Female Mice Hot for Guys Who Cry

Attempts at mixing up love potions go back at least to Tristan and Isolde, but since the discovery of pheromones it has become increasingly clear that many animals have only to look to their armpits - and an assortment of other glands - for an irresistible concoction of their own. Pheromones are small molecules that animals release into the air, and when another animal of the same species detects them, the pheromone will cause a specific social behavior – perhaps most notably, an increase in sexual receptivity. While many people are excited by the prospect of chemicals that might improve their sex lives, pheromones make neuroscientists randy for another reason: they represent an opportunity to dissect how the brain works. As far as we can tell, the brain is a huge network of smaller circuits. This means that to do things like control movement and store memories, the brain relies on circuits of nerve cells that communicate with one another to store info or output some kind of behavior. Presumably, the behavior associated with a pheromone relies on a specific neural circuit that is activated when a pheromone is detected by an animal. So, once a pheromone is isolated, you can use it to search out the neural circuit in the brain that is responsible for the behavior; just spray the chemical into the air and watch for a change in behavior of the animal you are studying. Theoretically, experiments like this may help determine exactly how small sets of nerve cells generate behavior. This is a big deal, because although we think small circuits run the brain, we know surprisingly little about the details of how these circuits are wired up.

This summer, a Japanese group in pursuit of a circuit to call their own published a study examining the role of a potential pheromone called ESP1 in sexual behavior of female mice. ESP1 has a quirk, though: it is released in the tears of male mice. Although tears and sex may seem an unlikely pairing to us humans, previous results suggested that ESP1 might be a sex pheromone. Besides, it would be the smell of the tears, not the look of them, causing the excitement. Banking on this, the group characterized ESP1, the proteins that detect it (its receptor) and the nerve cells that use this receptor to tell whether ESP1 is present in the air. By sticking electrodes up a female mouse’s nose, they found that ESP1 sprayed in the surroundings causes electrical responses in neurons of the vomeronasal organ - long thought to be solely responsible for pheromone detection. This organ contains a number of small populations of neurons that respond very specifically to single pheromone types. The group confirmed that ESP1 was indeed responsible for the electrical activity by testing mice whose ESP1 receptors were non-functional. As expected, females without functioning receptors showed no activity in their vomeronasal organ when exposed to ESP1.

The electrical activity in the ESP1-detecting neurons is likely relayed further into the brain to control sexual behavior by activating a neural circuit. To check this, the group exposed normal females and females with non-functional ESP1 receptors to ESP1, introduced them to male mice and watched the magic unfold. Normally, female mice play hard-to-get, and rightly so: although mouse courtship begins with the suitor chasing his crush around like we all used to do in the school yard, he quickly jumps straight to 3rd base, attempting “anogenital investigation.” He then immediately tries to mount – romance has apparently been dead in the mouse world for quite some time. When the female is finally convinced by his wares she initiates lordosis, a perhaps not unfamiliar backward curvature of the spine, facilitating the entry of the penis into the vagina. Females exposed to ESP1 before males were introduced were almost 5 times more likely to initiate lordosis and allow mating than those not exposed to ESP1, while the mutant females, who had no ESP1-evoked activity in their vomeronasal organs, were no more likely than unexposed females. Although most of these experiments were done by exposing the females to purified ESP1, the researchers also compared female responses to males who had ESP1 naturally in their tears and those who didn’t. The results weren’t quite as strong as with purified ESP1, but males who had ESP1 were more successful in their quest.

Although the exact circuitry involved in the sexual behavior has yet to be studied in depth, one thing is clear: female mice are turned on by the smell of tears in their man’s eyes. I wouldn’t count on crying as a go-to pick up line though; humans do respond physiologically to pheromones, but where in the brain and how we detect them is still a mystery, and anything similar to ESP1 has yet to be found in human tears. For now we should either get the good stuff by mail or keep counting on our armpits. (Two for one: the latter is apparently good for the environment.)

What rodents are telling us about human behavior and autism

A tales of two voles

Prairie voles are extremely social creatures, preferring to spend the majority of their time with other prairie voles. In contrast, the closely related montane voles are extremely asocial creatures, choosing a solitary lifestyle over one where they’d have to be tied down. Eerily, prairie voles and humans share many other social behaviors: after a male and female prairie vole decide to spend the night together, they fall madly in love (called pair-bonding), move into a shared nest and raise their children together (‘Till death do us part: 75% of prairie voles stay together until one partner dies). Like with humans, affairs are fairly common, jealousy is rampant and some males (>40%) just never settle down (known in the field as “wanderers”). Prairie voles are even known to enjoy an alcoholic drink every once in a while. With these similarities, it’s no wonder the prairie vole has been the model system of choice to study the physiological basis of social behavior, and why the montane vole has served as the perfect “asocial” control.

