No Two People Smell the Same

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."

Brain structure shows affinity with numbers

The structure of the brain shows the way in which we process numbers. People either do this spatially or non-spatially. A study by Florian Krause from the Donders Institute in Nijmegen shows for the first time that these individual differences have a structural basis in the brain. The Journal of Cognitive Neuroscience published the results in an early access version of the article.

People who process numbers spatially do this using an imaginary horizontal line along which the numbers are arranged from low to high, left to right. A non-spatial representation is also possible, by comparing numbers to other magnitudes such as force or luminosity.

Different grey matter volumes

Florian Krause identified this predisposition to spatial or non-spatial number processing in MRI scans of test subjects. He discovered differences in grey matter volume, which contains the cell bodies of nerve cells, in two specific locations. Spatially oriented brains have an above-average grey matter volume in the right precuneus, a small area of the brain associated with processing visual-spatial information. Non-spatially oriented brains have more grey matter in the left angular gyrus, an area associated with semantic and conceptual processing.

Spatial numbers

For a long time, scientists thought that everyone processed numbers predominantly in a spatial way. Krause demonstrates that this is not the case. In his own words: ‘Our current study stresses the importance of non-spatial number representations. This is important since researchers in the field tend to focus mainly on spatial representations. Personally, I think that numbers are understood in terms of our body experiences. We use information about size in real life to understand number size in our heads.’

Classifying numbers

The thirty people taking part in the study were put into an MRI scanner and were shown numbers between 1 and 9 (except 5). In two consecutive judgement tasks, they had to classify the presented digits as odd or even. Both tasks differed only in the required response: in the spatial task subjects had to click with their index finger or middle finger to classify the digits, and in the non-spatial task they applied either a small or a large force on a pressure sensor with their thumb. Both tests were carried out using the right hand. Importantly, participants coupled the spatial response as well as the force response to the size of the presented number, as they responded faster with a left or soft press for small numbers and with a right or hard press for large numbers. Krause worked out those couplings for each subject, and compared the scores with the information from their brain scan.

Potential benefits for teaching maths

At present, maths is largely taught on the basis of a spatial number processing. ‘People with a non-spatial representation of numbers would probably benefit from a different approach to maths teaching’, says Krause. ‘It is possible to let pupils experience the size of numbers in a non-spatial way. This could involve expressing numbers with your body while doing simple arithmetics, for example.’ Krause is planning several new studies to explore the scientific basis of methods like these in more detail.

Optogenetics as good as electrical stimulation

Neuroscientists are eagerly, but not always successfully, looking for proof that optogenetics – a celebrated technique that uses pulses of visible light to genetically alter brain cells to be excited or silenced – can be as successful in complex and large brains as it has been in rodent models.

A new study in the journal Current Biology may be the most definitive demonstration yet that the technique can work in nonhuman primates as well as, or even a little better than, the tried-and-true method of perturbing brain circuits with small bursts of electrical current. Brown University researchers directly compared the two techniques to test how well they could influence the visual decision-making behavior of two primates.

“For most of my colleagues in neuroscience to say ‘I’ll be able to incorporate [optogenetics] into my daily work with nonhuman primates,’ you have to get beyond ‘It does seem to sort of work’,” said study senior author David Sheinberg, professor of neuroscience professor affiliated with the Brown Institute for Brain Science. “In our comparison, one of the nice things is that in some ways we found quite analogous effects between electrical and optical [stimulation] but in the optical case it seemed more focused.”

Ultimately if it consistently proves safe and effective in the large, complex brains of primates, optogenetics could eventually be used in humans where it could provide a variety of potential diagnostic and therapeutic benefits.

Evidence in sight

With that in mind, Sheinberg, lead author Ji Dai and second author Daniel Brooks designed their experiments to determine whether and how much optical or electrical stimulation in a particular area of the brain called the lateral intraparietal area (LIP) would affect each subject’s decision making when presented with a choice between a target and a similar-looking, distracting character.

“This is an area of the brain involved in registering the location of salient objects in the visual world,” said Sheinberg who added that the experimental task was more cognitively sophisticated than those tested in optogenetics experiments in nonhuman primates before.

The main task for the subjects was to fixate on a central point in middle of the screen and then to look toward the letter “T” when it appeared around the edge of the screen. In some trials, they had to decide quickly between the T and a similar looking “+” or “†” character presented on opposite ends of the screen. They were rewarded if they glanced toward the T.

Before beginning those trials, the researchers had carefully placed a very thin combination sensor of an optical fiber and an electrode amid a small population of cells in the LIP of each subject. Then they mapped where on the screen an object should be in order for them to detect a response in those cells. They called that area the receptive field. With this information, they could then look to see what difference either optical or electrical stimulation of those cells would have on the subject’s inclination to look when the T or the distracting character appeared at various locations in visual space.

