FACS-array profiling of striatal projection neuron subtypes in juvenile and adult mouse brains

Nature Neuroscience 9, 443 - 452 (2006) Published online: 19 February 2006; doi:10.1038/nn1654
A major challenge in systems neuroscience is to perform precise molecular genetic analyses of a single neuronal population in the context of the complex mammalian brain. Existing technologies for profiling cell type–specific gene expression are largely limited to immature or morphologically identifiable neurons. In this study, we developed a simple method using fluorescent activated cell sorting (FACS) to purify genetically labeled neurons from juvenile and adult mouse brains for gene expression profiling. We identify and verify a new set of differentially expressed genes in the striatonigral and striatopallidal neurons, two functionally and clinically important projection neuron subtypes in the basal ganglia. We further demonstrate that Ebf1 is a lineage-specific transcription factor essential to the differentiation of striatonigral neurons. Our study provides a general approach for profiling cell type–specific gene expression in the mature mammalian brain and identifies a set of genes critical to the function and dysfunction of the striatal projection neuron circuit.

Depression model leaves mice with molecular scar

In addition to triggering a depression-like social withdrawal syndrome, repeated defeat by dominant animals leaves a mouse with an enduring "molecular scar" in its brain that could help to explain why depression is so difficult to cure, suggest researchers funded by the National Institutes of Health's (NIH) National Institute of Mental Health (NIMH).
In mice exposed to this animal model of depression, silencer molecules turned off a gene for a key protein in the brain's hippocampus. By activating a compensatory mechanism, an antidepressant temporarily restored the animals' sociability and the protein's expression, but it failed to remove the silencers. A true cure for depression would likely have to target this persistent stress-induced scar, say the researchers, led by Eric Nestler, M.D., The University of Texas Southwestern Medical Center, who report on their findings online in Nature Neuroscience during the week of February 26, 2005.
"Our study provides insight into how chronic stress triggers changes in the brain that are much more long-lived than the effects of existing antidepressants," explained Nestler.
Mice exposed to aggression by a different dominant mouse daily for 10 days became socially defeated; they vigorously avoided other mice, even weeks later. Expression of a representative gene in the hippocampus, a memory hub implicated in depression, plummeted three-fold and remained suppressed for weeks. However, chronic treatment with an antidepressant (the tricyclic imipramine) restored expression of the gene for brain derived neurotrophic factor (BDNF) to normal levels and reversed the social withdrawal behavior. BDNF in the hippocampus has been linked to memory, learning and depression, but Nestler said social defeat stress probably similarly affects other genes there as well.
The researchers pinpointed how social defeat changes the BDNF gene's internal machinery. They traced the gene expression changes to long-lasting modifications in histones, proteins that regulate the turning on-and-off of genes via a process called methylation. Methyl groups, the silencer molecules, attach themselves to the histones, turning off the gene. Notably, imipramine was unable to remove these silencer molecules, suggesting that they remained a latent source of vulnerability to future depression-like responses to stress.
Imipramine reversed the suppressed BDNF gene expression by triggering a compensatory mechanism, acetylation, in which molecular activators attach themselves to the gene and overcome the silencer molecules. Imipramine turned off an enzyme (Hdac5) that degrades the activators, allowing them to accumulate.
"The molecular scar induced by chronic stress in the hippocampus, and perhaps elsewhere in the brain, can't be easily reversed," said Nestler. "To really cure depression, we probably need to find new treatments that can remove the silencer molecules."

Tsankova NM, Berton O, Renthal W, Kumar A, Neve R, Nestler EJ. Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nature Neuroscience. Published online, 2/26/2006
To better understand the molecular mechanisms of depression and antidepressant action, we administered chronic social defeat stress followed by chronic imipramine (a tricyclic antidepressant) to mice and studied adaptations at the levels of gene expression and chromatin remodeling of five brain-derived neurotrophic factor (Bdnf) splice variant mRNAs (I-V) and their unique promoters in the hippocampus. Defeat stress induced lasting downregulation of Bdnf transcripts III and IV and robustly increased repressive histone methylation at their corresponding promoters. Chronic imipramine reversed this downregulation and increased histone acetylation at these promoters. This hyperacetylation by chronic imipramine was associated with a selective downregulation of histone deacetylase (Hdac) 5. Furthermore, viral-mediated HDAC5 overexpression in the hippocampus blocked imipramine's ability to reverse depression-like behavior. These experiments underscore an important role for histone remodeling in the pathophysiology and treatment of depression and highlight the therapeutic potential for histone methylation and deacetylation inhibitors in depression.

