Re: Ehdollistumisen biokemiallinen mekanismi tarkentuu

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Fields, R. Douglas

Although scientists have long regarded the brain's white matter as passive infrastructure, new work shows that it actively affects learning and mental illness


• White matter, long thought to be passive tissue, actively affects how the brain learns and dysfunctions.

• Although gray matter (composed of neurons) does the brain's thinking and calcula- ting, white matter (composed of myelin-coated axons) controls the signals that neurons share, coordinating how well brain regions work together.

• A new type of magnetic resonance technology, called diffusion tensor imaging (DTI), has for the first time shown white matter in action, revealing its underappreciated role.

•Myelin is only partially formed at birth and gradually develops in different regions throughout our 20s. The timing of growth and degree of completion can affect learning, self-control (and why teenagers may lack it), and mental illnesses such as schizophrenia, autism and even pathological lying.

--The Editors

Imagine if we could peek through the skull to see what makes one brain smarter than another. Or to discover whether hidden traits might be driving a person's schizophre- nia or dyslexia. A new kind of imaging technique is helping scientists observe such evidence, and it is revealing a surprise: intelligence, and a variety of mental syn- dromes,may be influenced by tracts within the brain made exclusively of white matter.

Gray matter, the stuff between your ears your teachers chided you about, is where mental computation takes place and memories are stored.This cortex is the "topsoil" of the brain;it is composed of densely packed neuronal cell bodies, the decision-ma- king parts of nerve cells, or neurons. Underneath it, however, is a bedrock of "white matter" that fills nearly half of the human brain -- a far larger percentage than found in the brains of other animals. White matter is composed of millions of communications cables, each one containing a long,individual wire, or axon, coated with a white, fatty substance called myelin. Like the trunk lines that connect telephones in different parts of a country, this white cabling connects neurons in one region of the brain with those in other regions.

For decades neuroscientists exhibited little interest in white matter. They considered the myelin to be mere insulation and the cables inside it little more than passive pas- sageways. Theories about learning memory and psychiatric disorders centered on molecular action inside the neurons and at the famous synapses the tiny contact points between them. But scientists are now realizing that we have underestimated the importance of white matter in the proper transfer of information among brain regions. New studies show that the extent of white matter varies in people who have different mental experiences or who have certain dysfunctions. It also changes within one person's brain as he or she learns or practices .1 skill such as playing the piano. Even though the neurons in gray matter execute mental and physical activities, the functioning of white matter may be just as critical to how people master mental and social skills, as well as to why it is hard for old dogs to learn new tricks.

More with Mastery

The myelin that gives white matter its color has always posed mysteries. For more than a century scientists looked at neurons through their microscopes and saw long fibers, the axons, extending from a neuronal cell body to a neigh boring one, like an outstretched, elongated finger. Each axon was found to be coated with a thick crystal- line gel. Anatomists surmised that the fatty covering must insulate axons like rubber sheathing along a copper wire. Strangely, however, many axons,especially the smal- ler filaments,were not coated at all. And even along insulated fibers, gaps in the insu- lation appeared every millimeter or so. The bare spots came to be known as nodes of Ranvier, after French anatomist Louis-Antoine Ranvier, who first described them.

Modern investigation has revealed that nerve impulses race down axons on the order of 100 times faster when they are coated with myelin and that myelin is laid on axons somewhat like electrical tape, wrapped up to 150 times between every node.The substance is manufactured in sheets by two types of glial cells. These cells are not neurons, but they are prevalent in the brain and nervous system [see "The Other Half of the Brain", by R. Douglas Fields; SCIENTIFIC AMERICAN, April 2004].

An octopus-shaped glial cell called an oligodendrocyte does the wrapping.

Electrical signals, unable to leak out through the sheath, jump swiftly down the axon from node to node. In nerves outside the brain and spinal cord, a sausage-shaped glial cell called a Schwann cell forms myelin.

Without myelin,the signal leaks and dissipates.For maximum conduction velocity, the insulation thickness must he strictly proportional to the diameter of the fiber inside. The optimal ratio of bare axon diameter divided by the total fiber diameter (including the myelin) is 0.6. We have no idea how oligodendrocytes "know" whether 10 or 100 layers of insulation are required to create the proper thickness on axons of different diameters. But recently biologist Klaus-Armin Nave of the Max Planck Institute for Ex- perimental Medicine in Göttingen, Germany, discovered that Schwann cells detect a protein called neuregulin that coats axons, and if the amount of this protein is aug- mented or inhibited, the Schwann cell will wrap more or fewer sheets of myelin around the axon. Interestingly, many people who suffer bipolar disorder or schizophrenia have a detect in the gene that regulates production of this protein.

