japan.
While continuing to validate the test method in CJD patients, Dr. Caughey’s group is looking to expand the study to diagnose forms of prion diseases in sheep, cattle and wildlife. The team continues to collaborate with Dr. Zanusso’s group, which is looking to replace the nasal brush with an even simpler swabbing approach.
For many animals, making sense of the clutter of sensory stimuli is often a matter or literal life or death.
Exactly how animals separate objects of interest, such as food sources or the scent of predators, from background information, however, remains largely unknown. Even the extent to which animals can make such distinctions, and how differences between scents might affect the process were largely a mystery – until now.
A new study, described in an August 3 paper in Nature Neuroscience, a team of researchers led by Venkatesh Murthy, Professor of Molecular and Cellular Biology, showed that while mice can be trained to detect specific odorants embedded in random mixtures, their performance drops steadily with increasing background components. The team included Dan Rokni, Vikrant Kapoor and Vivian Hemmelder, all from Harvard University.
"There is a continuous stream of information constantly arriving at our senses, coming from many different sources," Murthy said. "The classic example would be a cocktail party – though it may be noisy, and there may be many people talking, we are able to focus our attention on one person, while ignoring the background noise.
"Is the same also true for smells?" he continued. "We are bombarded with many smells all jumbled up. Can we pick out one smell "object" – the smell of jasmine, for example, amidst a riot of other smells? Our experience tells us indeed we can, but how do we pick out the ones that we need to pay attention to, and what are the limitations?"
To find answers to those, and other, questions, Murthy and colleagues turned to mice.
After training mice to detect specific scents, researchers presented the animals with a combination of smells – sometimes including the “target” scent, sometimes not. Though previous studies had suggested animals are poor at individual smells, and instead perceived the mixture as a single smell, their findings showed that mice were able to identify when a target scent was present with 85 percent accuracy or better.
"Although the mice do well overall, they perform progressively poorer when the number of background odors increases," Murthy explained.
Understanding why, however, meant first overcoming a problem particular to olfaction.
While the relationship between visual stimuli is relatively easy to understand – differences in color can be easily described as differences in the wavelength of light – no such system exists to describe how two odors relate to each other. Instead, the researchers sought to describe scents according to how they activated neurons in the brain.
Using fluorescent proteins, they created images that show how each of 14 different odors stimulated neurons in the olfactory bulb. What they found, Murthy said, was that the ability of mice to identify a particular smell was markedly diminished if background smells activated the same neurons as the target odor.
"Each odor gives rise to a particular spatial pattern of neural responses," Murthy said. "When the spatial pattern of the background odors overlapped with the target odor, the mice did much more poorly at detecting the target. Therefore, the difficulty of picking out a particular smell among a jumble of other odors, depends on how much the background interferes with your target smell. So, we were able to give a neural explanation for how well you can solve the cocktail party problem.
"This study is interesting because it first shows that smells are not always perceived as one whole object – they can be broken down into their pieces," he added. "This is perhaps not a surprise – there are in fact coffee or wine specialists that can detect faint whiffs of particular elements within the complex mixture of flavors in each coffee or wine. But by doing these studies in mice, we can now get a better understanding of how the brain does this. One can also imagine that understanding how this is done may also allow us to build artificial olfactory systems that can detect specific chemicals in the air that are buried amidst a plethora of other odors."
Learning the smell of fear: Mothers teach babies their own fears via odor
Babies can learn what to fear in the first days of life just by smelling the odor of their distressed mothers, new research suggests. And not just “natural” fears: If a mother experienced something before pregnancy that made her fear something specific, her baby will quickly learn to fear it too — through the odor she gives off when she feels fear.
In the first direct observation of this kind of fear transmission, a team of University of Michigan Medical School and New York University studied mother rats who had learned to fear the smell of peppermint – and showed how they “taught” this fear to their babies in their first days of life through their alarm odor released during distress.
In a new paper in the Proceedings of the National Academy of Sciences, the team reports how they pinpointed the specific area of the brain where this fear transmission takes root in the earliest days of life.
Their findings in animals may help explain a phenomenon that has puzzled mental health experts for generations: how a mother’s traumatic experience can affect her children in profound ways, even when it happened long before they were born.
The researchers also hope their work will lead to better understanding of why not all children of traumatized mothers, or of mothers with major phobias, other anxiety disorders or major depression, experience the same effects.
“During the early days of an infant rat’s life, they are immune to learning information about environmental dangers. But if their mother is the source of threat information, we have shown they can learn from her and produce lasting memories,” says Jacek Debiec, M.D., Ph.D., the U-M psychiatrist and neuroscientist who led the research.