PSYCHOLOGY: Unintentional Music Sharing

Might our selves be revealed by our choices in music? Rentfrow and Gosling explored this question by asking 74 college students to provide individual top-10 lists of their favorite songs, which were then recorded onto CDs. The students were also asked to provide self-report ratings on personality measures, such as extraversion and conscientiousness; terminal and instrumental values, such as a comfortable life and ambition; and affect and self-esteem. Eight listeners were then asked to rate the students on the same criteria, solely on the basis of hearing their music selections. The measures for which listener judgments correlated most strongly with the self-report data were the personality trait of openness to experience and the instrumental value of imagination. Furthermore, three other listeners had previously coded the songs for 25 experimentally tested musical attributes (for instance, the amount of singing), and these characteristics also displayed correlations with openness and imagination (along with several other traits and values). The results show a differentiating and consistent linkage between our musical tastes and the impressions of us that strangers form purely from learning which songs we like.
Psychol. Sci. 17, 236 (2006).

Rats Are Smarter Than We Think

Although both human and nonhuman animals may use basic associative mechanisms to learn about causal relations, humans have a deeper understanding of causal relations that cannot be reduced to associative learning. In contrast, there is no definite proof that animals, including nonhuman primates, possess deep causal understanding. Blaisdell et al. (p. 1020) present evidence that rats can reason about the effects of their causal interventions. Rats correctly predicted that interventions on one effect of a common-cause model would not affect the other effect. Thus, rats can engage in more sophisticated causal reasoning than predicted by associative models.

Science 17 February 2006:Vol. 311. no. 5763, pp. 1020 - 1022DOI: 10.1126/science.1121872
Causal Reasoning in Rats
Empirical research with nonhuman primates appears to support the view that causal reasoning is a key cognitive faculty that divides humans from animals. The claim is that animals approximate causal learning using associative processes. The present results cast doubt on that conclusion. Rats made causal inferences in a basic task that taps into core features of causal reasoning without requiring complex physical knowledge. They derived predictions of the outcomes of interventions after passive observational learning of different kinds of causal models. These competencies cannot be explained by current associative theories but are consistent with causal Bayes net theories.

Don't Think Too Much

Science 17 February 2006:Vol. 311. no. 5763, p. 935DOI: 10.1126/science.311.5763.935
Buying oven mitts and buying a car demand completely different types of decision-making. Most people would scarcely think about the mitts and agonize over the car. That's exactly the wrong way to go about it, according to a provocative new study.
On page 1005, Ap Dijksterhuis and colleagues at the University of Amsterdam in the Netherlands report a series of experiments with student volunteers and real-life shoppers that suggests that too much contemplation gets in the way of good decision-making--especially when the choice is complicated. Conscious deliberation is best suited for simple decisions such as choosing oven mitts, the researchers argue, whereas complex decisions like picking a car are best handled by the unconscious mind.
"They're elegant experiments with a simple design and eye-popping result," says Timothy Wilson, a psychologist at the University of Virginia in Charlottesville. The research should "stimulate some useful new thinking" among decision researchers, says Daniel Kahneman of Princeton University.
The problem with conscious thought, Dijksterhuis contends, is that you can only think about so many things at the same time. He hypothesized that decisions that require evaluating many factors may be better handled by unconscious thought processes.
To test the idea, Dijksterhuis and colleagues asked volunteers to read brief descriptions of four hypothetical cars and pick the one they'd like to buy after mulling it over for 4 minutes. The researchers made the decision far simpler than it is in real life by limiting the descriptions to just four attributes such as good gas mileage or poor legroom. One of the cars had more plusses than the others, and most participants chose this car. But when the researchers made the decision more complex by listing 12 attributes for each car, people identified the best car only about 25% of the time--no better than chance. The real surprise came when the researchers distracted the participants with anagram puzzles for 4 minutes before asking for their choices. More than half picked the best car. The counterintuitive conclusion, Dijksterhuis says, is that complex decisions are best made without conscious attention to the problem at hand.
To test the idea in a more natural setting, the researchers visited two stores: the international furniture store IKEA and a department store called Bijenkorf. A pilot study with volunteer subjects had suggested that shoppers weigh more attributes when buying furniture than when buying kitchen accessories and other simple products commonly purchased at Bijenkorf. The researchers quizzed shoppers at the two stores about how much time they'd spent thinking about their purchases and then called them a few weeks later to gauge their satisfaction. Bijenkorf shoppers who spent more time consciously deliberating their choices were more pleased with their purchases--evidence that conscious thought is good for simple decisions, Dijksterhuis says. But at IKEA, the reverse was true: Those who reported spending less time deliberating turned out to be the happiest.
Jonathan Schooler, a psychologist at the University of British Columbia in Vancouver, says the study builds on evidence that too much reflection is detrimental in some situations. But "it adds an important insight" by identifying complexity as a key factor in determining which kind of thought process leads to the best decision. Schooler isn't ready, however, to dispense with conscious thought when it comes to complex decisions. "What I think may be really critical is to engage in [conscious] reflection but not make a decision right away," says Schooler.
Dijksterhuis agrees. When an important decision arises, he gathers the relevant facts and gives it his full attention at first. Then, he says, "I sit on things and rely on my gut."

