Neuroscience
Month
This fall, science writers have made sport of yet another instance of bad neuroscience. The culprit this time is Naomi Wolf; her new book, “Vagina,” has been roundly drubbed for misrepresenting the brain and neurochemicals like dopamine and oxytocin.
Earlier in the year, Chris Mooney raised similar ire with the book “The Republican Brain,” which claims that Republicans are genetically different from — and, many readers deduced, lesser to — Democrats. “If Mooney’s argument sounds familiar to you, it should,” scoffed two science writers. “It’s called ‘eugenics,’ and it was based on the belief that some humans are genetically inferior.”
Sharp words from disapproving science writers are but the tip of the hippocampus: today’s pop neuroscience, coarsened for mass audiences, is under a much larger attack.
Meet the “neuro doubters.” The neuro doubter may like neuroscience but does not like what he or she considers its bastardization by glib, sometimes ill-informed, popularizers.
Neurobiologists from Heidelberg University’s Centre for Organismal Studies (COS) have gained new insights into how different types of nerve cells are formed in the developing animal. Through specialised microscopes, they were able to follow the development of the neural retina in the eye of living zebrafish embryos. Using high-resolution three-dimensional time-lapse images the researchers simultaneously observed the division of retinal nerve cells and changes in gene expression. This enabled them to gain insights into the way in which the two processes are linked during eye development and how the number and proportion of different cell types are regulated.
A central question in developmental and regenerative neurobiology concerns the growth processes in animal organisms: How does a growing animal control the generation of the right number of each type and subtype of nerve cell in the brain and what is the relationship between these cells? The retina consists of many different kinds of nerve cells, which are well characterised and common to all vertebrates. Thus, the retina is a particularly good model for studying neuronal development. The researchers studied such retinal developmental processes in living organisms using zebrafish embryos, which are completely transparent and grow rapidly outside their mother.
All retinal cells, which are either excitatory or inhibitory, arise from a relatively small number of apparently homogeneous progenitor cells. These progenitors are able to generate all the different retinal cell types. “It is a challenge to understand how each progenitor cell contributes to the correct number and subtype of nerve cells that compose the final retinal network. Our work contributes to the understanding of how different genes orchestrate neuronal diversity along a progenitor cell lineage, that is the number of cell divisions and types of neurons generated”, says Heidelberg researcher Dr. Lucia Poggi.
To tackle this challenge, Dr. Poggi’s team used different lines of transgenic zebrafish, in which fluorescent reporter proteins highlight the expression of different genes in dividing cells. Working in close cooperation with Dr. Patricia Jusuf of the Australian Regenerative Medicine Institute at Monash University, the researchers found that some particular kinds of excitatory and inhibitory nerve cells tend to be lineally related, i.e. they derive from a common progenitor cell. For the first time, 4D recordings permitted an in vivo analysis of how the generation of particular inhibitory cells is regulated through coordination of cell division mode and gene expression within individual retinal progenitors of excitatory nerve cells.
This study has established a model of how cell lineage influences neuronal subtype specification and neuronal circuitry formation in the native environment of the vertebrate brain. The results were published in the Journal of Neuroscience.
Chinese researchers have devised a new technique for reprogramming cells from human urine into immature brain cells that can form multiple types of functioning neurons and glial cells. The technique, published in the journal Nature Methods, could prove useful for studying the cellular mechanisms of neurodegenerative conditions such as Alzheimer’s and Parkinson’s and for testing the effects of new drugs that are being developed to treat them.
Stem cells offer the hope of treating these debilitating diseases, but obtaining them from human embryos poses an ethical dilemma. We now know that cells taken from the adult human body can be made to revert to a stem cell-like state and then transformed into virtually any other type of cell. This typically involves using genetically engineered viruses that shuttle control genes into the nucleus and inserts them into the chromosomes, whereupon they activate genes that make them pluripotent, or able to re-differentiate into another type of cell.
In 2008, for example, American researchers took skin cells from an 82-year-old patient with amyotrophic lateral sclerosis and reprogrammed them into motor neurons. Cells obtained in this way could help us gain a better understanding of such diseases. Grafts of patients’ own cells do not elicit an immune response, so this approach may eventually lead to effective cell transplantation therapies. But it also has its problems – it appears that the reprogramming process destabilizes the genome and causes mutations, and that iPSCs may therefore harbour genetic defects that render them useless.
Last year, Duanqing Pei of the Chinese Academy of Sciences and his colleagues reported that human urine contains skin-like cells from the lining of the kidney tubules which can be efficiently reprogrammed, via the pluripotent state, into neurons, glia, liver cells and heart muscle cells. Now they have improved on the approach, making it quicker, more efficient and possibly less prone to errors.