Researchers have focused much of their attention on the role of two neuropeptide hormones, oxytocin and vasopressin, in mediating these social behaviors. Oxytocin and vasopressin are well-known regulators of peripheral tissues involved in birth, lactation and water homeostasis. However, their receptors (the cell-surface molecules which bind to these hormones and transmit their signals to the inside of cells) are also found scattered throughout the brain. Turns out, these hormones are also released by prairie voles when they “spend the night”, suggesting that these hormones may induce the post-mating behaviors of prairie voles: partner preference, aggression towards intruders and parental care (characteristics of social monogamy… referred to as monogamy for the rest of the article). Indeed, researchers can induce partner preference and aggression in virgin male prairie voles by injecting them with vasopressin and can block these behaviors by blocking the vasopressin receptor during mating. The same can be done in female prairie voles, except with oxytocin and an oxytocin receptor blocker, reflecting gender-specific differences in how these hormones affect social behaviors. Only thing is, montane voles also release oxytocin and vasopressin following mating and giving them additional vasopressin fails to induce monogamy—what then results in the difference in post-mating behaviors seen between prairie and montane voles? Surprisingly, when researchers looked at the brains of montane and prairie voles, they found striking differences in the location of vasopressin and oxytocin receptors. Prairie voles had more receptors in the ventral pallidum and nucleus accumbens, areas associated with reward and reinforcement, whereas montane voles lacked receptors in these areas. Importantly, other monogamous species, such as marmosets and California mice, show a similar distribution of receptors to the prairie voles. These results suggest that monogamous species may perceive social attachments as pleasurable and rewarding, therefore reinforcing these behaviors, whereas these behaviors are not reinforced in non-monogamous species.

Of course, the goal of all these studies is to understand and possibly treat some human behaviors. Autism can be a particularly devastating neurodevelopmental disorder characterized by severe social deficits such as lack of eye contact, empathy and social attachment. It is therefore not surprising that researchers are looking to see whether oxytocin and vasopressin are dysregulated in autistic patients. Indeed, some cases of autism are associated with reduced levels of circulating oxytocin or complete deletion or mutations in the oxytocin or vasopressin receptor genes. Can administration of oxytocin or vasopressin help with the symptoms of autism? Surprisingly, administration of oxytocin to humans increases social behaviors such as eye contact, trust and empathy and reduces social anxiety. Initial trials with oxytocin and high-functioning autistics showed improvements in their ability to make eye contact and other social behaviors. Therefore, although a link between autism and the oxytocin or vasopressin systems is tenuous and much research remains to be done, research on voles may surprisingly hold the key to understanding human social and asocial behaviors.

For more information:
Oxytocin, vasopressin and autism (free full-text): http://rstb.royalsocietypublishing.org/content/361/1476/2187.long

Those binge-drinking voles:
http://www.oregonlive.com/health/index.ssf/2010/07/voles_a_party_animal_sheds_lig.html

Certiorari emptor; on informal routes of public science education

A recent editorial by Dr. Royce Murray, editor of the journal Analytical Chemistry, has garnered significant attention in its attacks on informal dissemination of scientific information to the general public. Given that public education of science is a relevant topic to this blog, I thought it merited a response here.

The basic premise is that the only trustworthy sources of scientific information that can be given to the general public are peer-reviewed journal articles and a small number of established news sources, the latter of which Dr. Murray correctly admits are faltering. To distill his point further, he doesn't like the rise of scientific blogging.

I readily agree that, "The picture of scientifically grounded innovations feeding progress in science is well established. I firmly believe that this system has served science well and that the scientific literature has provided generally reliable information and vast benefits to society over the centuries to the present and will continue doing so into the future." It's true that this information should reach the public for many reasons, including that it protects the public, reduces stigma and susceptibility to pseudoscience, influences public policy, and fosters a sense of scientific wonder in prospective scientists and non-scientists alike.

However, I reject the premise underlying his statement that, "...editors and reviewers reinforce the meaningfulness of Impact Factors by explicit attention to the reliability of submitted articles; if the Scientific Method has not been adequately followed, then there should be a downwardly adjusted evaluation of impact." This is a misrepresentation of impact factor, the measure of how frequently a journal's articles are cited relative to the number it publishes. Impact factor does not measure the extent to which an article follows the scientific method whatsoever; it is more an index of how novel and important, on average, an article published in a particular journal is likely to be, as assessed by how frequently other scientists refer to it in their own articles. The principles of impact factor, far from applying only to peer-reviewed sources, apply just as accurately to informal sources, in that their quality and novelty determine their audience and are reflected by how frequently they are referred to and discussed.

