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The popular delicacy foie gras (which is French for “fat liver”) is produced in a way that animal rights activists insist is barbaric. Ducks and geese are force-fed corn mash twice a day, through a tube that is inserted into the oesophagus. The birds are slaughtered 2-3 weeks later, and their engorged livers are then removed, to be sold whole or for use in making pâté, mousse or parfait.
But it seems that the slaughtered birds may be the ones who have the last laugh – researchers from the University of Tennessee Graduate School of Medicine, in collaboration with a group from Uppsala University in Sweden, have found a potential link between foie gras consumption and the development of a number of amyloidogenic diseases. The findings are published online this week, in the Proceedings of the National Academy of Sciences.
The amyloidogenic diseases include Alzheimer’s Disease, variant Creutzfeldt-Jakob Disease (vCJD), tuberculosis, diabetes and rheumatoid arthritis. They are termed “amyloidogenic” because they all involve a process called amyloidosis, whereby genetic mutations lead to the synthesis of abnormally folded and insoluble proteins which accumulate within or around cells and interfere with their function. In all the amyloidogenic diseases, the mutated proteins are believed to accumulate by a process called nucleation (or “seeding”).
The researchers purchased fresh duck- and goose-derived foie gras from three different commercial retail outlets in the United States and France. Histochemical analyses involving staining the liver tissue with amyloid protein-specific antibodies indicated that amyloid proteins were present in all the samples. And electron microscopy revealed that the fibrils which are characteristic of amyloidogenic diseases were indeed present in all the foie gras samples tested.
Then, mice carrying a mutated version of a gene that made them predisposed to amyloidosis were injected with amyloid protein extracts from the foie gras, or were fed with the foie gras for 8 weeks. Afterwards, the animals were dissected and examined, and it was found that 62% of the mice had amyloid deposits in the heart, kidneys, liver, and intestines. The amyloid proteins in the fois gras had significantly hastened the process of amyloidosis in those animals injected with or fed the food. The amyloidogenic effect of the foie gras was reduced, but not competely abolished, by cooking the livers in the way recommended by the suppliers. By contrast, no amyloid deposits were found in control animals that were not fed the foie gras.
Thus, the consumption of foie gras is potentially hazardous to those who are genetically predisposed to (i.e. have a family history of) amyloidogenic disorders. Discounting the consumption of infected brain tissue (during, for example, the ritual of mortuary cannibalism), this is the first time that a dietary component has been implicated in the amyloidogenic diseases.
Reference:
Solomon, A., et al. (2007). Amyloidogenic potential of foie gras. PNAS doi: 10.1073/pnas.0700848104. [Full text]
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From Myolgie complette en couleur et grandeur naturelle, by Jacques Fabian Gautier d’Agoty, 1746. Reproduced with permission from the W. W. Kellogg Health Sciences Library at Dalhousie University, Halifax, Nova Scotia, Canada.
(via a fantastic new blog called Morbid Anatomy)
Synaesthesia is a condition in which there is increased connectivity between the areas of the brain that process information received from each sense organ. This leads to a mingling of the senses: for example, sounds may elicit perceptions of colour in a synaesthete who has increased connectivity between the brain’s visual and auditory pathways.
The first scientific description of the condition was provided by Francis Galton in the 1880s. But one form of the condition, called mirror-touch synaesthesia, was described for the first time only two years ago. People with this type of synaesthesia experience tactile sensations when they observe another person being touched. And a new study published online in Nature Neuroscience shows that mirror-touch synaesthetes are more empathetic than non-synaesthetes.
The study was led by Jamie Ward, of the Department of Psychology at University College London, who first described mirror-touch synaesthesia, and gave the condition its name, in 2005. Together with Michael Banissy, one of his graduate students, Ward recruited 10 synaesthetes who claimed to experience tactile sensations when they observed someone else being touched. In a series of experiments, the authenticity of the synaesthetes were verified. The participants were touched on the cheeks or the hands. At the same, they observed someone else being touched, either on the same part of the body that they were touched, or elsewhere. They were asked to report where they were touched, while ignoring their observations of someone else being touched.
It was found that the synaesthetic participants were much faster than the non-synaesthetes at reporting being touched when their observations corresponded to their own experiences. But the researchers were more interested in the situations when the observations of the synaesthetes did not correspond to their own sensations. They had reasoned that synaesthetes should find it harder than non-synaesthetes to distinguish between the sensations elicited by actually being touched and those elicited by observing someone else being touched. And this was indeed found to be the case: the synaesthetic participants made more “mirror-touch errors” than non-synaeshetic controls. That is, they often reported being touched on the same part of the body as those people they observed, even if they were touched on part of the body and person they observed was touched on a different part.
Banissy and Ward then measured the empathy quotients of their synaesthetic and non-synaesthetic participants. Both the experimental and control groups were asked to respond to a list of statements designed to measure their emotional and social skills. It was found that there was a strong correlation between mirror-touch synaesthesia and empathy – the synaesthetes responded more positively than non-synaesthetes to statements such as “I am good at predicting how someone will feel” and “I get upset when I see people suffering on news programmes.”