They found that stimulating with either method increased both subjects’ accuracy in choosing the target when it appeared in their receptive field. They also found the primates became less accurate when the distracting character appeared in their receptive field. Generally accuracy was unchanged when neither character was in the receptive field.

In other words, the stimulation of a particular group of LIP cells significantly biased the subjects to look at objects that appeared in the receptive field associated with those cells. Either stimulation method could therefore make the subjects more accurate or effectively distract them from making the right choice.

The magnitude of the difference made by either stimulation method compared to no stimulation were small, but statistically significant. When the T was in the receptive field, one research subject became 10 percentage points more accurate (80 percent vs. 70 percent) when optically stimulated and eight points more accurate when electrically stimulated. The subject was five points less accurate (73 percent vs. 78 percent) with optical stimulation and six percentage points less accurate with electrical stimulation when the distracting character was in the receptive field.

The other subject showed similar differences. In all, the two primates made thousands of choices over scores of sessions between the T and the distracting character with either kind of stimulation or none. Compared head-to-head in a statistical analysis, electrical and optical stimulation showed essentially similar effects in biasing the decisions.

Optical advantages

Although the two methods performed at parity on the main measure of accuracy, the optogenetic method had a couple of advantages, Sheinberg said.

Electrical stimulation appeared to be less precise in the cells it reached, a possibility suggested by a reduction in electrically stimulated subjects’ reaction time when the T appeared outside the receptive field. Optogenetic stimulation, Sheinberg said, did not produce such unintended effects.

Electrical stimulation also makes simultaneous electrical recording very difficult, Sheinberg said. That makes it hard to understand what neurons do when they are stimulated. Optogenetics, he said, allows for easier simultaneous electrical recording of neural activity.

Sheinberg said he is encouraged about using optogenetics to investigate even more sophisticated questions of cognition.

“Our goal is to be able to now expand this and use it again as a daily tool to probe circuits in more complicated paradigms,” Sheinberg said.

He plans a new study in which his group will look at memory of visual cues in the LIP.

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Brain Trauma Raises Risk of Later PTSD in Active-Duty Marines
Deployment-related injuries are biggest predictor, but not the only factor   

In a novel study of U.S. Marines investigating the association between traumatic brain injury (TBI) and the risk of post-traumatic stress disorder (PTSD) over time, a team of scientists led by researchers from the Veterans Affairs San Diego Healthcare System and University of California, San Diego School of Medicine report that TBIs suffered during active-duty deployment to Iraq and Afghanistan were the greatest predictor for subsequent PTSD, but found pre-deployment PTSD symptoms and high combat intensity were also significant factors.

The findings are published in the December 11 online issue of JAMA Psychiatry.

The team, headed by principal investigator Dewleen G. Baker, MD, research director at the VA Center of Excellence for Stress and Mental Health, professor in the Department of Psychiatry at UC San Diego and a practicing psychiatrist in the VA San Diego Healthcare System, analyzed 1,648 active-duty Marines and Navy servicemen from four infantry battalions of the First Marine Division based at Camp Pendleton in north San Diego County. The servicemen were evaluated approximately one month before a scheduled 7-month deployment to Iraq or Afghanistan, one week after deployment had concluded, and again three and six months later.

PTSD is a psychiatric condition in which stress reactions become abnormal, chronic and may worsen over time. The condition is linked to depression, suicidal tendencies, substance abuse, memory and cognition dysfunction and other health problems.

The servicemen were assessed at each evaluation using the Clinician-Administered PTSD Scale or CAPS, a structured interview widely employed to diagnose PTSD and severity. Researchers asked about any head injuries sustained prior to joining the service and any head injuries sustained during deployment from a blast or explosion, vehicle accident, fall or head wound from a bullet or fragment.

Traumatic brain injuries are common. At least 1.7 million Americans annually sustain a TBI, with an estimated 5 million Americans living with TBI-related disabilities. More than half (56.8 percent) of the servicemen reported a TBI prior to deployment; almost a fifth (19.8 percent) reported a TBI during deployment. The vast majority of deployment-related TBIs (87.2 percent) were deemed mild, with less than 24 hours of post-traumatic amnesia. Of the 117 Marines whose TBI resulted in lost consciousness, 111 said it was less than 30 minutes.

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Sleep-Deprived Mice Show Connections Among Lack of Shut-eye, Diabetes, Age

Sleep, or the lack of it, seems to affect just about every aspect of human physiology. Yet, the molecular pathways through which sleep deprivation wreaks its detrimental effects on the body remain poorly understood. Although numerous studies have looked at the consequences of sleep deprivation on the brain, comparatively few have directly tested its effects on peripheral organs.

During sleep deprivation cells upregulate the UPR – the unfolded protein response – a process where misfolded proteins get refolded or degraded.