More importantly, it's false to say that the optimal venue for dissemination of knowledge from scientist to layperson is necessarily a published journal article. Scientific articles are not accessible to the general public, even to those members that actively seek them out; restrictive language and jargon, in tandem with prohibitively high costs for accessing articles, prevent access to anyone aside from university-affiliated experts in the respective fields, which defeats the entire concept of limiting the scientific information available to the public to peer-reviewed articles.

In agreement with Dr. Murray, I'm not a fan of the word 'blogger' or its derivatives, but I fear by his attempted definition that he does not understand the term, in that he assumes their primary motivation is to be "entrepreneurs who sell 'news'". This blatantly overlooks the fact that the vast majority of the population he attempts to describe act not out of personal financial gain but rather out of an altruistic desire to educate, and this is especially true of scientific writers in this medium.

Dr. Murray warns, 'caveat emptor'; let the buyer beware, as communication through informal channels increases the risk of malicious misinformation. I propose an alternate viewpoint. Certiorari emptor; let the consumer of these media be informed. This is the ultimate goal of those who seek to educate regardless of medium.

References:

Murray, R. 2010. Science Blogs and Caveat Emptor. Analytical Chemistry 82: 8755.

- Ian Mahar

(Adapted from an article originally appearing here).

Electricity and the brain

Part 1 of 3 : Ions

Most people know that the brain uses electricity to operate. However, what most people do not realize is that the electricity produced by the brain is different from the one produced by batteries or the companies that provide electricity to your home. Indeed, the source of electricity in these examples comes from chemical reactions or from natural resources. This electricity is then routed to your house, for your use, by transfer of electrons between metal atoms that make up the electrical wiring. We can thus define electricity as a movement of electric charges between a potential difference or voltage. However, the brain uses a slightly different system to generate and propagate electricity. Some basic concepts are needed before we can understand how brain cells (neurons) generate electricity in their cell body and propagate it along their axons (Figure 1).

Matter can be divided into basic elements called atoms. Calcium, sodium, potassium and chlorine are examples of atoms. Table salt contains mostly sodium chloride, that is a sodium (Na) and a chloride (Cl) atom. If the two atoms are to be held together, each atom carries a charge (sodium has a positive charge and chloride has a negative charge). Since each atom has an opposite charge, they attract each other, much like the poles of two magnets. However, the forces that attract these two atoms are weak so that when you put the salt in an aquarium filled with water (Figure 2), atoms dissociate to form ions, a positively charged sodium (Na +) and a negatively charged chloride (Cl-). The atoms then diffuse so as to be uniformly distributed in the aquarium. It must be noted that although the atoms of the salt are dissociated and they are charged, the aquarium is electrically neutral (as much positive charges as negative charges).

Adding other specific components in this tank (potassium chloride (K + and Cl-), magnesium chloride (Mg 2 + and 2Cl-), glucose (sugar), calcium chloride (2Cl- and Ca2 +), sodium bicarbonate (Na + and HOCOO-), proteins and oxygen) will result in a uniform distribution of these constituents in the aquarium. We then get a liquid that roughly reconstitutes the fluid that neurons bathe in (cerebral-spinal fluid).

Eric Trudel

Neuroscientific Art

Exactly where the threshold between Science and the Arts lies can be a touchy subject. Like a lot of dichotomies that were once assumed to be fixed opposites, these days it’s looking more like there is a science - arts continuum. This is particularly valid in the nebulous field of neuroscience, where the overarching goal is to bring together disciplines that study the mind and how it works - like philosophy, sociology, psychology - with fields that study the physical processes that underlie brain function - such as neurobiology, -chemistry and electrophysiology. A word to the wise: before you get into the science/arts debate with someone who studies the mind or brain, resign yourself to accepting them as a scientist - safer to keep your reservations about their place on the spectrum to yourself. (Personally, I think we should all call ourselves artists in keeping with the Latin use of “Art,” meaning skill or craft.)

While the debate rages over what should be included in the realm of “Science,” some scientists are working hard to go the other way. A number of Microscopic Art competitions have sprung up, showcasing beautiful images taken by biologists studying things too small for the human eye to see in all their glory. You may have seen the perennial scanning electron micrographs of pollen in National Geographic, but events like Olympus’ BioScapes and Nikon’s Small World Competition comprise images of many different subjects taken by many types of microscopes (the type of microscope used can drastically change the flavor of the picture). This year’s Olympus Bioscapes competition winners were announced last week, and neuroscientists took 1rst, 3rd and 7th places plus some honorable mentions. Take a look here.