In the new study, they isolated cells from urine samples given by three donors, aged 10, 25 and 37, and converted them directly into neural progenitors. They then grew these cells in Petri dishes and drove them to differentiate into mature neurons that can generate nervous impulses, and also into astrocytes and oligodendrocytes, two types of glial cell found in the human brain. Finally, they transplanted the re-programmed neurons and astrocytes into the brains of newborn rats, and found that the cells had survived when they examined the brains a month later, but it remains to be seen if they can survive for longer, and if they integrate into the existing circuits to be become functional.
This isn’t the first time that one type of cell has been converted into another without going through the pluripotent stage – in 2010, researchers from Stanford converted mouse connective tissue cells directly into neurons. The new technique does have a number of advantages, however.
Instead of using a virus to deliver the reprogramming genes, the researchers used a small circular piece of bacterial DNA which can replicate in the cytoplasm. This not only speeds up the process, but also eliminates the need to integrate the reprogramming genes into the chromosome, which is one potential source of genetic mutation, but it’s still not clear whether these cells contain fewer mutations than those reprogrammed using viruses.
Even so, the technique also makes the procedure of generating iPSCs far easier and non-invasive, as the cells can be obtained from a urine sample instead of a blood sample or biopsy. The next logical step will be to generate neurons from urine samples obtained from patients with Alzheimer’s, Parkinson’s, and other neurodegenerative diseases and to determine the extent to which this new non-viral technique damages the DNA.
Wellcome Trust researchers have discovered how the brain assesses confidence in its decisions. The findings explain why some people have better insight into their choices than others.
Throughout life, we’re constantly evaluating our options and making decisions based on the information we have available. How confident we are in those decisions has clear consequences. For example, investment bankers have to be confident that they’re making the right choice when deciding where to put their clients’ money.
Researchers at the Wellcome Trust Centre for Neuroimaging at UCL led by Professor Ray Dolan have pinpointed the specific areas of the brain that interact to compute both the value of the choices we have in front of us and our confidence in those choices, giving us the ability to know what we want.
The team used functional magnetic resonance imaging (fMRI) to measure activity in the brains of twenty hungry volunteers while they made choices between food items that they would later eat. To determine the subjective value of the snack options, the participants were asked to indicate how much they would be willing to pay for each snack. Then after making their choice, they were asked to report how confident they were that they had made the right decision and selected the best snack.
It has previously been shown that a region at the front of the brain, the ventromedial prefrontal cortex, is important for working out the value of decision options. The new findings reveal that the level of activity in this area is also linked to the level of confidence participants placed on choosing the best option. The study also shows that the interaction between this area of the brain and an adjacent area reflects participants’ ability to access and report their level of confidence in their choices.
Dr Steve Fleming, a Sir Henry Wellcome Postdoctoral Fellow now based at New York University, explains: “We found that people’s confidence varied from decision to decision. While we knew where to look for signals of value computation, it was very interesting to also observe neural signals of confidence in the same brain region.”
Dr Benedetto De Martino, a Sir Henry Wellcome Postdoctoral Fellow at UCL, added: “Overall, we think our results provide an initial account both of how people make choices, and also their insight into the decision process.”
The treatment of inflammatory pain can be improved by endogenous opioid peptides acting directly in injured tissue. Scientists at the Charité – Universitätsmedizin Berlin and the Université Paris Descartes showed that pain can be successfully treated by targeting immune and nerve cells outside the brain or spinal cord. The study is published in the current issue of The FASEB Journal.
Inflammatory pain is the most common form of painful diseases. Examples are acute pain after surgery, and chronic pain as in the case of rheumatoid arthritis. However, the treatment of inflammatory pain is often difficult because it rarely responds to conventional therapies. Furthermore, opiates, such as morphine, produce serious side effects including addiction mediated in the brain, while drugs, such as ibuprofen, may cause stomach ulcers, internal bleeding, and cardiovascular complications. The activation of opiate receptors in nerve cells outside the brain or spinal cord can alleviate pain without serious side effects. This can be achieved by synthetic opiates or endogenous opioid peptides, e.g. enkephalins and endorphins. However, these peptides are rapidly inactivated by two major enzymes, aminopeptidase N (APN) and neutral endopeptidase (NEP), which limit their analgesic effects.