Why Sex?

Science 17 February 2006:Vol. 311. no. 5763, pp. 960 - 961DOI: 10.1126/science.1124663
Why sex? This has been one of the most fundamental questions in evolutionary biology. In many species, males do not provide parental care to the offspring. Clearly, the rate of reproduction could be increased if all individuals were born as females and reproduced asexually without the need to mate with a male (parthenogenetic reproduction). Parthenogenetically reproducing females arising in a sexual population should have a twofold fitness advantage because they, on average, leave twice as many gene copies in the next generation. Nonetheless, sexual reproduction is ubiquitous in higher organisms. Why do all these species bother to have males, if males are associated with a reduction in fitness? The main solution that population geneticists have proposed to this conundrum is that sexual reproduction allows genetic recombination, and that genetic recombination is advantageous because it allows natural Darwinian selection to work more efficiently. New empirical evidence supporting this theory now comes from a study by Paland and Lynch on page 990 in this issue (1).
One reason why selection works more efficiently in the presence of recombination--that is, the exchange of genetic material between chromosomes--is that selected mutations tend to interfere with each other in the absence of recombination (2, 3). Imagine, for example, a beneficial mutation (A) arising in one individual and another beneficial mutation (B) arising in another gene in an individual that does not carry mutation A. In the absence of recombination, mutation B would be eliminated when mutation A reaches a frequency of 100% in the population, and vice versa. No individual carrying both beneficial mutations could be created, and only one of the mutations could eventually reach a frequency of one in the population. Recombination speeds up the rate of adaptive evolution because it allows several beneficial mutations to be combined in the same individual. Likewise, when multiple deleterious mutations are present in the population, recombination has the potential for creating new offspring chromosomes with fewer deleterious mutations than either of the parental chromosomes. The famous population geneticist John Maynard- Smith compared this situation to having two cars: one with a broken engine and one with a broken transmission. Neither of them can run, but if you can replace the broken part in one car with a part from the other car you can produce a new functional car. Recombination allows broken parts to be shuffled among chromosomes, allowing new combinations to arise for selection to act on. Under suitable assumptions regarding the way deleterious mutations affect organismal fitness, the advantage of recombination in eliminating deleterious mutations can outweigh the twofold cost of sex (3).
However, the selection theories are not free of contradictions and problems. Some of them rely on so-called group-selection arguments, where adaptive properties are properties of a whole population and not of individuals. If sexually reproducing individuals and their offspring do not have an immediate selective advantage in otherwise asexual populations, it is hard to see how populations can ever evolve from asexual to sexual reproduction. Additionally, the best explanations regarding deleterious mutations rely on strong assumptions regarding the distribution of selective effects (3), and there may be other factors favoring sex, such as increased resistance to pathogens (4). An observed genomic correlation between the rate of recombination and variability within species (5) suggests that there is an interaction between selection and recombination, but a direct difference between sexual and asexual populations has been hard to establish.
However, the new study by Paland and Lynch (1) provides direct empirical support for an excess accumulation of mutations in asexually reproducing populations compared to sexual populations. They examined different populations of the small crustacean Daphnia pulex, a type of water flea. Daphnia are excellent organisms to study in this regard because parthenogenetic Daphnia populations have arisen multiple times from sexual populations. Comparing asexual and sexual populations of Daphnia is, therefore, the perfect tool for examining the population genetic consequences of sexual reproduction (see the figure).
Paland and Lynch (1) compared the number of mutations with possible functional effects (nonsynonymous mutations) to the number of mutations with no functional effects (synonymous mutations) in 14 asexual and 14 sexual Daphnia populations. They observed a clear excess of nonsynonymous mutations in the asexual populations. They also estimated that close to 90% of the nonsynonymous mutations were subject to selection. These results suggest that the asexually reproducing species carry a higher load of deleterious mutations and that selection is not as efficient in the asexual as in the sexual populations. It does not directly demonstrate that selection against deleterious mutations is what maintains sexual reproduction, but the results do confirm the most important component of the selection theory: Asexual reproduction leads to an accumulation of deleterious mutations. It seems that males are allowed to exist after all, because they help females get rid of deleterious mutations.
The study is also interesting from another point of view. The estimate of the proportion of new mutations in Daphnia that are under selection is fairly high (>90%). Over the past 30 years, the paradigmatic theory in molecular evolution has been the Neutral Theory (6), which assumes that the vast majority of genetic polymorphisms have little or no selection acting upon them. However, the study by Paland and Lynch (1), and other recent studies (7, 8), suggest instead that many or most polymorphisms may be under selection. Slowly, our weltanschauung in evolutionary biology is changing from a static view of a largely optimized genome to a dynamic view of organisms constantly challenged by selection and struggling with the large genetic load imposed by deleterious and new advantageous mutations segregating in the population.