The wrapping occurs at different ages. Myelin is prevalent only in a few brain regions at birth, expands in spurts and is not fully laid until age 25 or 30 in certain places. Myelination generally proceeds in a wave from the back the cerebral cortex (shirt collar) to its trout (forehead) as we grow into adulthood. The frontal lobes are the last places where myelination occurs. These regions are responsible for higher-level reasoning,planning and judgment,skills that only come with experience. Researchers have speculated that skimpy fore brain myelin is one reason that teenagers do not have adult decision- making abilities. Such observations suggest that myelin is important to intelligence.

Presumably the brain does not finish wrapping human axons until early adulthood because, throughout that time, axons continue to grow, gain new branches and trim others in response to experience. Once axons are myelinated, the changes they can undergo become more limited. Still, for a long time a question remained: Is myelin formation totally programmed, or do our life experiences alter the degree of wrapping and thus how well we learn? Does myelin actually build cognitive ability, or is cognition simply limited in regions where it has not yet formed?

Piano virtuoso Fredrik Ullén decided to find out.Ullén also happens to be an asso- ciate professor at the Stockholm Brain Institute in Sweden. In 2005 he and his collea- gues used a new brain scanning technology called diffusion tensor imaging (DTI) to investigate the brains of professional pianists.DTI is done with the same kind of mag- netic resonance imaging machines found in hospitals but involves a different type of magnetic field and different algorithms to create the many brain-image slices that are assembled into a three-dimensional picture. The slices display the vectors (mathe-matically defined as tensors) of water that diffuses in tissue. In gray matter the DTI signals are low because water diffuses symmetrically. But water diffuses asymmetri- cally along bundles of axons; this irregular pattern illuminates while mailer, exposing the major highways of information that flow among brain regions. The more tightly-packed and heavily coated with myelin the fibers are, the stronger the DTI signal.

Ullén found that in professional pianists, certain white matter regions are more highly developed than in nonmusicians. These regions connect parts of the cerebral cortex that are crucial to coordinated movement of the fingers with areas involving other cognitive processes that operate when making music.

He also found that the more hours a day a musician had practiced over time, the stronger the DTI signals were in these while matter tracts; the axons were more hea- vily myelinated or tightly packed. Of course, the axons could simply have expanded, requiring more myelin to maintain the optimal 0.6 ratio. Without performing an autop- sy, the question remains open.The discovery is important, however,because it shows that when learning a complex skill, noticeable changes occur in white matter - a brain structure that contains no neuronal cell bodies or synapses,only axons and glia. Stu- dies on animals, in which brains can be physically examined, show myelin can change in response to mental experience and a creature's developmental environ- ment. Recently neurobiologist William T. Greenough of the University of Illinois at Urbana-Champaign confirmed that rats raised in "enriched" environments (with ac- cess to abundant toys and social interaction) had more myelinated fibers in the cor- pus callosum - the hefty bundle of axons that connects the brain's two hemispheres.

These results seem to jibe with DTI studies performed by neuroscientist Vincent J. Schmithorst of Cincinnati Children's Hospital, which compared white matter in child- ren ages five to 18.A higher development of white matter structure,Schmithorst found, correlates directly with higher 1Q. Other reports reveal that children who suffer severe neglect have up to 17 percent less white matter in the corpus callosum.

Stimulating Change

Such findings strongly suggest that experience influences myelin formation and that the resulting myelin supports learning and improvement of skills. But to be fully con- vinced of that conclusion,investigators need a plausible explanation of how abundant myelin can enhance cognition, as well as some direct evidence that defects can impair mental abilities.

My lab has uncovered several ways in which an individual's experiences can influ- ence myelin formation.In the brain,neurons fire electrical impulses down axons; by growing neurons from fetal mice in culture dishes equipped with platinum electrodes, we can impose patterns of impulses on them.We found that these impulses can regu- late specific genes in neurons.One of the genes causes production of a sticks protein called L1-CAM that is crucial for pasting the first layer of membrane around an axon as myelin begins to form.

We also found that glia can "listen in" on impulses shooting through axons and that the traffic heard alters the degree of myelination; a type of glial cell called an astro- cyte releases a chemical factor when it senses increased impulse traffic. This chemi- cal code stimulates oligodendrocytes to form more myelin. Children who succumb to Alexander disease, a fatal childhood disorder causing mental retardation and abnormal myelin, have a mutation of an astrocyte gene.

Logic, too, helps to explain how white matter can influence cognitive ability. It might seem that, by analogy to the Internet,all information in the brain should be transmitted as quickly as possible. That would mean all axons should be equally myelinated. But for neurons, faster is not always better.