The aim of the research group of Prof. Halina Machelska-Stein from the Klinik für Anästhesiologie at Campus Benjamin Franklin was to prevent the breakdown of endogenous opioid peptides directly in the inflamed tissue. In an animal model, the group has shown that inflammatory pain can be alleviated if the two enzymes (APN and NEP), responsible for the inactivation of the opioid peptides, were blocked by the selective inhibitors. In preparations from immune or nerve cells, which express these enzymes, the opioid peptides were quickly broken down. This was prevented by the enzyme inhibitors, bestatin, thiorpan and P8B. As a result, the sensation of pain was either markedly reduced or completely disappeared. “Targeting of endogenous opioid peptides directly in injured tissues might be a promising strategy to treat inflammatory pain without serious side effects,” states Prof. Machelska-Stein, explaining the results of the investigation. Furthermore, blocking pain at the site of its origin may prevent excitatory mechanisms in the nervous system, which lead to the development of chronic pain.
Scientists have until now not fully understood how animals see in color, since visual pigments in eyes contain exactly the same chromophore (light absorbing segment of the molecule) and yet can absorb different wavelengths of light.
The chromophore retinal (Vitamin A aldehyde or retinaldehyde) is used by all animals but, depending on the photoreceptor proteins (opsins) associated with it, the same molecule can absorb a spectrum of colors from blues or even ultraviolet to reds. How a single molecule can do this has until now been uncertain.
Now researchers, led by Prof. Babak Borhan of Michigan State University at East Lansing, set out to try to understand the mechanism by which the opsins change the light absorption spectrum of the chromophore retinal. They concentrated their efforts on a pigment found in human retinal photoreceptor cells, rhodopsin, which consists of opsin and chromophore components.
One of the major theories about how retinal works is that because it is strongly positively charged at one end it could distribute this electrostatic charge across the chromophore molecule, and this would enable it to absorb the longer wavelengths at the red end of the spectrum. Another theory held that a change in shape of the chromophore-opsin complex could alter the absorption capabilities.
The problem with testing the theories, Borhan said, is that the visual pigments have proved difficult to work with. So instead, Borhan and colleagues used human cellular retinol binding protein II, (hCRBPII), a gut protein that binds retinol, which is closely related to retinal but which tolerates mutations more readily.
The team first created a mutation of hCRPBII that could bind retinal. They then changed the distribution of the electrostatic charge on the retinal molecule by replacing amino acids at the binding site retinal uses on hCRPBII in various ways, and in so doing created a range of pigment proteins.
The team then used spectrophotometry to compare the light entering and leaving the proteins to determine which wavelengths were being absorbed. Using this approach they were able to prove the charge distribution theory was correct and that no change in shape was necessary.
A by-product of the new research is the production of the 11 new artificial pigments, which could be used in tracking proteins or cell types being studied, as well as other possible applications such as in food dyes. One of the new pigments could absorb a red wavelength of 644 nanometers (nm), which is above the theoretical maximum wavelength retinal can absorb (560 nm) and is close to infrared (750 nm +).
The paper was published in the journal Science.
Humans may be endowed with the ability to perform complex forms of learning, attention and function but the evolutionary process that led to this has put us at risk of mental illness.
Data from new research, published today in the journal Nature Neuroscience, was analysed by Dr Richard Emes, a bioinformatics expert from the School of Veterinary Medicine and Science at The University of Nottingham. The results showed that disease-causing mutations occur in the genes that evolved to make us smarter than our fellow animals.
Dr Emes, Director of The University of Nottingham’s Advanced Data Analysis Centre, conducted an analysis of the evolutionary history of the Discs Large homolog (Dlg) family of genes which make some of the essential building blocks of the synapse — the connection between nerve cells in the brain. He said: “This study highlights the importance of the synapse proteome — the proteins involved in the brains signalling processes — in the understanding of cognition and the power of comparative studies to investigate human disease.”
The study involved scientists from The University of Edinburgh, The Wellcome Trust Sanger Institute, the University of Aberdeen, The University of Nottingham and the University of Cambridge.
This cross-disciplinary team of experts carried out what they believe to be the first genetic dissection of the vertebrate’s ability to perform complex forms of learning, attention and function. They focussed on Dlg — a family of genes that humans shared with the ancestor of all backboned animals some 550 million years ago. Gene families like the Dlgs arose by duplication of DNA, changed by mutation over millions of years and now contribute to the complex cognitive processes we have today. However, this redundancy and subsequent accumulation of changes in the DNA may have led to increased susceptibility to some diseases.
Components of the human cognitive repertoire are routinely assessed by using computerised touch-screen methods. By using the same technique with mice researchers were able to probe the cognitive mechanisms conserved since humans and mice shared a common ancestor — around 100 million years ago. By comparing the effect of DNA changes on behavioural test outcomes this research showed a common cause of mutation and effect of learning changes in both mice and humans.
Dr Emes said: “This research shows the importance of discerning information from data and how the power of computational research combined with behavioural and cognitive studies can provide such novel insight into the basis of clinical disorders. This research provides continued support that discovery occurs at the boundary of disciplines by the integration of data.”