Reproductive Social Behavior: Cooperative Games to Replace Sexual Selection

Science 17 February 2006:Vol. 311. no. 5763, pp. 965 - 969DOI: 10.1126/science.1110105

A recent review of diversity in animal reproductive social behavior (1) raises questions about Darwin's 1871 theory of sexual selection (2). Unlike the theories of evolution through common descent and of evolutionary change by natural selection, Darwin's theory of sexual selection has continually drawn criticism from evolutionists, notably Huxley in 1938 (3). Darwin wrote "Males of almost all animals have stronger passions than females" and "the female... with the rarest of exceptions is less eager than the male... she is coy." Darwin explained these templates as resulting from females choosing mates who are "vigorous and well-armed... just as man can improve the breed of his game-cocks by the selection of those birds which are victorious in the cock-pit." He continues, "Many female progenitors of the peacock must... have... by the continued preference of the most beautiful males, rendered the peacock the most splendid of living birds."
Since 1871, sexual selection theory has often been restated (4), yet contemporary definitions share Darwin's central narrative: "We now understand... Males, who can produce many offspring with only minimal investment, spread their genes most effectively by mating promiscuously... Female reproductive output is far more constrained by the metabolic costs of producing eggs or offspring, and thus a female's interests are served more by mate quality than by mate quantity" (5). This narrative is taught in biology textbooks (6), is axiomatic to evolutionary psychology (7), and is broadcast in popular media (8).
The reproductive social behavior of most species has not been studied, but a great many of those that have been do not conform to Darwinian sexual-selection templates. We suggest that sexual selection is always mistaken, even where gender roles superficially match the Darwinian templates.
There are fundamental problems that universally undercut all applications of sexual selection theory to any species, including the contradiction between sexual selection's rationale and the reason for sexual versus asexual reproduction, the difficulty of sustaining a stable hierarchy of genetic quality within a gene pool in the face of continued directional selection for high-ranked genotypes, and the use of different fitness definitions for males and females. These and other fatal problems are detailed in the references accompanying table S1.
We think that the notion of females choosing the genetically best males is mistaken. Studies repeatedly show that females exert choice to increase number, not genetic quality, of offspring and not to express an arbitrary feminine aesthetic. Instead, we suggest that animals cooperate to rear the largest number of offspring possible, because offspring are investments held in common. We therefore propose replacing sexual selection theory with an approach to explaining reproductive social behavior that has its basis in cooperative game theory. We introduce a notion of allocating time into various relationships to maximize cooperative, or "team," fitness. In this theory, we can observe that diverse social organizations emerge from how individuals accrue direct benefits from the relationships they develop with one another within diverse ecological contexts.
Cooperative Games in Reproductive Social Behavior
Here, we explain reproductive social behavior in developmental time, not evolutionary time. A social system develops from the interaction of individuals just as body parts develop from the interaction of tissues. In our model, each animal acts continually as an individual or as a team member, and the value of an action is scored by how it contributes to that animal's average fitness accumulation rate (9). An individual's actions involve obtaining and exchanging direct benefits to increase the number of offspring successfully reared (10–14). We further envision a future two-tier theory that will embed this phenotypic treatment within an overarching evolutionary-genetic model.
Maynard Smith introduced game theory to biology in the 1980s, including the evolutionary stable strategy (ESS), a population-genetic counterpart to the Nash competitive equilibrium (NCE) of game theory (15). A competitive game ends when an NCE is attained, i.e., the state where each player cannot better its position, given the positions of the other players. In competitive games, the players do not communicate.
In cooperative games, players make threats, promises, and side payments to each other; play together as teams; and form and dissolve coalitions. Cooperative games usually end up at different solutions to an NCE. Nash also investigated cooperative games and introduced the concept of a Nash bargaining solution (NBS) as an outcome of these games (16).
Logic of bargaining and side payments. To illustrate, consider a "payoff matrix" that indicates the direct benefit each player receives in every scenario (17)
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Molecule that may hold key to learning and memory