Information must travel enormous distances between brain centers. Each center car- ries out its particular function and sends the output to another region for the next step of analysis. For complex learning, such as learning the piano, information must be shuttled back and forth among many regions; information flowing over different dis- tances must arrive simultaneously at one place at a certain time. For such precision to occur, delays are necessary. If all axons transmitted information at the maximum rate, signals from distant neurons would always arrive later than signals from neigh-boring neurons.An impulse typically takes 30 milliseconds to travel from one cerebral hemisphere to the other through myelinated axons in the corpus callosum, compared with 150 to 300 milliseconds through unmyelinated axons. None of the corpus callo- sum's axons are myelinated at birth, and by adulthood 30 percent remain that way. The variation helps to coordinate transmission speeds.

Perhaps just as crucial are the nodes of Ranvier.In the past few years scientists have concluded that far from being mistakes,the nodes act as intricate,bioelectric repeaters -- relay stations that generate, regulate and rapidly propagate electrical signals along an axon. By studying owls' excellent hearing, neurobiologists have shown that during myelination the oligodendrocytes insert more nodes than are optimal for fast signaling along certain axons to slow signals traveling along them.

Clearly,the speed of impulse transmission is a vital aspect of brain function. We know that memory and learning occur when certain neuronal circuits connect more strong- ly. It seems likely that myelin affects this strength, by adjusting conduction velocity so that volleys of electrical impulses arrive at the same neuron simultaneously from mul- tiple axons. When this convergence occurs, the individual voltage blips pile up, in- creasing the strength of the signal,thus making a stronger connection among the neu- rons involved. Much more research must be done to explore this theory, but there is no doubt that myelin responds to the environment and participates in learning skills.

Learning and Mental Illness

With this new perspective,it is not hard to imagine how faulty transmission could lead to mental challenges. After decades of searching gray matter for the causes of mental disabilities, neuroscientists now have circumstantial evidence suggesting that white matter plays a role. Dyslexia, for example, results from disrupted timing of information transmission in circuits required for reading; brain imaging has revealed reduced white matter in these tracts, which could cause such disruption. The white matter abnormalities are thought to reflect both defects in myelination and developmental abnormalities in neurons affecting these white matter connections.

Tone deafness results from defects in higher-level processing in the cerebral cortex where sounds are analyzed;psychologist Kristi L.Hyde of McGill University has found that white matter is reduced in a specific fiber bundle in the right forebrain of tone- deaf individuals. Furthermore, recent research by Leslie K. Jacobsen of Yale Univer- sity indicates that exposure to tobacco smoke during late fetal development or ado- lescence, when this bundle is undergoing myelination, disrupts the white matter. The structure,as seen by DTI, correlates directly with performance on auditory tests. Nico- tine is known to affect receptors on oligodendrocytes that regulate the cells' develop- ment. Exposure to environmental factors during crucial periods of myelination can have lifelong consequences.

Schizophrenia is now understood to be a developmental disorder that involves ab- normal connectivity. The evidence is multifold. Doctors have always wondered why schizophrenia typically develops during adolescence, but recall that this is the pri- mary age when the forebrain is being myelinated. The neurons there have largely been established,but the myelin is changing,making it suspect.In addition, nearly 20 studies in recent years have concluded that white matter is abnormal (possessing fewer oligodendrocytes than it should) in several regions of the schizophrenic brain. And when gene chips - tiny diagnostic devices that can survey thousands of genes at a time--recently became available, researchers were startled to discover that many of the mutated genes linked to schizophrenia were involved in myelin formation. White matter abnormalities have also been found in people affected by ADHD, bipolar dis- order, language disorders, autism,cognitive decline in aging and Alzheimer's disease and even in individuals afflicted with pathological lying.

Of course, underdeveloped or withered myelin could be a result of poor signaling among neurons, not necessarily a cause. After all, cognitive function does depend on neuronal communication across synapses in the cortex's gray matter, where most psychoactive drugs act. Yet optimal communication among brain regions, which is also fundamental to proper cognition, depends on the white matter bedrock connec- ting the regions. In 2007 Gabriel Corfas, a neurologist at Children's Hospital Boston, showed that experimental disruption of genes in oligodendrocytes -- not in neurons -- of mice causes striking behavioral changes that mimic schizophrenia. And the beha- vioral effects involve one of the same genes, neuregulin, found to be abnormal in biopsies of schizophrenic brains.

The chicken-and-egg question of whether changes in myelin alter neurons or whe- ther changing neuronal patterns alter myelin will be settled the same way such di- lemmas always are: with the acknowledgment that there is a close interdependence between the two mechanisms. Myelinating glia can respond to changes in axon dia- meter, but they also regulate that diameter. And they can determine whether or not a given axon survives. In multiple sclerosis, for example, axons and neurons can die after myelin is lost as a result of the disease.