“Our research demonstrates that infants can learn from maternal expression of fear, very early in life,” he adds. “Before they can even make their own experiences, they basically acquire their mothers’ experiences. Most importantly, these maternally-transmitted memories are long-lived, whereas other types of infant learning, if not repeated, rapidly perish.”
Peering inside the fearful brain
Debiec, who treats children and mothers with anxiety and other conditions in the U-M Department of Psychiatry, notes that the research on rats allows scientists to see what’s going on inside the brain during fear transmission, in ways they could never do in humans.
He began the research during his fellowship at NYU with Regina Marie Sullivan, Ph.D., senior author of the new paper, and continues it in his new lab at U-M’s Molecular and Behavioral Neuroscience Institute.
The researchers taught female rats to fear the smell of peppermint by exposing them to mild, unpleasant electric shocks while they smelled the scent, before they were pregnant. Then after they gave birth, the team exposed the mothers to just the minty smell, without the shocks, to provoke the fear response. They also used a comparison group of female rats that didn’t fear peppermint.
They exposed the pups of both groups of mothers to the peppermint smell, under many different conditions with and without their mothers present.
Using special brain imaging, and studies of genetic activity in individual brain cells and cortisol in the blood, they zeroed in on a brain structure called the lateral amygdala as the key location for learning fears. During later life, this area is key to detecting and planning response to threats – so it makes sense that it would also be the hub for learning new fears.
But the fact that these fears could be learned in a way that lasted, during a time when the baby rat’s ability to learn any fears directly was naturally suppressed, is what makes the new findings so interesting, says Debiec.
The team even showed that the newborns could learn their mothers’ fears even when the mothers weren’t present. Just the piped-in scent of their mother reacting to the peppermint odor she feared was enough to make them fear the same thing.
Even when just the odor of the frightened mother was piped in to a chamber where baby rats were exposed to peppermint smell, the babies developed a fear of the same smell, and their blood cortisol levels rose when they smelled it.
And when the researchers gave the baby rats a substance that blocked activity in the amygdala, they failed to learn the fear of peppermint smell from their mothers. This suggests, Debiec says, that there may be ways to intervene to prevent children from learning irrational or harmful fear responses from their mothers, or reduce their impact.
From animals to humans: next steps
The new research builds on what scientists have learned over time about the fear circuitry in the brain, and what can go wrong with it. That work has helped psychiatrists develop new treatments for human patients with phobias and other anxiety disorders – for instance, exposure therapy that helps them overcome fears by gradually confronting the thing or experience that causes their fear.
In much the same way, Debiec hopes that exploring the roots of fear in infancy, and how maternal trauma can affect subsequent generations, could help human patients. While it’s too soon to know if the same odor-based effect happens between human mothers and babies, the role of a mother’s scent in calming human babies has been shown.
Debiec, who hails from Poland, recalls working with the grown children of Holocaust survivors, who experienced nightmares, avoidance instincts and even flashbacks related to traumatic experiences they never had themselves. While they would have learned about the Holocaust from their parents, this deeply ingrained fear suggests something more at work, he says.
(Source: uofmhealth.org)
The human body produces chemical cues that communicate gender to members of the opposite sex, according to researchers who report their findings in the Cell Press journal Current Biology on May 1. Whiffs of the active steroid ingredients (androstadienone in males and estratetraenol in females) influence our perceptions of movement as being either more masculine or more feminine. The effect, which occurs completely without awareness, depends on both our biological sex and our sexual orientations.
"Our findings argue for the existence of human sex pheromones," says Wen Zhou of the Chinese Academy of Sciences. "They show that the nose can sniff out gender from body secretions even when we don’t think we smell anything on the conscious level."
Earlier studies showed that androstadienone, found in male semen and armpits, can promote positive mood in females as opposed to males. Estratetraenol, first identified in female urine, has similar effects on males. But it wasn’t clear whether those chemicals were truly acting as sexual cues.
In the new study, Zhou and her colleagues asked males and females, both heterosexual and homosexual, to watch what are known as point-light walkers (PLWs) move in place on a screen. PLWs consist of 15 dots representing the 12 major joints in the human body, plus the pelvis, thorax, and head. The task was to decide whether those digitally morphed gaits were more masculine or feminine.
Individuals completed that task over a series of days while being exposed to androstadienone, estratetraenol, or a control solution, all of which smelled like cloves. The results revealed that smelling androstadienone systematically biased heterosexual females, but not males, toward perceiving walkers as more masculine. By contrast, the researchers report, smelling estratetraenol systematically biased heterosexual males, but not females, toward perceiving walkers as more feminine.