Independent research teams from Harvard Medical School and Children's Hospital Boston have identified a master protein that sheds light on one of neurobiology's biggest mysteries--how neurons change as a result of individual experiences. The research, which appears in two papers in the latest issue of Science (Feb 17), identifies a central protein that regulates the growth and pruning of neurons throughout life in response to environmental stimuli. This protein, and the molecular pathway it guides, could help investigators understand the process of learning and memory, as well as lead to new therapies for diseases in which synapses either fail to form or run rampant, such as autism, neurodegenerative diseases, and psychiatric disorders.
Though axons and dendrites can be easily spotted waxing and waning under the microscope, the molecular middlemen working inside the cell to shape the neuron's sinewy processes have been much more elusive. The teams found a protein that works in the nucleus of neurons that either pares down or promotes synapses depending on whether or not the neuron is being activated. The protein, myocyte enhancer factor 2 (MEF2), turns on and off genes that control dendritic remodeling. In addition, one of the teams has identified how MEF2 switches from one program to the other, that is, from dendrite-promoting to dendrite-pruning, and the researchers have identified some of MEF2's targets.
The uncovering of the MEF2 pathway and its genetic switch helps fill in a theoretical blank in neurobiology, but what excites the researchers are the potential implications for the clinic. "Changes in the morphology of synapses could turn out to be very important in a whole host of diseases including neurodegenerative as well as psychiatric disorders," said Azad Bonni, MD, PhD, HMS Associate Professor of Pathology who, with colleagues, authored one of the papers. Michael Greenberg, PhD, HMS Professor of Neurology at Children's Hospital Boston, who led the other team, believes that the MEF2 pathway could play a role in autism and other neurodevelopmental diseases.
The protein works by either activating or actively repressing target genes. In working on a group of neurons in the developing rat cerebellum, HMS research fellow in pathology Aryaman Shalizi, and HST medical student Brice Gaudilliere along with Bonni and their colleagues, found the MEF2 repressor promoted synaptic differentiation. In a separate study, Steven Flavell, a graduate student in neurology, Greenberg, and their colleagues found the MEF2 activator inhibited the growth of dendritic spines in the rat hippocampus, an area of the brain associated with memory and learning. Flavell, and also the Bonni team, found the activated, or dendrite-whittling, form of MEF2 comes on in response to increased neuronal activity.
That MEF2 activation leads to the inhibition of synapse formation, makes sense in light of what is known about the nervous system. In memory and learning, as well as development, activity leads to a sculpting, or cutting away, of synapses. What may be more surprising is the way activity causes MEF2 to switch from repressor to activator.
What Bonni and his colleagues found is that molecules modify a particular spot on MEF2, and transform it into a repressor. By removing the modification, known as sumoylation, MEF2 becomes an activator.
MEF2 was first identified in neurons in the 1990s. In 1999, Zixu Mao, then an HMS research fellow, working with Bonni, Greenberg, and colleagues showed that MEF2 promotes neuronal survival but little else was known about the protein. Though they knew that MEF2 comes in activated and repressor forms, neither team knew how exactly the protein works. They suspected it might play a role in regulating activity-dependent synaptic remodeling and set out to find out if that was the case.
Taken together, the findings of the two groups might appear puzzling for they seem to say that MEF2 promotes synapse formation by repressing genes and suppresses synapse formation by activating genes. The puzzle resolves itself when one considers the possibility that the genes being turned on and off act to discourage synapse formation. In fact, Flavell and his colleagues have identified two of MEF2's targets, arc and SynGAP. The arc protein appears to play a role in internalizing glutamate receptors, which occurs when dendrites are being disassembled. SynGAP works to turn off the synapse-promoting ras gene. Bonni and his colleagues have identified yet a third target, Nur77. There are bound to be others.
The identification of these targets, and more generally the opening up of the MEF2 pathway, could lead to new therapies for a host of diseases in which synapses either fail to form or run rampant. In fact, Greenberg is currently a member of a consortium that is trying to get at the molecular underpinnings of autism. "We think the MEF2 pathway may be central," he said.

Learning and memory stimulated by gut hormone

Researchers at Yale School of Medicine have found evidence that a hormone produced in the stomach directly stimulates the higher brain functions of spatial learning and memory development, and further suggests that we may learn best on an empty stomach.
Published in the February 19 online issue of Nature Neuroscience by investigators at Yale and other institutes, the study showed that the hormone ghrelin, produced in the stomach and previously associated with growth hormone release and appetite, has a direct, rapid and powerful influence on the hippocampus, a higher brain region critical for learning and memory.
The team, led by Tamas L. Horvath, chair and associate professor of the Section of Comparative Medicine at Yale School of Medicine, and associate professor in the Department of Obstetrics, Gynecology & Reproductive Sciences, and Neurobiology, first observed that peripheral ghrelin can enter the hippocampus and bind to local neurons promoting alterations in connections between nerve cells in mice and rats. Further study of behavior in the animals showed that these changes in brain circuitry are linked to enhanced learning and memory performance.
Because ghrelin is highest in the circulation during the day and when the stomach is empty, these results also indicate that learning may be most effective before meal-time.
"Based on our observations in animal models, a practical recommendation could be that children may benefit from not overeating at breakfast in order to make the most out of their morning hours at school," said Horvath. "The current obesity epidemic among American school children, which to some degree has been attributed to bad eating habits in the school environment, has been paralleled by a decline of learning performance. It is however too early to speculate if hormonal links between eating and learning are involved in that phenomenon."
Horvath said that high ghrelin levels or administration of ghrelin-like drugs could also protect against certain forms of dementia, because aging and obesity are associated with a decline in ghrelin levels and an increased incidence of conditions of memory loss like Alzheimer's disease.