Remodeling Old Age

Whatever the mechanism, as our brain matures from childhood to adulthood the pre- cision of connections among regions improves. How well the connections are made may dictate how well we can learn certain skills at certain ages.

Indeed, Ullén's studies of accomplished pianists revealed an additional finding: white matter was more highly developed throughout the brains of individuals who had taken up the instrument at an earlier age. In people who learned after adolescence, white matter development was increased only in the forebrain - the region that was still undergoing myelination.

This finding suggests that the insulating of nerve fibers in part determines age limits for learning new skills - windows of opportunity,or critical periods,when certain lear- ning can occur or at least can occur readily. Learn a foreign language after puberty, and you are destined to speak it with an accent; learn the language as a child, and you will speak it like a native. The difference occurs because the brain circuits that detect speech rewire according to the sounds we hear only as a child. We literally lose the connections that would allow us to hear sounds unique to foreign langua- ges. In evolutionary terms, the brain has no reason to retain connections to detect sounds that it has never heard after years of childhood. Critical periods are also one of the main reasons adults do not recover as well from brain injuries as children do.

Specialists have identified specific protein molecules in myelin that stop axons from sprouting and forming new connections. Martin E.Schwab, a brain researcher at the University of Zurich,revealed the first of several myelin proteins that cause young sprouts from axons to wither instantly on contact. When this protein, which he named Nogo (now referred to as Nogo-A), is neutralized, animals with a spinal cord injury can repair their damaged connections and recover sensation and movement.Recent- ly Stephen M. Strittmatter of Yale found that the critical period for wiring the brains of animals through experience could be reopened by blocking signals from Nogo.When the protein is disrupted in old mice, the critters can rewire connections for vision.

If myelination is largely finished in a person's 20s, however, does that contradict recent claims that the brain remains plastic throughout middle and old age? For example, studies show that mental exercise into a person's 60s, 70s and 80s helps to delay the onset of Alzheimer's. And how does a person's wisdom increase over the decades?Answers are still forthcoming. Researchers have not yet looked for myelin changes in older animals. Other experiments suggest myelination continues into our mid-50s but on a much subtler level.

Certainly white matter is key to types of learning that require prolonged practice and repetition,as well as extensive integration among greatly separated regions of the ce- rebral cortex. Children whose brains are still myelinating widely find it much easier to acquire new skills than their grandparents do. For a range of intellectual and athletic abilities, if an individual wants to reach world-class level he or she must start young. You built the brain you have today by interacting with the environment while you were growing up and your neural connections were still myelinating. You can adapt those abilities in many ways, but neither you nor I will become a world-class pianist, chess player or tennis pro unless we began our training when we were children.

Of course, old geezers can still learn, but they are engaged in a different kind of lear- ning involving the synapses directly.And yet intensive training causes neurons to fire, so the potential exists for that firing to stimulate myelination.Perhaps someday, when we fully understand when and why white matter forms, we can devise treatments to change it, even as it grows old. To deliver on that speculation, we would need to find the signal that tells an oligodendrocyte to myelinate one axon and not anotherone nearby. That discovery,buried deep underneath the gray matter,awaits unearthing by future explorers.

Einsteinin aivojen ainoa erikoisuus johti aivojen toimintateorian jäljille
Kirjoitti: RK (IP rekisteröity)
Päiväys: 15. elokuuta 2008 18.03

RK kirjoitti:
> see "The Other Half of the Brain," by R. Douglas Fields; SCIENTIFIC AMERICAN, April 2004

Fieldsin teoria on julkaistu jo v. 2004, mutta se on nyt tarkentunut ja vahvistunut kehittyneimmillä aivokuvantamismenetelmillä.

The Other Half of the Brain.

Fields, R. Douglas


The recent book Driving Mr. Albert tells the true story of pathologist Thomas Harvey, who performed the autopsy of Albert Einstein in 1955. After finishing his task, Harvey irreverently took Einstein's brain home, where he kept it floa- ting in a plastic container for the next 40 years. From time to time Harvey doled out small brain slices to scientists and pseudoscientists around the world who probed the tissue for clues to Einstein's genius. But when Harvey reached his 80s, he placed what was left of the brain in the trunk of his Buick Skylark and embarked on a road trip across the country to return it to Einstein's granddaughter.

One of the respected scientists who examined sections of the prized brain was Marian C. Diamond of the University of California at Berkeley. She found no- thing unusual about the number or size of its neurons (nerve cells). But in the association cortex, responsible for high-level cognition, she did discover a surprisingly large number of nonneuronal cells known as glia -- a much greater concentration than that found in the average Albert's head.