A region of the brain called the somatosensory cortex receives inputs from; the body is mapped onto this part of the brain, such that when one is touched, the subregion of the somatosensory cortex corresponding to that part of the body becomes active. It is activity in the somatosensory cortex that leads to the sensation of being touched, and it is now known that observing another person being touched also activates the somatosensory cortex. And several years ago, a neuroimaging study conducted by Ward and his colleagues showed that this region of the brain is hyperactivated in mirror-touch synaesthetes when they observe someone else being touched.
The somatosensory cortex and the areas surrounding it (including the primary motor cortex) are hypothesized to be a major component of the brain’s “mirror system”. The mirror system is composed of neurons which fire not just when one is performing a particular action, but also when one observes another performing that action. Thus, it is believed that these cells are involved in “mirroring” the behaviour of others so that the brain can generate simulations of their experiences. It has further been suggested that the mirror system is crucial for the acquisition of behaviors that are learnt through imitiation, such as language, and that it is impaired in conditions such as autism.
Banissy and Ward show for the first time that the sensations elicited in mirror-touch synaesthetes while observing someone else being touched are indistinguishable from those felt when they are actually touched. The researchers had no difficulty in recruiting participants for their study, and all those involved were actually unaware that they had the condition – they believed that their synaesthetic experiences were completely normal. Mirror-touch synaesthesia may, therefore, be relatively common. Perhaps the condition has gone by another name; the somatosensory hyperactivation that occurs when observing others may cause feelings of discomfort, or even pain, when observing someone being hurt. Thus, maybe mirror-touch synaesthesia is in fact the condition formerly known as “squeamishness.”
Read more about this study at Nature and ScienceNow.
References:
Banissy, M. J. & Ward, J. (2007). Mirror-touch synesthesia is linked with empathy. Nature Neurosci. doi: 10.1038/nn1926. [Abstract]
Blakemore, S. -J., et al. (2005). Somatosensory activations during the observation of touch and a case of vision-touch synaesthesia. Brain 128: 1571-1583. [Abstract]
Related:
The name Ivan Pavlov should ring a few bells for anybody who has studied psychology. About 100 years ago, Pavlov, a Russian physiologist, performed a series of classic experiments which showed that dogs could be taught to respond in a particular way to a given stimulus. Pavlov was therefore the first to demonstrate a form of behaviour modification called classical conditioning.
Aversion therapy, a form of behaviour modification used by psychiatrists, is based on classical (or Pavlovian) conditioning. For example, in dealing with a patient prone to alcoholism, the therapist might repeatedly pair alcohol with an emetic drug (one that induces vomiting), in the hope that the association between the two would elicit in the patient a feeling of sickness that leads to the avoidance of alcoholic drinks. In the U.S., aversion therapy was used to “treat” homosexuals and sexual deviants until rather recently: the American Psychological Association declared that it was dangerous and ineffective in 1994.
Classical conditioning (and aversion therapy) are effective in modifying behaviour. However, if the association between the two stimuli is not constantly reinforced, the elicited response becomes weaker and eventually disappears, in a process called extinction. Pavlov’s method has been demonstrated not only in humans and in dogs, but also in an invertebrate – the sea slug Aplysia californica. And now, researchers from Tohoku University in Sendai, Japan show that such conditioned responses can also be elicited in an insect – they have created Pavlov’s cockroach.
Just as Pavlov conditioned his dogs to salivate in response to the sound of a bell, the Japanese team conditioned their cockroaches to salivate when presented with a particular smell. They exposed the cockroaches to vanilla and peppermint odours. During exposure to one of them, the insects were also presented with a sucrose solution. After repeated pairings, they learnt to associate that odour with the sucrose solution, so that, when the odour was placed on its antennae, it would salivate in anticipation of a sugary drink. Exposure to the other odour, however, elicited no such response. The researchers even measured the amounts of saliva secreted by their experimental cockroaches in response to the odour associated with the sucrise solution: 100-200 nanolitres of saliva per second.
In the cockroach, the salivary glanda are innervated by three types of neurons, each of which releases a different neurotransmitter – one type, termed SN1, synthesizes and releases dopamine; the second, termed SN2, uses GABA; and the third uses serotonin. The authors had previously shown that these salivary neurons fire in response to conditioned stimuli, and that their activity caused the cockroach to salivate. And last year, researchers from the University of Edinburgh showed that cells in the hypothalamus of the rat fire in response to both food and anticipation of it. But little else is known about the neural bases of classical conditioning. Significantly, this study shows that the cellular mechanisms for controlling salivation, and perhaps the other autonomic functions, in the cockroach are somewhat similar to those of vertebrates. So researchers may have a simple animal model for those same mechanisms in the mammalian brain.