The Incredible Human GPS

        Ever wonder how a cab driver is able to get you from point A to point “who knows where” without using GPS? Its cause his brain is bigger than yours… well… his hippocampus is. The hippocampus is a region in the brain important for long-term memory and spatial navigation. While it was long thought that talents were innate and had to be nurtured at a young age, researchers studying London cab drivers say that an old dog can learn new tricks. London cab drivers have to learn the layout of over 25, 000 streets through 3-4 years of schooling after which only 25% of aspiring cabbies make it out with a London cab certificate to attest to their ability to find their way through the city’s complexly interconnected web of streets. Through Magnetic Resonance Imaging, researchers have determined that London cab drivers have an increase in volume of the back part or posterior part of their hippocampus, indicating that the adult brain is still capable of changing its structure to meet certain demands. This means that talents are not necessarily innate but can also be acquired through repeated application. That’s right. Practice does make perfect.

        When compared to non-cab drivers or bus drivers, who follow a simple set route, cab drivers have a larger posterior hippocampus, which grows with years of cab driving experience, demonstrating that the posterior portion of the hippocampus is important for spatial representation of highly complex environments. However there is a catch. While the posterior portion of the hippocampus grows larger with driving experience, the anterior or frontal portion becomes smaller than those of bus drivers and non-cab drivers. This decrease in anterior hippocampal volume has been associated with a decrease in anterograde memory performance, that is, while cab drivers were better at spatial representation they were deficient in acquiring and retaining other new types of information such as directing movements in space as indicated by their lower performance in the Rey-Osterrieth test. This means that when cab drivers were shown a complex line figure and asked to draw it from memory, they were able to recall less than than bus drivers or non-cab drivers.

        Cab drivers don't only show that practice makes perfect, they also show that if you don't use it you lose it. Researchers compared the hippocampus of present cab drivers to retired cab drivers and found that the structural changes that occur in full-time taxi drivers are reversed in retired taxi drivers. Furthermore, retired taxi drivers scored less on their ability to navigate around London, however performed better in the Rey-Osterrieth test than full-time cab drivers.

        These observations are a testament to the fact that the adult human brain is not static but is quite dynamic, always adapting to our surrounding environment. This has implications in several fields such as education or rehabilitation of patients with cognitive impairments such as autism or even in Parkinson's disease. Researchers at UCL believe that with the right brain exercises we can strengthen those parts of the brain that are deficient or damaged. So those of you who claim to be "too old" to learn anything new, pick up that crossword puzzle, take that class you've been dying to take, start a new hobby and practice, practice, practice!

                         Michael Tibshirani

                          McGill University

Head and Shoulders, Knees and Toes...

Part 1:

If you found out that you were going to lose the use of your arms and legs in the next two years what would you do?

  ALS, more commonly known as Lou Gehrig’s disease, is one of the most common neurodegenerative diseases and is characterized by the death of motor neurons. Motor neurons are cells located in the brain and spinal cord that send out long projections and control your muscles, sort of like the electrical wires of the body. If these wires are removed, muscles in your body won’t get the message to move. This means that those diagnosed with ALS experience a progressive paralysis, losing the use of their bodies one part at a time. Every year 1 in 100,000 people are affected by ALS; slowly losing their independence, unable to walk, speak, or even express emotion through facial expression while still fully aware of their surroundings, trapped in a body that won’t listen to them.  Eventually, usually within 2-5 years of diagnosis, patients die from respiratory failure because the motor neurons controlling the muscles that help you breathe die as well.  This devastating disease can affect anyone. Although the usual onset of ALS is between 40-70 years of age a small proportion of ALS sufferers experienced symptoms, like the great Stephen Hawking, in their early twenties. It is twenty percent more common in men than in women however the incidence is more equal among men and women with increasing age. 

The cause of ALS is still a little unclear and is thought to be a multifactorial disease and so research has investigated several disciplines such as inflammation, excitotoxicity and cell-cell communication. While only 10% of ALS cases are familial, meaning the cause can be linked to defects in your genes, 90% of cases are sporadic, however there is a silver lining to this. When we look at nervous tissue taken from ALS patients, the common characteristic we find between both familial and sporadic cases is the presence of protein clusters called aggregates. By studying familial cases and the genes involved in ALS, we can generate models that allow us to investigate the mechanisms behind ALS and what makes motor neurons particularly vulnerable to protein aggregation. 

In normal cells, proteins initially come out as a string that must be folded properly to function. When these proteins are misfolded either under cell stress or as part of a disease pathway, they tend to stick to each other and form clumps or aggregates in the cell, which interfere with various cell processes and, if not taken care of, will lead to cell death. Whether protein aggregate formation is the beginning or the end of the pathogenic pathway involved in ALS, it is clear by experimentation that motor neurons don’t like having aggregates in them, and so a lot of ALS research has been focused on trying to understand the role aggregate formation plays in the pathogenesis of ALS.  In the next segment we will discuss current research, which explores the cell’s responses to these aggregates and possible explanations why motor neurons specifically show aggregate formation in patients with ALS. Stay tuned!

Michael Tibshirani

McGill University