An odd curiosity? Perhaps not. A growing body of evidence suggests that glial cells play a far more important role than historically presumed. For decades, physiologists focused on neurons as the brain's prime communicators. Glia, even though they out- number nerve cells nine to one, were thought to have only a maintenance role: brin- ging nutrients from blood vessels to neurons,maintaining a healthy balance of ions in the brain, and warding off pathogens that evaded the immune system. Propped up by glia,
neurons were free to communicate across tiny contact points called synapses and to establish a web of connections that allow us to think, remember and jump for joy.

That long-held model of brain function could change dramatically if new findings about gila pan out. In the past several years, sensitive imaging tests have shown that neurons and glia engage in a two-way dialogue from embryonic development through old age. Glia influence the formation of synapses and help to determine which neural connections get stronger or weaker over time; such changes are essen- tial to learning and to storing long-term memories. And the most recent work shows that gila also communicate among themselves, in a separate but parallel network to the neural network, influencing how well the brain performs. Neuroscientists are cautious about assigning new prominence to glia too quickly, yet they are excited by the prospect that more than half the brain has gone largely unexplored and may contain a trove of information about how the mind works.

See Me, Hear Me

THE MENTAL PICTURE most people have of our nervous system resembles a tangle of wires that connect neurons. Each neuron has a long, outstretched branch -- an axon -- that carries electrical signals to buds at its end. Each bud emits neuro-transmitters -- chemical messenger molecules--across a short synaptic gap to a twig like receptor, or dendrite, on an adjacent neuron. But packed around the neurons and axons is a diverse population of glial cells. By the time of Einstein's death, neurosci-entists suspected that glial cells might contribute to information processing, but con- vincing evidence eluded them. They eventually demoted glia, and research on these cells slid into the backwater of science for a long time.

Neuroscientists failed to detect signaling among glia, partly because they had insuf-ficient technology analytical but primarily because they were looking in tie wrong place. They incorrectly assumed that if glia could chatter they would use the same electrical mode of communication seen in neurons. That is, they would generate electrical impulses called action potentials that would ultimately cause the cells to release neurotransmitters across synapses, igniting more impulses in other neurons. Investigators did discover that glia had many of the same voltage-sensitive ion chan- nels that generate electrical signals in axons, but they surmised that these channels merely allowed glia to sense indirectly the level of activity of adjacent neurons. They found that glial cells lacked the membrane properties required to actually propagate their own action potentials. What they missed, and what advanced imaging tech- niques have now revealed, is that glia rely on chemical signals instead of electrical ones to convey messages.

Valuable insights into how glia detect neuronal activity emerged by the mid-1990s, after neuroscientists established that glia had a variety of receptors on their mem- branes that could respond to a range of chemicals, including, in some cases, neuro-tranimitters. This discovery suggested that glia might communicate using chemical signals that neurons did not recognize and at limes might react directly to neurotransmitters emitted by neurons.

To prove such assertions, scientists first had to show that glia actually do "listen in" on neuronal communication and take action based on what they "hear'" Earlier work indicated that an influx of calcium into glial cells could be a sign that they had been stimulated. Based on that notion, investigators devised a laboratory method called calcium imaging to see whether glial cells known as terminal Schwann cells --. which surround synapses where nerves meet muscle cells--were sensitive to neuronal sig- nals emitted at these junctions. The method confirmed that Schwann Cells, at least, did respond to synaptic firing and that the reaction involved an influx of calcium ions into the cells.

But were glia limited only to eavesdropping on neuronal activity, by scavenging traces of neurotransmitter leaking from a synapse? More general-function Schwann cells also surround axons all along nerves in the body, not just at synapses, and oli- godencrocyte glia cells wrap around axons in the central nervous sys-tern (brain and spinal cord). At my National Institutes of Health lab, we wanted to know if glia could monitor neural activity anywhere as it flowed through axons in neural circuits. If so, how was that communication mediated? More important, how exactly would glia be affected by what they heard?

To find answers, we cultured sensory neurons (dorsal root ganglion, or DRG, cells) from mice in special lab dishes equipped with electrodes that would enable us to trigger action potentials in the axons. We added Schwann cells to some cultures and oligodendrocytes to others.

We needed to tap independently into the activity of the axons and the glia to deter- mine if the latter were detecting the axon messages. We used a calcium-imaging technique to record visually what the cells were doing, introducing dye that fluores- ces if it binds to calcium ions. When an axon fires, voltage-sensitive ion channels in the neuron's membrane open, allowing calcium ions to enter. We would therefore expect to see the firing as a flash of green fluorescence lighting up the entire neuron from the inside. As the concentration of calcium rose in a cell, the fluorescence would get brighter. The intensity could be measured by a photomultiplier tube, and images of the glowing cells could be digitized and displayed in pseudocolor on a monitor in real time -- looking something like the radar images of rainstorms shown on weather reports.If glial cells heard the neuronal signals and did so in part by taking up calcium from their surroundings, they would light up as well, only later.