Five years ago, researchers at the Perelman School of Medicine, University of Pennsylvania, showed that the UPR is an adaptive response to stress induced by sleep deprivation and is impaired in the brains of old mice. Those findings suggested that inadequate sleep in the elderly, who normally experience sleep disturbances, could exacerbate an already-impaired protective response to protein misfolding that happens in aging cells. Protein misfolding and clumping is associated with many diseases such as Alzheimer’s and Parkinson’s, noted Nirinjini Naidoo, Ph.D., research associate professor in the Division of Sleep Medicine in that study.

Naidoo is also senior author of a follow-up study in Aging Cell this month that shows, for the first time, an effect of sleep deprivation on the UPR in peripheral tissue, in this case, the pancreas. They showed that stress in pancreatic cells due to sleep deprivation may contribute to the loss or dysfunction of these cells important to maintaining proper blood sugar levels, and that these functions may be exacerbated by normal aging.

“The combined effect of aging and sleep deprivation resulted in a loss of control of blood sugar reminiscent of pre-diabetes in mice,” says Naidoo. “We hypothesize that older humans might be especially susceptible to the effects of sleep deprivation on the disruption of glucose homeostasis via cell stress.”

Working with Penn colleague Joe Baur, Ph.D., assistant professor of Physiology, Naidoo started a collaboration to look at the relationship of sleep deprivation, the UPR, and metabolic response with age. Other researchers had suggested that the death of beta cells associated with type 2 diabetes may be due to stress in a cell compartment called the endoplasmic reticulum (ER). The UPR is one part of the quality control system in the ER, where some proteins are made.

Knowing this, Naidoo and Baur asked if sleep deprivation (SD) causes ER stress in the pancreas, via an increase in protein misfolding, and in turn, how this relates to aging.

The team examined tissues in mice for cellular stress following acute SD, and they also looked for cellular stress in aging mice. Their results show that both age and SD combine to induce cellular stress in the pancreas.

Older mice fared markedly worse when subjected to sleep deprivation. Pancreas tissue from older mice or from young animals subjected to sleep deprivation exhibited signs of protein misfolding, yet both were able to maintain insulin secretion and control blood sugar levels. Pancreas tissue from acutely sleep-deprived aged animals exhibited a marked increase in CHOP, a protein associated with cell death, suggesting a maladaptive response to cellular stress with age that was amplified by sleep deprivation.

Acute sleep deprivation caused increased plasma glucose levels in both young and old animals. However, this change was not overtly related to stress in beta cells, since plasma insulin levels were not lower following acute lack of sleep.

Accordingly, young animals subjected to acute sleep deprivation remained tolerant to a glucose challenge. In a chronic sleep deprivation experiment, young mice were sensitized to insulin and had improved control of their blood sugar, whereas aged animals became hyperglycemic and failed to maintain appropriate plasma insulin concentrations.

While changes in insulin secretion are unlikely to play a major role in the acute effects of SD, cellular stress in pancreatic tissue suggests that chronic SD may contribute to the loss or dysfunction of endocrine cells, and that these effects may be exacerbated by normal aging, say the researchers.

Study Raises Questions about Longstanding Forensic Identification Technique

Forensic experts have long used the shape of a person’s skull to make positive identifications of human remains. But those findings may now be called into question, since a new study from North Carolina State University shows that there is not enough variation in skull shapes to make a positive ID.

“In a lot of cases, murder victims or the victims of disasters are from lower socioeconomic backgrounds and don’t have extensive dental records we can use to make a match,” says Dr. Ann Ross, a forensic expert and professor of anthropology at NC State who is senior author of a paper on the new study. “But those people may have been in car accidents or other incidents that led them to have their skulls X-rayed in emergency rooms or elsewhere. And those skull X-rays have often been used to make IDs. I’ve done it myself.

“But now we’ve tried to validate this technique, and our research shows that the shape of the skull isn’t enough to make a positive ID,” Ross says.

At issue is the “cranial vault outline,” not the “face” of the skull. The cranial vault outline is the profile of the skull when viewed from the side, running from just above the bridge of the nose to the point where the skull and neck meet.

For the study, the researchers surveyed 106 members of the American Academy of Forensic Sciences. Survey participants were asked to evaluate 14 antemortem X-rays and five postmortem X-rays. Participants were then asked to match the 5 postmortem X-rays with the appropriate antemortem X-ray, effectively establishing a positive ID.

But the researchers found that only 47 percent of the participants made accurate identifications on all five skulls. Participants who have Ph.D.s did slightly better, with 56 percent of them getting all five correct. (The test has been made available here so that anyone can take it.)

“This doesn’t mean that cranial vault outlines aren’t useful,” says Ashley Maxwell, lead author of the paper and a former graduate student at NC State. “For example, outlines can be valuable if teeth or other features are missing or have been destroyed. But it does mean that cranial vault outlines shouldn’t be given too much weight.

“The more characteristics we can take into account, such as facial features and cranial vault outlines, the more accurate we can be,” Maxwell says.