Across China's frontier

China has become the preferred place for international firms to open research labs — and Japan is leading the way.
Electronics engineer Min-Yu Hsueh wasn't planning to swap California for Beijing, but when the invite came he found it very hard to refuse. A Chinese-American entrepreneur based in San Jose, Hsueh was three years ago working on setting up his next company. Then, out of the blue, Japanese electronics giant NEC offered him the chance to run its first research lab in China."They said: 'China is expanding its market, so we want to play there more efficiently, and we need to invent new technologies'," Hsueh recalls. He was impressed by the plans, and now runs NEC Laboratories China in Beijing, leading a team of 40 researchers, most of them computer scientists.NEC is just one of a host of Japanese companies to have set up research facilities in China in recent years. These firms hope to hire China's well-trained and relatively inexpensive young scientists, and to adapt existing products to the burgeoning Chinese market. The companies are encouraged by generous tax relief for investing in research and development, and hopes that they will be able to secure intellectual property in China (see Nature 438, 420–421; 2005).But for research managers brought up in Japan's system of teamwork and corporate loyalty, the fast-moving, Mandarin-speaking environment takes some getting used to. "It's challenging for them," says Hironori Uchibori, senior economist at Mizuho Research Institute in Tokyo. "But the importance of China is rising, so they are trying to make it work."In 2005, Mizuho surveyed almost 1,400 medium and large industrial firms in Japan and found that more than 250 had already established research labs in China. Only 116 had done so in the United States.Japanese firms are not the only ones heading for China. US electronics company Motorola was the first foreign firm to set up a research lab there, back in 1993. Since then there's been a veritable gold rush, and there are now some 700 labs operated by multinational companies, according to a 2005 United Nations report. That report found that firms favoured China more than any other nation as the location for expanding research and development over the next five years (see graph). In the survey, 60% of European companies said that they had plans to expand their research abroad, but fully 90% of Japanese ones said so.Competition to hire top graduates is stiff in China, and many Japanese companies are strengthening their ties with universities in a bid to snag students after they graduate. For example, Osaka-based Matsushita Electric Industrial Company has researchers that teach classes at Dalian University of Technology in the northeastern province of Liaoning. The company, best known for its Panasonic brand, has several labs in China and opened a software development facility in Dalian in 2004.
"It's tough to recruit good students there, so we want them to get interested in us," says Atsushi Ando of Matsushita's research strategy group. Matsushita says that over the next few years it will triple or quadruple the number of researchers and engineers at its Dalian lab from the current 100.But recruitment isn't the only issue: many Japanese firms are keen to train the Chinese students in their corporate ethos so that their recruits stay put. Hitachi and Fujitsu both say that they are trying to imbue young researchers with Japanese virtues, such as teamwork and corporate loyalty. Since Hitachi established a Chinese lab in 2000, it has invited many of its 60 Chinese researchers to Japan for six months to learn these virtues. "We started from scratch, so educating researchers was the toughest thing for our first five years," says Michiharu Nakamura, a Hitachi vice-president in charge of the Beijing laboratory.Lab managers may laud the quality of Chinese graduates, but the monthly salaries paid the recruits are only about a quarter of the US$2,000 or so that similar graduates get in Japan. And managers are aware that US companies such as Microsoft and IBM have a more positive image among students. Many Japanese employers also acknowledge that the research 'culture' in China, with its strong emphasis on individualism and competition, has more in common with that of the United States than with the Japanese model.This might explain why NEC has let Hsueh take a Western approach to running his lab. His management practices are more Californian than Japanese: English is the working language, and researchers get financial bonuses for filing patents, publishing papers and producing ideas that become incorporated into prototypes. "This approach is a first for NEC," Hsueh says.Other companies are also shifting responsibility from Japanese managers to Chinese nationals. Many group leaders at Hitachi, for example, are now Chinese. The main challenge over the next few years, Nakamura says, is to develop products there not just for China, but for global markets as well.