Staring at a computer monitor in a darkened room, my NIH colleague, biologist Beth Stevens, and I knew that after months of preparation our hypothesis was about to be tested with the flick of a switch. When we turned on the stimulator, the DRG neurons responded instantly, changing from blue to green to red and then white on a pseudo- coior scale of calcium concentration,as calcium flooded into the axons.Initially,there were no changes in the Schwann cells or oligodendrocytes, but about 15 long se- conds later the glia suddenly began to light up like bulbs on a string of Christmas lights [see illustration on page 59]. Somehow the cells had detected the impulse ac- tivity in the axons and responded by raising the concentration of calcium in their own cytoplasm.

Gila Communicating with Glia

THUS FAR WE HAD confirmed that gila sense axon activity by taking in calcium. In neurons, calcium activates enzymes that produce neurotransmitters. Presumably, the influx in glial cells would also activate enzymes that would marshal a response. But what response was the cell attempting? More fundamentally, what exactly had triggered the calcium influx?

Clues came from previous work on other gliai cells in the brain known as astrocytes. One of their functions is to carry nutrients from capillaries to nerve cells; another is to maintain the optimal ionic conditions around neurons necessary for firing impulses. Part of the latter job is to remove excess neurotransmitters and ions that neurons re- lease when they fire. In a classic 1990 study, a group led by Stephen J. Smith of Yale University (now at Stanford University) used calcium imaging to show that the cal- cium concentration in an astrocyte would rise suddenly when the neurotransmitter glutamate was added to a cell culture. Calcium waves soon spread throughout all the astrocytes in the culture. The astrocytes were responding as if the neurotransmitter had just been released by a neuron, and they were essentially discussing the news of presumed neuronal firing among themselves.

Some neuroscientists wondered whether the communication occurred because cal- cium ions or related signaling molecules simply passed through open doorways con- necting abutting astrocytes. In 1996 S. Ben Kater and his colleagues at the University of Utah defused that suspicion. Using a sharp microelectrode, they cut a straight line through a layer of astrocytes in culture, forming a cell-free void that would act like a highway separating burning forests on either side. But when they stimulated calcium waves on one side of the break, the waves spread to astrocytes across the void with no difficulty. The astrocytes had to be sending signals through the extracellular medium,rather than through physical contact.

Intensive research in many laboratories over the next few year! showed similar re- sults. Calcium responses could be induced in astrocytes by adding neurotransmitters or by using electrodes to stimulate the release of neurotransmitters from synapses. Meanwhile physiologists and biochemists were finding that glia had receptors for many of the same neurotransmitters neurons use for synaptic communication, as well as most of the ion channels that enable neurons to fire action potentials.

ATP Is the Messenger

THESE AND OTHER RESULTS led to confusion. Glial communication is controlled by calcium influxes just as neuronal communication is. But electrical impulses trigger calcium changes in neurons, and no such impulse exists in or reaches glia. Was glial calcium influx initiated by a different electrical phenomenon or some other mechanism?

In their glial experiments, researchers were noticing that a familiar molecule kept cropping up -- ATP (adenosine triphosphate), known to every biology student as the energy source for cellular activities. Although it makes a great power pack, ATP also has many features that make it an excellent messenger molecule between cells. It is highly abundant inside cells but rare outside of them. It is small and therefore diffuses rapidly, and it breaks down quickly. All these traits ensure that new messages con- veyed by ATP molecules are not confused with old messages.Moreover,ATF is neat- ly packaged inside the tips of axons where neurotransmitter molecules are stored; it is released together with neurotransmitters at synapses and can travel outside synapses, too.

In 1999 Peter B. Guthrie and his colleagues at the University of Utah shouted con- clusively that when excited, astrocytes release ATP into their surroundings. The ATP binds to receptors on nearby astrocytes, prompting ion channels to open and allow an influx of calcium. The rise triggers ATP release from those cells, setting off a chain reaction of AT mediated calcium responses across the population of astrocytes.

A model of how glia around an axon sense neuronal activity and then communicate to other glia residing at the axon's synapse was coming together. The firing of neu- rons somehow induces glial cells around an axon to emit ATP, which causes cal- cium intake in neighboring glia, prompting more ATP release,thereby activating com- munication along a string of glia that can reach far from the initiating neuron. But how could the glia in our experiment be detecting the neuronal firing, given that the axons made no synaptic, connections with the glia and the axonal gila were nowhere near the synapse? Neurotransmitters were not the answer; they do not diffuse out of axons (if they did, they could act in unintended places in the brain, wreaking havoc). Perhaps ATP, which is released along with neurotransmitters when axons fire, was somehow escaping along the axon.