Reference:
Watanabe, H. & Mizunaim, M. (2007). Pavlov’s cockroach: Classical conditioning of salivation in an insect. PLoS ONE 2(6): e529. doi:10.1371/journal.pone.0000529. [Full text]
Trepanation, or trephination (both derived from the Greek word trypanon, meaning “to bore”) is perhaps the oldest form of neurosurgery. The procedure, which is called a craniotomy in medical terminology, involves the removal of a piece of bone from the skull, and it has been performed since prehistoric times. The oldest trepanned skull, found at a neolithic burial site of Ensisheim in France, is more than 7,000 years old, and trepanation was practised by the Ancient Egyptians, Chinese, Indians, Romans, Greeks and the early Mesoamerican civilizations. The procedure is still performed today, for both medical and non-medical reasons.
The trepanned skulls found at prehistoric European sites contained round holes, which varied in size from just a few centimetres in diameter to nearly half of the skull. They are most commonly found in the parietal bone, and also in the occipital and frontal bones, but rarely in the temporal bone. In the earliest European trepanned skulls, the holes were made by scraping the bone away with sharp stones such as flint or obsidian; later, primitive drilling tools were used to drill small holes arranged in circles, after which the piece of bone inside the circle was removed. The late Medieval period saw the introduction of mechanical drilling and sawing instruments, whose sophistication would continue to increase for several hundred years.
There is a great deal of speculation about why ancient civilizations used trepanation, as it was – and still is – carried out in the absence of head trauma. However, it is almost certain that all those who used it did so because they somehow linked the brain with behaviour. Some anthropologists suggest that trepanation was performed as part of tribal or superstitious rituals. Other researchers believe that the procedure was used as a treatment for conditions such as headaches, epilepsy, hydrocephalus and mental disorders. These were presumably attributed to possession by evil demons, such that a hole in the skull would have provided the spirits a passage for escape. Although the reasons for trepanning and the instruments used for the procedure differ with time and from culture to culture, the result is always the same: a hole in the head, usually made when the individual was fully conscious and, often, unanaesthetized.
Some suggest that trepanation was used specifically to treat depressed skull fractures, and there is historical evidence that it was used for medical reasons. For example, the ancient Greek physicians used various instruments for trepanning, including the terebra (right). The way this instrument was used is easily inferred from its structure: the cross-beam was used to wind the thong tightly around the central beam. When released, the centre beam rotated quickly, so that applying downward pressure on the instrument would cause it to bore through the skull. This instrument may have been used to drill single small holes, but it is more likely to have been used to make multiple holes arranged in a circle, so that the piece of bone within the circle was made easier to remove.
Hippocrates (460-370 B.C.E.) describes the types of injuries for which trepanning was used in this passage from On the Injuries of the Head:
…the contusion, whether the bone be laid bare or not; and the fissure, whether apparent or not. And if, when an indentation by a weapon takes place in a bone it be attended with fracture and contusion, and even if contusion alone, without fracture, be combined with the indentation, it requires trepanning…those [bones] which are most pressed and broken require trepanning the least.
The first specimen of a trepanned skull was found in 1685 by Bernard de Montfauchon at a site in Cocherel, France, but its importance was not recognized. In 1816, a second specimen was found by Alexander Francois Barbie du Bovage at Nogentles-les-Vierges. This time, it was recognized that the skull had belonged to an individual on whom a craniotomy had been performed, apparently years before his death. However, the second specimen was considered to be exceptional, and little thought was given to why the skull had been perforated. In 1839, Samuel George Morton depicted a trepanned skull in his book Crania Americana, but mistakenly assumed the hole had occurred as the result of a battle wound. Although the second specimen to be found was recognized as a craniotomy, the real significance of the skulls had escaped scientists and physicians.
It was not until the latter half of the nineteenth century that investigators began to appreciate the significance of trepanation. Ephraim George Squier (1821-1888) had acquired a specimen of a trepanned skull, and brought it to the attention of the scientific and medical communities in America and Europe. Squier was a self-taught archaeologist and a respected writer and journalist, who was appointed by Abraham Lincoln to act as the U. S. Commissioner to Peru. He first encountered the now famous specimen during a visit to the home of a wealthy woman, in the Peruvian region of Cuczo. As he marvelled at the woman’s collection of artifacts – which he later described as the finest collection of pre-Columbian art in Peru – Squier noticed a fragment of a skull containing a square hole measuring 15 x 17 mm (top left). He immediately recognized that the hole was man-made.
In this passage from his book about Peru, Squier describes his first impressions of the skull fragment, and how its owner allowed him to take it with him so that it could be examined:
…the most important relic in Señora Zentino’s collection is the frontal bone of a skull, from the Inca cemetery in the valley of Yucay, which exhibits a clear case of trepanning before death. The señora was kind enough to give it to me for investigation, and it has been submitted to the criticism of the best surgeons of the United States and Europe, and regarded by all as the most remarkable evidence of a knowledge of surgery among the aborigines yet discovered on this continent; for trepanning is one of the most difficult surgical processes. The cutting through the bone was not performed with a saw, but evidently with a burin, or tool like that used by engravers on wood and metal. The opening is fifty-eight hundredths of an inch wide and seventy hundredths long.