Why you should go with your gut

Study says unconscious consideration yields most satisfying decisions. http://www.nature.com/news/2006/060213/full/060213-9.html
The best way to make a tough decision is to put your feet up and think about something else. So says an investigation of people shopping for cars, clothes and furniture.Many people assume that the best way to tackle a difficult choice is to list the pros and cons and ponder them deeply. Others believe we do better to sleep on it, leaving the decision-making to our unconscious, or intuition.A team of researchers at the University of Amsterdam, The Netherlands, carried out a series of studies to distinguish between these ideas. In one experiment, university students read a list of features about four different cars, such as facts on their mileage and legroom, before deciding which car to pick.The experiment was set so that some students were presented with a short list of features, making for a simple decision, while others faced a bafflingly long list of 12 competing characteristics. Some students were left to think about their decisions for a few minutes, whereas others were distracted by being asked to solve anagrams.Don't think about itFor the simple decisions, students made better choices when they thought consciously about the problem. But for the more complex choice, they did better after not thinking about it, Ap Dijksterhuis and his colleagues report in Science1. To carry this idea into the real world, the team also studied people who were shopping: either in an Amsterdam department store, where they bought straightforward clothes or kitchenware, or in IKEA, where they bought furniture, which one might expect to be a more complicated decision-making process. The team asked the shoppers whether they had thought hard about their purchase beforehand, and a few weeks later asked them whether they were happy with it.These results confirmed the earlier ones. Department-store shoppers who made simple purchases were happier if they had thought consciously about their choice in advance. IKEA shoppers, on the other hand, were happier with their choice if they hadn't mulled them over.At least when making some complicated decisions, such as choosing a car or house, the results suggest that we would actually do better to go with our gut.The big pictureResearchers do not know exactly why this unconscious deliberation should be so successful. But it is well accepted that our conscious brain can only process a limited amount of information at one time. This could mean that we simply lose the big picture with complex decisions.Dijksterhuis and his team also propose that, although we are unaware of it, our brains are churning through the mass of information involved in a complex decision and sifting out the best option.The study ties in with a growing trend in psychology research over the past 15 years, suggesting that our unconscious mind is more important than we once thought. "A lot of complicated processes occur without our being aware of it," says Daniel Kahneman, an authority on decision making at Princeton University, New Jersey.Snap decisionsThe results might help to explain why experts, such as doctors or firemen, can sometimes make seemingly intuitive snap decisions that turn out to be correct. These people have a wealth of knowledge, but they don't need to consciously work through it to make an accurate judgement.
But the theory doesn't mean that going purely on impulse is a good idea: you still need some information to mull over before making your decision. Particularly when making potentially life-changing judgments such as whom to marry or which career to choose, experts say, study and deliberation are vital to reveal all the options open to us."I would not advise people to buy a car or house without making a list," Kahneman says. "You will probably improve your intuitions by making a list and then sleeping on it."

Possible 'universal strategy' to combat addiction

An international research team led by the University of Saskatchewan has discovered a signaling pathway in the brain involved in drug addiction, together with a method for blocking its action, that may point to a single treatment strategy for most addictions.
Their findings appear in the March issue of the prestigious journal Nature Medicine.
The team, led by Xia Zhang, associate professor in the U of S department of psychiatry, found that a naturally occurring enzyme known as PTEN acts on the part of the brain where many drugs of abuse exert their rewarding effects - the ventral tegmental area (VTA).
"Our results suggest a potential universal strategy for treating drug addiction," Zhang says. "Most drugs of abuse act on the neurons in this area."
He cautions that much work remains to be done before a treatment based on the discovery could be developed to help drug addicts. This includes several years of further testing, including animal and, finally, human trials.
"We have our peptide, but there's a long way to go before a clinical application," he says.
"Dr. Zhang's research is important to our understanding of drug addiction. His work epitomizes how health research holds the key to improved health and quality of life for Canadians and people throughout the world," said Dr. Rémi Quirion, Scientific Director of the Canadian Institutes of Health Research Institute of Neurosciences, Mental Health and Addiction.
Zhang, who worked with colleagues at the U of S, University of Toronto, and Vanderbilt University in Tennessee on the project, explains that VTA brain cells are sensitive to serotonin, a hormone associated with learning, sleep and mood. The team discovered that PTEN acts on these serotonin receptors, increasing brain cell activity. This is the same "reward" process sparked by drugs of abuse.
Armed with this knowledge, the team designed a molecule called a peptide, tailored to fit the serotonin receptors and block PTEN. When rats were treated with this PTEN-blocker, it shut down the drug reward process – including the process that induces craving and withdrawal.
The study, funded by the Canadian Institutes of Health Research and the Natural Sciences and Engineering Research Council, looked at nicotine and THC (the active ingredient in marijuana). However, Zhang says the results could also hold true for other drugs such as cocaine, heroin, and even methamphetamine.
Zhang's U of S research team is part of the Neural Systems and Plasticity Research Group, one of several interdisciplinary health sciences research groups at the University.
The group, dedicated to the study of brain systems and how they change with experience, draws expertise from numerous departments across six colleges on campus.