To test this notion, we electrically stimulated pure cultures of DRG axons and then analyzed the medium. By exploiting the enzyme that allows fireflies to glow -- a re- action that requires ATP -- we were able to detect the release of ATP from axons by seeing the medium glow when axons fired. We then added Schwann cells to the cul- ture and measured the calcium responses. They also lit up after axons fired an action potential. Yet when we added the enzyme apyrase, which rapidly destroys ATP -- thereby intercepting the ATP before it could reach any Schwann cells -- the glia re- mained dark when axons fired. The calcium response in the Schwann cells had been blocked, because the cells never received the ATP message.

ATP released from an axon was indeed triggering calcium influx into Schwann cells. Using biochemical analysis and digital microscopy, we also showed that the influx caused signals to travel from the cells' membrane to the nucleus, where the genes are stored, causing various genes to switch on. Amazingly, by firing to communicate with other neurons, an axon could instruct the readout of genes in a glial cell and thus influence its behavior.

Axons Control Glia's Fate

TO THIS POINT, work by us and others had led to the conclusion that a glial cell senses neuronal action potentials by detecting ATP that is either released by a firing axon or leaked from the synapse. The gliai cell relays the message inside itself via calcium ions. The ions activate enzymes that release ATP to other glial cells or activate enzymes that control the readout of genes.

This insight made us wonder what functions the genes might be controlling. Were they telling the glia to act in ways that would influence the neurons around them? Stevens set out to answer this question by focusing on the process that prompts pro- duction of the myelin insulation around axons, which clearly would affect a neuron. This insulation is key to the conduction of nerve impulses at high speed over long distances. Its growth enables a baby to gradually hold up its head, and its destruction by diseases such as multiple sclerosis causes severe impairment.

We turned to myelin because we were curious about how an immature Schwann cell on an axon in the peripheral nervous system of a fetus or infant knows which axons will need myelin and when to start sheathing those axons and, alternatively, how it knows if it should transform itself into a cell that will not make insulation. Generally, only large-diameter axons need myelin. Could axon impulses or ATP release affect these decisions? We found that Schwann cells in culture proliferated more slowly when gathered around axons that were firing than around axons that were quiet. Moreover, the Schwann cells' development was arrested and myelin formation was blocked. Adding ATP produced the same effects.

Working with Vittorio Gallo and his colleagues in the adjacent NIH lab, however, we found a contrasting situation with the oligodendrocyte glia that form myelin in the brain. ATP did not inhibit their proliferation, but adenosine, the substance left when phosphate molecules in ATP are removed, stimulated the cells to mature and form myelin. The two findings indicate that different receptors on glia provide a clever way for a neuron to send separate messages to glial cells in the central or peripheral nervous system without having to make separate messenger molecules or specify message destinations.

Better understanding of myelination is important. Every year thousands of people die and countless more are paralyzed or blinded because of demyelinating disease. Mul- tiple sclerosis, for example, strikes one in 700 people. No one knows what exactly initiates myelinadon, but adenosine is the first substance derived from an axon that has been found to stimulate the process. The fact that adenosine is released from axons in response to axon firing means activity in the brain actually influences myeli-nation. Such findings could mark paths to treatment. Drugs resembling adenosine might help. Adding adenosine to Stem cells could perhaps turn them into myelinating gila that are transplanted into damaged nerves.

Outside the Neuronal Box

EXPERIMENTS IN OUR LAB and others strongly suggest that ATP and adenosine mediate the messages coursing through networks of Schwann and oligodendrocyte gila cells and that calcium messages are induced in astrocyte glia cells by ATP alone. But do glia have the power to regulate the functioning of neurons, other than by producing myelin?

The answer appears to he "yes." Richard Robitaille of the University of Montreal saw the voltage produced by synapses on frog muscle become stronger or weaker de- pending on what chemicals he injected into Schwann cells at the synapse.When Eric A. Newman of the University of Minnesota touched the retina of a rat, waves of cal- cium sent by glia changed the visual neurons' rate of firing.Studying slices of rat brain taken from the hippocampus - a region involved in memory - Maiken Nedergaard of New York Medical College observed synapses increase their electrical activity when adjacent astrocytes stimulated calcium waves.Such changes in synaptic strength are thought to be the fundamental means by which the nervous system changes its response through experience - a concept termed plasticity, suggesting that glia might play a role in the cellular basis of learning.