The operation of Trepan, from Illustrations of the Great Operations of Surgery: Trepan, Hernia, Amputation, Aneurism and Lithotomy, by Charles Bell, 1815. (John Martin Rare Book Room at the University of Iowa’s Hardin Library for the Health Sciences.)
Squier left Peru, and took the skull fragment to the New York Academy of Medicine, where he asked Dr. August K. Gardner to examine it and present it to the other members of the Academy. At the time, the relationship between brain size, race and intelligence was a hotly debated topic in scientific academies around the world. The general consensus among academics was that the three factors were intimately linked: non-whites were less intelligent than white because they had smaller skulls and brains. There was, therefore, great interest in the skull that Squier had acquired, as it provided the first evidence for trepanation in an ancient and “primitive” culture.
Most of the physicians at the Academy interpreted Squeir’s specimen as “a case of trephining.” This interpretation is documented in the minutes of the Bulletin of the New York Academy of Medicine:
The skull showed that during the patient’s life an operation for trephining had been performed, a square-shaped piece of bone having been removed from the frontal bone, by what would appear to have been a gouging instrument. At one portion of the opening there seemed to be evidence of the attempt on the part of nature to form new bone, to repair the injury done by the operation.
All of the Academy’s members agreed that the hole was man-made, but a few argued that there was no evidence of bone growth, and that it must therefore have been made after the individual’s death. Squier then crossed the Atlantic and took the skull to Paul Broca, a leading anthropologist who had founded the Société d’Anthropologie de Paris in 1859. Broca had been interested in craniometry for some time, particularly in relation to the ongoing debates about the relationship between brain size, race and intelligence. Upon examination of the specimen, Broca found no sign of fracture, and wondered why the procedure had been performed. He suggested that the had been perforated to relieve built-up intracranial pressure that had 
followed a closed head injury, and that the patient had died several days after the trepanation was performed:
There is no fracture or fissure of either external or internal table…and the surgeon who performed the operation could consequently only be governed by functional troubles when diagnosing the existence of an intra-cranial lesion. Was this diagnosis correct? Did the operation succeed in evacuating a fluid poured into the cranium? I am far from affirming this, but am tempted to believe it. In effect, the internal table around the opening is the seat of a very different alteration from that which existed on the external table around the denudation…These peculiarities and several others, which would take too long to detail, are well explained, if we suppose that there had been for some days before the operation an effusion of blood under the dura mater.
Contrary to the widely-held belief that all ancient, and particularly non-white, civilizations were primitive, Broca – who not only accepted the popular view himself, but was also partly responsible for its formation – concluded that the skull fragment was strong evidence of “advanced surgery” by the ancient Peruvians:
What astonishes me is not the boldness of the operation, as ignorance is often the mother of boldness. To trepan on an apparent fracture at the bottom of a wound is a sufficiently simple conception and does not necessitate the existence of advanced surgical arts. But here the trepanning was performed on a point where there was no fracture, and probably not even a wound, so that the surgical act was preceded by a diagnosis. Whether this diagnosis was correct, as is probable, or false, we are in either case authorized to conclude that there was in Peru, before the European era, a surgery already very advanced – and this entirely new notion is not without interest for American anthropology.
Broca also experimented with trepanation himself. He found that a hole could very easily be made in the skull of a deceased 2-year-old child; using a simple glass scraper, the procedure took him about 4 minutes. But the same procedure took about 50 minutes when performed on a skull from an adult. (Young childrens’ crania are easier to perforate than those of adults because the process of calcification is not yet complete.) Broca therefore wrongly assumed that the Incas usually performed trepanation on the young.
By 1867, following the presentation of Squier’s specimen in New York, and Broca’s publication of his observations of the skull fragment, there was increasing interest in trepanation. This led search for more specimens and subsequently, hundreds of trepanned skulls would be found in every corner of Europe. One French site, for example, contained 120 skulls, 40 of which had been trepanned.
The specimen Squeir had obtained came from the Cuczo region of Peru, where many other trepanned skulls have since been found. At one Paracas Indian necropolis located south of Lima, for example, 10,000 complete and well-preserved bodies were found. They belonged to the Incas and to the pre-Inca Tallan and Mochica cultures; around 6% had been trepanned, and many contained multiple holes. From these subsequent discoveries it is clear that the square opening in Squeir’s specimen – which is housed at the American Museum of Natural History in New York and is now dated to 1400-1530 – is not at all unusual.