Interestingly, the researchers found that homosexual males responded to gender pheromones more like heterosexual females did. Bisexual or homosexual female responses to the same scents fell somewhere in between those of heterosexual males and females.
"When the visual gender cues were extremely ambiguous, smelling androstadienone versus estratetraenol produced about an eight percent change in gender perception," Zhou says, a statistically very significant effect.
"The results provide the first direct evidence that the two human steroids communicate opposite gender information that is differentially effective to the two sex groups based on their sexual orientation," the researchers write. "Moreover, they demonstrate that human visual gender perception draws on subconscious chemosensory biological cues, an effect that has been hitherto unsuspected."
Sniff study suggests humans can distinguish more than 1 trillion scents
The human sense of smell does not get the respect it deserves, new research suggests. In an experiment led by Andreas Keller, of Rockefeller’s Laboratory of Neurogenetics and Behavior, researchers tested volunteers’ ability to distinguish between complex mixtures of scents. Based on the sensitivity of these people’s noses and brains, the team calculated the human sense of smell can detect more than 1 trillion odor mixtures, far more discrete stimuli than previous smell studies have estimated.
The existing generally accepted number is just 10,000, says Leslie Vosshall, Robert Chemers Neustein Professor and head of the laboratory. “Everyone in the field had the general sense that this number was ludicrously small, but Andreas was the first to put the number to a real scientific test,” Vosshall says.
In fact, even 1 trillion may be understating it, says Keller. “The message here is that we have more sensitivity in our sense of smell than for which we give ourselves credit. We just don’t pay attention to it and don’t use it in everyday life,” he says.
The quality of an odor has multiple dimensions, because the odors we encounter in real life are composed of complex mixes of molecules. For instance, the characteristic scent of rose has 275 components, but only a small percentage of those dominate the perceived smell. That makes odor much more difficult to study than vision and hearing, which require us to detect variations in a single dimension. For comparison, researchers estimate the number of colors we can distinguish at between 2.3 and 7.5 million and audible tones at about 340,000.
To overcome this complexity, Keller combined odors and asked volunteers whether they could distinguish between mixtures with some components in common. “Our trick is we use mixtures of odor molecules, and we use the percentage of overlap between two mixtures to measure the sensitivity of a person’s sense of smell,” Keller says. To create his mixtures, Keller drew upon 128 odor molecules responsible for scents such as orange, anise and spearmint. He mixed these in combinations of 10, 20 and 30 with different proportions of components in common. The volunteers received three vials, two of which contained identical mixes, and they were asked to pick out the odd one.
This approach was inspired by previous work at the Weizmann Institute in Israel, in which researchers combined odors at similar intensities to create neutral smelling “olfactory white.” In that experiment and in Keller’s study, the researchers were interested in the perception of odor qualities, such as fishy, floral or musky — not their intensity. But since intensity can interfere with the perceived qualities, both had to account for it.
The results, published this week in Science, show that while individual volunteers’ performance varied greatly, on average they could tell the difference between mixtures containing as much as 51 percent of the same components. Once the mixes shared more than half of their components, fewer volunteers could tell the difference between them. This was true for mixes of 10, 20 and 30 odors.
By analyzing the data, the researchers could calculate the total number of distinguishable mixtures.
“It turns out that the resolution of the olfactory system is not extraordinary – you need to change a fair fraction of the components before the change can be reliably detected by more than 50 percent of the subjects,” says collaborator Marcelo O. Magnasco, head of the Laboratory of Mathematical Physics at Rockefeller. “However, because the number of combinations is quite literally astronomical, even after accounting for this limitation the total number of distinguishable odor combinations is quite large.” The 1 trillion estimate is almost certainly too low, the researchers say, because there are many, many more odor molecules in the real world that can be mixed in many more ways.
Keller theorizes that our ancestors had much more use and appreciation for our sense of smell than we do. Humans’ upright posture lifted our noses far from the ground where most smells originate, and more recently, conveniences such as refrigerators and daily showers, have effectively limited odors in the modern world. “This could explain our attitude that smell is unimportant, compared to hearing and vision,” he says.
Nevertheless, the sense of smell remains closely linked to human behavior, and studying it can tell us a lot about how our brains process complex information. The results of this study are a step toward an elusive quantitative science of odor perception that can help drive further research, Keller says.
Rats’ brains may “remember” odor experienced while under general anesthesia
Rats’ brains may remember odors they were exposed to while deeply anesthetized, suggests research in rats published in the April issue of Anesthesiology.
Previous research has led to the belief that sensory information is received by the brain under general anesthesia but not perceived by it. These new findings suggest the brain not only receives sensory information, but also registers the information at the cellular level while anesthetized without behavioral reporting of the same information after recovering from anesthesia.