Apocalypse now: fears of gene doping are realised

by Owen Slot
A new substance has emerged that suggests the next stage in the drugs battle has started
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THE grim new world of gene doping, for so long viewed as the apocalyptic future of illegal performance-enhancement in sport, has dawned in Germany. Experts had been concerned that advances in gene therapy would start to impact on sport by the time of the Beijing Olympics in 2008. However, evidence from a court case in Magdeburg, Germany, suggests that a new brand of cheats could be injecting in time for the Turin Winter Games, which start next week.
Gene doping is the big fear among those fighting for clean sport. It involves manipulation of the human genetic code and thus evades standard detection methods. And a German court has identified the distribution among coaches of a substance called Repoxygen, which works in this way to produce erythropoietin (EPO) indigenously.
“You would have to be blind not to see that the next generation of doping will be genetic,” Dick Pound, the chairman of the World Anti-Doping Agency, told scientists only two months ago. It seems that this next generation has arrived.
Evidence of gene doping has been stumbled upon at the trial of Thomas Springstein, the coach and partner of Grit Breuer, twice the European 400 metres champion, who was banned for taking the stimulant Clenbuterol. Springstein is accused of supplying steroids to female athletes that he has been coaching in Germany; the body of evidence against him was fortified by a police raid on the home he shares with Breuer, during which 20 chemical substances were said to have been found, 12 of which are yet to be identified.
Also removed from their house was Springstein’s laptop. At the start of his trial, Springstein’s lawyer failed in his plea to keep private the contents of his e-mail inbox. Certain e-mails were read out in court and it was in one exchange with the doctor of a Dutch speed-skating club that the incriminating evidence was allegedly discovered. Among a large number of doping products discussed, the prosecution claims, was the use of the aforementioned ground-breaker, Repoxygen.
The e-mails were passed on to Professor Werner Franke, a German cell biologist largely responsible for exposing those behind the drugs regimes of the former East German sports system. Franke told The Times that he was “devastated” by what he read. “We have been expecting gene doping, but not so soon,” he said. “I don’t know how they have it, but they do. This is the crossing of the Rubicon. This is a real advance in criminality.”
His reaction was matched by Michele Verroken, the director of the consultancy Sporting Integrity and former head of anti-doping at UK Sport. “When I first read about it, I thought, ‘Wow, someone’s cracked it,’” she said. “This is a really significant development.”
Repoxygen was pioneered in 2002 by Oxford Biomedica, an Oxford-based pharmaceutical company. It is a hugely significant breakthrough for the healthcare market for which it had been intended, primarily to treat serious anaemia.
The human body already produces EPO indigenously. EPO, in turn, is the agent that produces the red blood cells that carry oxygen to the muscles. When an athlete’s body is tiring, it is because it craves oxygen. This is why athletes can enhance performance by injecting synthetic EPO, the illegal part of the process. The brilliance of Repoxygen is that it gives the body the gene with which it can stimulate further EPO production on its own.
In announcing its breakthrough product on June 6, 2002, Oxford Biomedica explained that use of Repoxyen allows the body to “switch a gene on in response” to a low oxygen level and then, when that level has been raised, to “switch the gene off, providing an exquisite control mechanism for the production of EPO in situ”.
Within three months, the anti-doping movement had registered its concern over misuse. “We see Repoxygen as a significant threat,” Larry Bowers, the managing director of the US Anti-Doping Agency, said after a meeting in Atlanta in October 2002. “You can turn it on and off. It acts more or less like the body.”
While Bowers et al attempt to pioneer a test for gene doping, the immediate question is how Repoxygen got on to the black market. While Oxford Biomedica made the Repoxygen prototype, it never went into production because the company believed that it could not compete in the pharmaceutical market where EPO was already so readily available.
“We didn’t develop it any further,” Professor Alan Kingsman, Oxford Biomedica’s chief executive, said. “So it simply remains in the fridge. And we maintain very close controls, so I’d be extremely surprised if anything we made got on to the black market.”
One conclusion is that other laboratories had reproduced Repoxygen from information gleaned from Oxford Biomedica’s launch. “It would take a fairly advanced lab to make it,” Kingsman said. “But it would be very irresponsible for a number of reasons. For a start, we only went as far as testing it on mice. To use it in the human body would be playing with fire.”