In both pre-Inca and Inca cultures, trepanation was performed using a cermonial knife called a tumi (above right). The patient’s head was held tightly between the surgeon’s knees, and the tumi blade, which consisted of a sharp piece of flint or copper, was then rubbed back and forth along the surface of the skull. In this way, four incisions arranged in a criss cross pattern, were made in the skull (these are clearly visible in Ephraim’s drawing at the top). The tumi blade increased in thickness close to the sharp edge, thus it was prevented from suddenly penetrating the skull to far. When the incisions were deep enough, the square-shaped piece of bone in the middle of the criss cross was prized out from the skull. An exact survival rate cannot be determined, but the presence of multiple holes in many of the Peru skulls suggests that the individuals survived more than one procedure; some estimates, based on the rate of bone growth seen around the holes in the skulls, put the survival rate at greater than 60%. The Aztecs used similar trepanning instruments, consisting of a sharp semicircular piece of obsidian attached to a wooden handle. Some copper and bronze instruments have also been found, sometimes with ornate and elaborate handles.
Abu al-Qasim al-Zahrawi (Latinized as Albucasis) provides descriptions of the instruments used by Arab surgeons in the twelfth century. A sharp pointed borer was used to make small holes arranged in a cirlce, and another with a spear-shaped head was then used to remove the round piece of bone in the middle. Ambroise Paré (1517-1590), a barber-surgeon who often operated on the battlefield, employed trepanning instruments that had braces or drill stocks to which saws were attached with binding screws. In his treatises on surgery, Paré also described “trepanes or round saws for cutting out a circular piece of bone with a sharp-pointed nail in the centre projecting beyond the teeth,” and another trepan with a transverse handle. The mechanical cogwheel trepan (above left) was invented by Matthia Narvatio in Antwerp in 1575. The cogwheel was connected to a second wheel which rotated a circular saw that cut through the bone. This instrument was used much in the same way as a modern hand drill – held in one hand and cranked with the other. But it was extremely heavy and cumbersome, and therefore did not become popular among the surgeons of the time.
A further and highly significant advance in trepanning instruments came with the invention of a central screw. In the mid-sixteenth century, a trepan consisting of a head brace and drill stock to which a circular saw or sharp perforator was widely available. In 1632, Joannis Scultetus, who was one of the most accomplished seventeenth century surgeons, described an instrument called a trioploides, which he used for raising depressed skull fractures. This was a three-legged instrument with a long centrally-placed screw, similar to the “crown” trepan in the image on the right. In his book Armamentarium chirurgicum, which was published in 1655, Scultetus provided beautiful illustrations of various types of cranial surgery, including trepanation, as well as the instruments used to perform them (below). He also described what he called “male” and “female” instruments, the former with, and the latter without, central screws, and explained how together they were used for trepanning:
Before we use the females, we must make a print on the skull with the male so that the female may stand faster upon it. Now for to trepan the skull the Chyrurgian must have at hand at least three trepans exactly equal to each other; one male and two females, so that he may oft-times change them.
Today, trepanning is still used routinely by doctors to treat traumatic brain injuries. The biggest advocate of trepanation for non-medical purposes is a Dutchman named Bart Hughes, who makes pseudoscientific claims that the procedure can be used to reach a higher state of consciousness:
I met [someone who] used to stand on his head…for considerable periods of time. When I asked him why he did it, he said it got him high. [Later, I was given] some mescaline, and it was then that I got my first clear picture of the mechanism, realizing that it was the increase in the volume of brainblood [sic] that gave the expanded consciousness…[which] must have been caused by more blood in the brain which meant there must have been less of something else. Then I realized that it must be the volume of cerebrospinal fluid that was decreased.
…I thought about making a hole at the base of the spine to let the fluid out, and while thinking about holes I realized that pressure was necessary to squeeze the cerebrospinal fluid out of the system. Then, having concluded upon the nil pressure inside the adult skull (in most people the skull seals between the ages of eighteen and twenty-two) I saw that any hole in the bony surrounding of the system would give the pressure back. But after a time I realized a hole in the spine would heal over so it had to be in the skull, where holes stay open.
In 1965, Hughes famously performed a trepanation on himself using an electric drill, a surgical knife and a hypodermic needle to administer a local anaesthetic. He has followers who have also performed self-trepanation, or have asked friends to do it for them.
Two prints from Armamentarium chirurgicum, by Johannes Scultetus (1655), showing how trepanation was performed (left) and a set of trepanation instruments (right).
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Sea sponges are sedentary organisms that attach themselves to the sea bed and filter nutrients from the water that they force through their porous bodies with flagella. They are the most primitive of all multicellular animals, with just four different types of cells making up partially differentiated tissues in a simply organized body.
Because of the lifestyle they lead, sea sponges do not need, and therefore lack, nerve cells, muscle cells and internal organs of any kind. However, researchers from the University of California at Santa Barbara now find that one species of sea sponge, called Amphimedon queenslandica, synthesizes many of the proteins that are essential for the cell-to-cell communication that takes place within nervous systems. These surprising findings, which are published in the open access journal PLoS One, therefore provide clues about how the first neurons may have evolved in the most ancient of animals.