In the study, rats were exposed to a specific odor while under general anesthesia. Examination of the brain tissue after they had recovered from anesthesia revealed evidence of cellular imprinting, even though the rats behaved as if they had never encountered the odor before.
“It raises the question of whether our brains are being imprinted during anesthesia in ways we don’t recognize because we simply don’t remember,” said Yan Xu, Ph.D., lead author and vice chairman for basic sciences in the Department of Anesthesiology at the University of Pittsburgh School of Medicine. “The fact that an anesthetized brain can receive sensory information – and distinguish whether that information is novel or familiar during and after anesthesia, even if one does not remember receiving it – suggests a need to re-evaluate how the depth of anesthesia should be measured clinically.”
Researchers randomly assigned 107 rats to 12 different anesthesia and odor exposure paradigms: some were exposed to the same odor during and after anesthesia, some to air before and an odor after, some to familiar odors, others to novel odors, and still others were not exposed to odors at all. After the rats had recovered from the anesthesia, researchers observed their behavior of looking for hidden odors or interacting with scented beads to determine their memory of the smell. Researchers then analyzed the rats’ brains at a cellular level. While the rats had no memory of being exposed to the odor under anesthesia, changes in the brain tissue on a cellular level suggested the rats “remembered” the exposure to the odor under anesthesia and no longer registered the odor as novel.
“This study reveals important new information about how anesthesia affects our brains,” said Dr. Xu. “The results highlight a need for additional research into the effects of general anesthesia on learning and memory.”
Odor receptors discovered in lungs
Your nose is not the only organ in your body that can sense cigarette smoke wafting through the air. Scientists at Washington University in St. Louis and the University of Iowa have shown that your lungs have odor receptors as well.
Unlike the receptors in your nose, which are located in the membranes of nerve cells, the ones in your lungs are in the membranes of neuroendocrine cells. Instead of sending nerve impulses to your brain that allow it to “perceive” the acrid smell of a burning cigarette somewhere in the vicinity, they trigger the flask-shaped neuroendocrine cells to dump hormones that make your airways constrict.
The newly discovered class of cells expressing olfactory receptors in human airways, called pulmonary neuroendocrine cells, or PNECs, were found by a team led by Yehuda Ben-Shahar, PhD, assistant professor of biology, in Arts & Sciences, and of medicine at Washington University in St. Louis, and including colleagues Steven L. Brody, MD, and Michael J. Holtzman, MD, of the Washington University School of Medicine, and Michel J. Welsh, MD, of the University of Iowa Carver College of Medicine.
“We forget,” said Ben-Shahar, “that our body plan is a tube within a tube, so our lungs and our gut are open to the external environment. Although they’re inside us, they’re actually part of our external layer. So they constantly suffer environmental insults,” he said, “and it makes sense that we evolved mechanisms to protect ourselves.”
In other words, the PNECs, described in the March issue of the American Journal of Respiratory Cell and Molecular Biology, are sentinels, guards whose job it is to exclude irritating or toxic chemicals.
The cells might be responsible for the chemical hypersensitivity that characterizes respiratory diseases, such as chronic obstructive pulmonary disease (COPD) and asthma. Patients with these diseases are told to avoid traffic fumes, pungent odors, perfumes and similar irritants, which can trigger airway constriction and breathing difficulties.
The odor receptors on the cells might be a therapeutic target, Ben-Shahar suggests. By blocking them, it might be possible to prevent some attacks, allowing people to cut down on the use of steroids or bronchodilators.
Every breath you take
When a mammal inhales, volatile chemicals flow over two patches of specialized epithelial tissue high up in the nasal passages. These patches are rich in nerve cells with specialized odorant-binding molecules embedded in their membranes.
If a chemical docks on one of these receptors, the neuron fires, sending impulses along the olfactory nerve to the olfactory bulb in the brain, where the signal is integrated with those from hundreds of other similar cells to conjure the scent of old leather or dried lavender.
Aware that airway diseases are characterized by hypersensitivity to volatile stimuli, Ben-Shahar and his colleagues realized that the lungs, like the nose, must have some means of detecting inhaled chemicals.
Earlier, a team at the University of Iowa, where Ben-Shahar was a postdoctoral research associate, had searched for genes expressed by patches of tissue from lung transplant donors. They found a group of ciliated cells that express bitter taste receptors. When offending substances were detected, the cilia beat more strongly to sweep them out of the airway. This result was featured on the cover of the Aug. 28, 2009, issue of Science.