Neurons are specialized to communicate with one another. The signalling between one nerve cell and another takes place at a structure called the synapse, a miniscule gap of about 40 nanometres found at the junction between adjacent cells. The gap itself is no more than a space across which chemical signals (the neurotransmitters) diffuse. The active elements of the synapse are the two apposed cell membranes – the pre-synaptic membrane, from which the chemical signals are released, and the post-synaptic membrane, which detects the signals and responds to them in the appropriate way by communicating to the interior of the cell.
Each neuron has regions of its cell membrane specialized for sending the chemical signals, and others specialized for receiving them. The signalling process is known to involve many dozens of proteins that are either embedded within, or located just inside, the membrane. Each type of protein has a specific role in the signalling process. At the pre-synaptic membrane, for example, neurotransmitter molecules are packaged in synaptic vesicles, which remain “docked” at release sites along the inside of the membrane until needed. When a nervous impulse reaches the nerve terminal, it causes the vesicles to fuse with the membrane and to release their contents into the synapse. Once a vesicle is emptied of its cargo, it goes through an elaborate process of recycling. Docking of vesicles is mediated by one family of proteins; fusion of the vesicles with the membrane is mediated by another protein family, and a number of different families of protein are involved in the vesicle recycling process.
As the neurotransmitters diffuse across the synapse, they bind to receptors, Some receptors are voltage-gated ion channels; these are barrel-shaped proteins with a central pore that spans the membrane and opens in response to binding of a transmitter molecule. When the channel opens, it allows the passage of a specific type of ion (sodium, say, or potassium) into or out of the cell. This is a typical response of a neuron – the ion movements change the voltage across the membrane, altering the pattern of signals generated by that cell. Other receptors do not contain pores but instead are specialized to interact with various other proteins inside the cell, in response to a signal. These interactions initiate biochemical reactions within the cell, or communicate the signal to the cell membrane so that the activity of a specific gene or set of genes is altered.
For synaptic signalling to be effective, it is crucial that all the proteins involved are organized correctly. At both the pre- and post-synaptic membranes, this organization is achieved by a scaffold of proteins called the pre- and post-synaptic densities (left, click to enlarge). These structures are a specialization of the cytoskeleton found just beneath the pre- and post-synaptic nerve cell membranes. The density is a highly complex network – in humans it contains perhaps several hundred different types of protein – which organizes the molecular machinery needed for a neuron to detect and respond to the chemical signals sent to it by adjacent cells.
The density also regulates the movements of the machinery within the membrane and the area immediately inside it, and, so, is a highly dynamic structure. The dynamic nature of the density is believed to be crucial the strengthening of synapses that occurs during memory formation. Shuffling of proteins within the post-synaptic density after an initial stimulus may, for example, lead to an increase in the number of receptors at a certain region of the membrane, such that the subsequent response to the same stimulus becomes more efficient. Thus the density is essential in maintaining the integrity of the synapse, and is a major player in the neuronal plasticity that underlies learning and memory.
In the new study, Kenneth Kosic and his colleagues analyzed the Amphimedon genome, and found that it contains 36 families of genes known to encode proteins of the post-synaptic density. So, even though it has no neurons, this sea sponge synthesizes an almost complete set of post-synaptic density proteins. A comparison of the DNA sequences from the 36 sea sponge genes with the homologous sequences from humans, Drosophila melanogaster (fruit flies) and Nematostella vectensis (a cnidarian with a simple nervous system, consisting of a loose network of nerves) revealed striking similarities between the genes in all four species. One gene, called dlg, encodes a crucial component of the post-synaptic density scaffold. The protein product of that gene contains a number of regions that form the protein-protein bonds that hold the scaffold together. The segment of the dlg gene encoding these binding regions was found to be highly conserved – the DNA sequences in the sea sponge gene were identical to the human sequences. This suggests that in the sea sponge these proteins interact in exactly the same way as they do in the human post-synaptic density.
Amphimedon has nearly all the components required to make a post-synaptic density; only a few of the human postsynaptic density genes are missing from the sea sponge’s genome – those encoding ion channel receptors for the neurotransmitter glutamate. (These genes are, however, present in the cnidarian, which expresses them in its simple nervous system.) In sponges, the genes are expressed predominantly in the flask cells of the free-swimming larvae, where they may be involved in sensing chemical cues found in the organism’s environment. Flask cells with post-synaptic densities may predate the first neurons. If so, the first synapses may have evolved from post-synatic densities in a process called exaptation, whereby a pre-existing structure is modified slightly to perform a new function. It is, however, also possible that flask cells evolved from simple neurons that lost some of their synaptic components.
Reference:
Sakarya O., et al. (2007). A post-synaptic scaffold at the origin of the animal kingdom. PLoS ONE 2 (6): e506. doi:10.1371/journal.pone.0000506. [Full text]
Related:
A new study into the biophysical properties of a highly reflective and self-organizing squid protein called reflectin will inform researchers about the process of “bottom-up” synthesis of nanoscale structures and could lead to the development of thin-film coatings for microstructured materials, bringing scientists one step closer to the development of an “invisibility cloak.”
The reflectin protein comes from the Hawaiian Bobtail squid, Euprymna scolopes, which is native to the Central Pacific ocean. E. scolopes leads a nocturnal existence in the shallow waters off the coasts of Hawaii and Midway Island. Like other cephalopods, this species can manipulate the sunlight falling upon it to produce rapid changes in colouration and bioluminescence in order to camouflage from predators and prey and, as was recently discovered, to communicate with each other.
These changes are produced by a number of neurally-controlled photonic structures found throughout the squid’s body. One of these, called the bilobed light organ, houses bioluminescent bacteria of the species Vibrio fischera. The squid and the bacteria have a symbiotic relationship – in return for generating light, the bacteria receive nutrients from the squid. The bacteria colonize the hatchling squid and secrete a toxin called tracheal cytotoxin. This toxin, which is a small fragment of a bacterial cell surface protein called peptidoglycan, causes whooping cough and gonorrhea in humans. But in E. scolopes, it serves a more useful function – it acts in synergy with various other substances to regulate the development of the light organ. The entire surface of the squid’s body can also be considered as a light organ, as it contains reflective tissues in the mantle. Unlike the bilobed organ, whose reflectivity is static, the organs in the skin mantle have variable reflectivity, changes in which can quickly camouflage the squid and even make it invisibile.
The light organ and the reflective tissues in the skin mantle consist largely of proteins called reflectins. These are encoded by at least six genes which appear to be unique to squid. Nearly 44% of the reflectin primary sequence (the string of amino acids encoded in the reflectin gene) is made up of aromatic amino acid residues and amino acids containing sulphur. Reflectins are insoluble, and are deposited inside the light organs as flat, stacked structures called platelets. The reflectin molecules in the platelets are organized irregularly, and the layers formed by the stack of platelets alternate between areas of high and low refractive indices, so that the stacks act as multilayer reflectors (see the image below on the right). Because of this structure, incident light is reflected and scattered in all directions. The rapid changes in colouration that are characteristic of squid are the result of rearrangements in the organization of reflectin deposits within the reflective tissues, which may occur as a result of post-transcriptional modifications to the protein. Because of their chemical composition and the way in which they assemble themselves, the reflectins have the highest refractive index of any known proteins.
In the new study, which is published in Nature Materials, Rajesh Naik and his colleagues at the Air Force Research Laboratory in Dayton, Ohio inserted the gene encoding reflectin 1a into Escherichia coli bacteria. The recombinant protein synthesized by the E. coli cells was isolated and purified, and the self-assembly of the molecules was investigated under different conditions. The photonic properties of the structures were then investigated, and transmission electron microscopy was used to examine the structures formed in detail.
Naik’s group found that the reflectin molecules formed a number of different types of structure, depending on the conditions in which they were assembled. In solutions of very low concentration, the reflectin molecules spontaneously precipitated to form nanospheres with diameters of 50-1,000 nanometres (nm, billionths of a metre), while with higher concentrations they formed . At low concentrations in non-reducing conditions (that is, in the absence of spare electrons), the precipitated nanospheres were optically clear – light could pass unhindered through them. But in reducing conditions (with spare electrons available) precipitation led to the formation of filamentous structures. (These fibres different from the fibres associated with aggregation of abnormally folded proteins in neurodegenerative disorders such as Alzheimer’s Disease and the transmissible spongiform encephalopathies, which are formed by crystallization and not by precipitation.) And when left at 4°C for several weeks, these filaments formed a webbed structure that assembled itself into ribbons.
The researchers then sought to process the recombinant reflectin protein into films and fibres. They used a technique called flow-coating: small amounts of protein solution were added onto a silicon wafer substrate, and the edge of a blade was used to spread the solution across the surface of the wafer. This cast a thin film of the protein across the surface of the wafer. By altering the concentration of the solution used, films of different thickness were formed. The thickness of the film was found to determine the wavelength of light reflected by it. For example, exposure to water vapour dramatically increased film thickness from ~120 nm to ~207 nm. As a result, the wavelength of light reflected by the film changed from 760 nm (which corresponds to red light) to around 400 nm, which gave rise to a blue reflectance. When the water vapour was removed, the film became thinner and then began to reflect red light once again. In this way, the researchers formed films that reflected every colour in the visible light region of the electromagnetic spectrum; They also made gradient films whose thickness differed, so that a rainbow of colours was reflected along the length of the film.
The reflectin solution on the silicon wafer substrate was then dipped into an ionic solution (i.e. one containing positively or negatively charged atoms) called BMIM. This resulted in the formation of striped patterns of reflectin protein on the wafers. The patterns had highly regular spacing which extended unblemished for distances of up to several millimetres. The researchers found that the spacing between the stripes depended upon the velocity of dipping – the greater the velocity, the smaller the space between each stripe. These striped patterns are what materials scientists call diffraction gratings – reflective or transparent elements that split incident light into its constituent wavelengths and are used in a variety of optical devices. Light reflection by the reflectin stripes was observed even while the silicon wafers were still submerged in the solvent, and the wavelength of light scattered could be changed by increasing or decreasing spacing between the stripes.