But since people are sensitive to many inhaled substances, not just bitter ones, Ben-Shahar decided to look again. This time he found that these tissues also express odor receptors, not on ciliated cells but instead on neuroendocrine cells, flask-shaped cells that dump serotonin and various neuropeptides when they are stimulated.
This made sense. “When people with airway disease have pathological responses to odors, they’re usually pretty fast and violent,” said Ben-Shahar. “Patients suddenly shut down and can’t breathe, and these cells may explain why.”
Ben-Shahar stresses the differences between chemosensation in the nose and in the lung. The cells in the nose are neurons, he points out, each with a narrowly tuned receptor, and their signals must be woven together in the brain to interpret our odor environment.
The cells in the airways are secretory, not neuronal, cells, and they may carry more than one receptor, so they are broadly tuned. Instead of sending nerve impulses to the brain, they flood local nerves and muscles with serotonin and neuropeptides. “They are possibly designed,” he said, “to elicit a rapid, physiological response if you inhale something that is bad for you.”
The different mechanisms explain why cognition plays a much stronger role in taste and smell than in coughing in response to an irritant. It is possible, for example, to develop a taste for beer. But nobody learns not to cough; the response is rapid and largely automatic.
The scientists suspect these pulmonary neuroscretory cells contribute to the hypersensitivity of patients with COPD to airborne irritants. COPD is a group of diseases, including emphysema, that is characterized by coughing, wheezing, shortness of breath and chest tightness.
When the scientists looked at the airway tissues from patients with COPD, they discovered that they had more of these neurosecretory cells than airway tissues from healthy donors.
Of mice and men
As a geneticist, Ben-Shahar would like to go farther, knocking out genes to make sure that the derangement of neurosecretory cells isn’t just correlated with airway diseases but instead suffices to produce it.
But there is a problem. “For example, a liver from a mouse and a liver from a human are pretty similar, they express the same types of cells. But the lungs from different mammalian species are often very different; you can see it at a glance,” Ben-Shahar said.
“Clearly, primates have evolved distinct cell lineages and signaling systems for respiratory-specific functions.”
This makes it challenging to unravel the biomolecular mechanisms of respiratory diseases.
Still, he is hopeful that the PNEC pathways will provide targets for drugs that would better control asthma, COPD and other respiratory diseases. They would be welcome. There has been a steep rise in these diseases in the past few decades, treatment options have been limited, and there are no cures.
A difference at the smallest level of DNA — one amino acid on one gene — can determine whether you find a given smell pleasant. A different amino acid on the same gene in your friend’s body could mean he finds the same odor offensive, according to researchers at Duke University.
There are about 400 genes coding for the receptors in our noses, and according to the 1000 Genomes Project, there are more than 900,000 variations of those genes. These receptors control the sensors that determine how we smell odors. A given odor will activate a suite of receptors in the nose, creating a specific signal for the brain.
But the receptors don’t work the same for all of us, said Hiroaki Matsunami, Ph.D., associate professor of molecular genetics and microbiology at the Duke University School of Medicine. In fact, when comparing the receptors in any two people, they should be about 30 percent different, said Matsunami, who is also a member of the Neurobiology Graduate Program and the Duke Institute for Brain Sciences.
"There are many cases when you say you like the way something smells and other people don’t. That’s very common," Matsunami said. But what the researchers found is that no two people smell things the same way. "We found that individuals can be very different at the receptor levels, meaning that when we smell something, the receptors that are activated can be very different (from one person to the next) depending on your genome."
The study didn’t look at the promoter regions of the genes, which are highly variable, or gene copy number variation, which is very high in odor receptors, so the 30 percent figure for the difference between individuals is probably conservative, Matsunami said.
While researchers had earlier identified the genes that encode for odor receptors, it has been a mystery how the receptors are activated, Matsunami said. To determine what turns the receptors on, his team cloned more than 500 receptors each from 20 people that had slight variations of only one or two amino acids and systematically exposed them to odor molecules that might excite the receptors.
By exposing each receptor to a very small concentration — 1, 10, or 100 micromoles — of 73 odorants, such as vanillin or guaiacol, the group was able to identify 27 receptors that had a significant response to at least one odorant. This finding, published in the December issue of Nature Neuroscience, doubles the number of known odorant-activated receptors, bringing the number to 40.
Matsunami said this research could have a big impact for the flavors, fragrance, and food industries.
"These manufacturers all want to know a rational way to produce new chemicals of interest, whether it’s a new perfume or new-flavored ingredient, and right now there’s no scientific basis for doing that," he said. "To do that, we need to know which receptors are being activated by certain chemicals and the consequences of those activations in terms of how we feel and smell."