The researchers had provoked nature into initiating some of her own mechanisms of nanofabrication. The reflectin molecules assembled themselves into nanometre-sized spheres and striped microstructures with photonic properties that could be manipulated. Knowledge of how the self-assembly of reflectins can be manipulated will inform researchers who are trying to synthesize supramolecular nanostructures from the “bottom up”. But a better understanding of these mechanisms and of the properties of reflectin has another potential application: the synthesis of small-scale materials for use in the development of invisibility cloaks.
To this aim, various research groups are using so-called metamaterials, whose nanoscale properties alter the way in which their surfaces reflect visible light. Objects are visible because light bounces off them; in theory, a material which could cause incident light to pass round it could be used in a cloak that covers objects and renders them invisible. The military is, of course, very interested in developing such a material. As the current research was partly funded by DARPA (the research and development arm of the Pentagon), the development of an invisibility cloak could well be the ultimate aim of the project.
References:
Kramer, R. M., et al. (2007). The self-organizing properties of squid reflectin protein. Nature Mater. doi: 10.1038/nmat1930. [Abstract]
Crookes, W. J., et al. (2004). Reflectins: The unusual proteins of squid reflective proteins. Science 303: 235-238. [Full text]
Researchers at the Hebrew University of Jerusalem have developed a miniature image-guided robot for use during keyhole neurosurgery.
The MiniAture Robot for Surgical Applications (MARS) was designed and developed by Leo Joskowicz and his colleagues at the Hebrew University’s Computer Aided Surgery and Medical Image Processing Laboratory. It measures 5 x 5 x 8.5 cm and weighs just one quarter of a kilogram.
The MARS device can be mounted on the patient’s head using a clamp, or attached directly to the skull with two small screws. It positions itself with respect to the structures being operated on. It is programmed to do so using data obtained pre-operatively by computed tomography (CT) or functional magnetic resonance imaging (fMRI). The robot can then be used by surgeons to target neuroanatomical structures. This targeting is at least as accurate, if not more so, than that of existing neurosurgical robots – structures in the brain can be targeted to within 1 mm.
This will provide improved dexterity for surgeons as they guide their instruments towards target structures in the brain. MARS is already being used for spinal and orthopaedic surgery, and has proved to be safe. It could also be used for procedures such as brain biopsies, the draining of cerebral hemorrhage, and the insertion and placement of catheters or implants containing electrodes.
Recall of a particular memory often involves its selection from several memories which are similar to it. Although these other memories are irrelevant, their similarity to the “target” memory leads to competition for retrieval, placing demands on the cognitive mechanisms by which the correct memory is selected.
A new study by researchers at Stanford University now shows that forgetting may be part of the process of remembering. Anthony Wagner and his colleagues at the Stanford Memory Laboratory provide evidence that the active suppression by the brain of competing memories is essential for proper memory function. Their findings – that to remember something involves forgetting something similar – have been published online in Nature Neuroscience.
In the study, 20 participants performed a simple memory test. They were first asked to study and remember a series of three word pairs. Two of these word pairs (ATTIC-junk and ATTIC-dust) were similar and could easily be confused with each other, while the third (MOVIE-reel) was completely unrelated. The participants were asked to examine one of the two similar word pairs (ATTIC-dust) again. They were then presented with retrieval cues (the capitalised words) to help them recall all three pairs.
The researchers had hypothesized that during retrieval the similarity of the two word pairs containing the word ‘ATTIC’ would lead to competition between the two, and that the presentation of one of the pairs a second time would cause the memory of the other to be suppressed. This was indeed the case – the participants had greater difficulty retrieving the ATTIC-dust word pair than in recalling the other two word pairs. For example, the unrelated word pair, MOVIE-reel, was recalled 15% more of the time than was ATTIC-dust.
With practice, the participants became more adept at retrieving one word pair and suppressing the memory of the other. Using functional magnetic resonance imaging (fMRI) the researchers showed that this “increased forgetting” of the competing word pair was closely correlated with changes in the activity of a region in the prefrontal cortex called the anterior cingulate cortex (ACC), is known to be involved in detecting similarities in, and conflict between, similar (or competing) information. It was found that activity in the ACC decreased with each successive trial.
This retrieval-induced forgetting has its benefits – the suppression of competing but irrelevant memories reduces the demands placed on the cognitive control mechanisms mediating selection of memories for retrieval. The process by which the relevant memory is selected for retrieval therefore becomes more efficient. Thus, forgetting may be crucial to remembering.
Reference:
Kuhl, B. A., et al (2007). Decreased demands on cognitive control reveal the neural processing benefits of forgetting. Nat. Neurosci. doi:10.1038/nn1918. [Abstract]
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