One problem arises from these observations. Like a wave of cheering fans sweeping across a stadium, the calcium waves spread throughout the entire population of astrocytes. This large-scale response is effective for managing the entire group, but it cannot convey a very complex message. The equivalent of "Go team!" might be use- ful in coordinating general activity in the brain during the sleep-wake cycle or during a seizure, but local conversations are necessary if glial cells are to be involved in the intricacies of information processing.

In a footnote to their 1990paper,Smith and his colleagues stated that they believed neutrons and glia carried on more discrete conversations. Still, the researchers lacked experimental methods precise enough to deliver a. neurotransmitter in a way that resembled what an astrocyte would realistically experience at a synapse.In 2003 Philip G. Haydon of the University of Pennsylvania achieved this objective. He used improved laser technology to release such a small quantity of glutamate in a hippo-campal brain slice that t would be detected by only a single astrocyte. Under this con- dition, Haydon observed that an astrocyte sent specific calcium signals to just a small number of nearby astrocytes.As Haydon put it,in addition to calcium waves that affect astrocytes globally, "there is short-range connectivity between astrocytes."

In other words,discrete astrocyte circuits in the brain coordinate activity with neuronal circuits. (The physical or biochemical factors that define these discrete astrocytic cir- cuits are unknown at present.) Investigation by others has also indicated that astro- cytes may strengthen signaling at synapses by secreting the same neurotransmitter the axon is releasing--in effect, amplifying the signal.

The working hypothesis that Haydon and I, along with our colleagues, are reaching from these dis- coveries is that communication among astrocytes helps to activate neurons whose axons terminate relatively far away and that this activity, in turn, contributes to the release of neurotransmitters at distant synapses. This action would regulate how susceptible remote synapses are to undergoing a change in strength, which is the cellular mechanism underlying learning and memory.

Results announced at the Society for Neuroscience's annual meeting in November 2003 support this notion and possibly expand the role of glia to include participation in the formation of new synapses [see box on opposite page]. Some of the findings build on research done two years earlier by Ben A. Barres, Frank W. Pfrieger and their colleagues at Stanford, who reported that rat neurons grown in culture made more synapses when in the presence of astrocytes.

Working in Barres's lab, postdoctoral students Karen S. Christopherson and Erik M. ULlian have subsequently found that a protein called thrombospondin, presumably from the astrocyte, was the chemical messenger that spurred synapse building.

Thrombospondin plays various biological roles but was not thought to be a major factor in the nervous system. The more thrombospondin they added to the astrocyte culture, though,the more synapses appeared. Thrombospondin may be responsible for bringing together proteins and other compounds needed to create a synapse when young nerve networks grow and therefore might contribute to the modification of synapses as the networks age.

Future experiments could advance our emerging understanding of how glia affect our brains. One challenge would be to show that memory -- or a cellular analogue of me- mory, such as long-term potentiation -- is affected by synaptic astrocytes. Another challenge would be to determine precisely how remote synapses might be influenced by signals sent through astrocyte circuits.

Perhaps it should not be surprising that astrocytes can affect synapse formation at a distance. To form associations between stimuli that are processed by different cir- cuits of neurons-the smell of a certain perfume, say,and the emotions it stirs about the person who wears it -- the brain must have ways to establish fast communication bet- ween neuronal circuits that are not wired together directly, if neurons are like tele- phones communicating electrically through hardwired synaptic connections, astro- cytes may be like cell phones, communicating with chemical signals that are broad- cast widely but can be detected only by other astrocytes that have the appropriate re- ceptors tuned to receive the message. If signals can travel extensively through astro- cyte circuits, then glia at one site could activate distant gila to coordinate the firing of neural networks across regions of the brain.

Comparisons of brains reveal that the proportion of glia to neurons increases greatly as animals move up the evolutionary ladder. Haydon wonders whether extensive connectivity among astrocytes might contribute to a greater capacity for learning. He and others are investigating this hypothesis in new experiments. Perhaps a higher concentration of glia, or a more potent type of glia, is what elevates certain humans to genius. Einstein taught us the value of daring to think outside the box.

Neuroscientists looking beyond neurons to see how glia may be involved in information processing are following that lead.


Driving Mr. Albert: A Trip across America with Einstein's Brain. Michael Paterniti. Delta, 2001.

New Insights into Neuron-Glia Communication. R. D. Fields and B. Stevens-Graham in Science, Vol. 298, pages 556-562; October 18, 2002.

Adenosine: A Neuron-Glial Transmitter Promoting Myelination in the CNS in Response to Action Potentials. B. Stevens, S. Porta, L. L. Haak, V. Gallo, and R. D. Fields in Neuron, Vol. 36, No. 5, pages 855-868; December 5, 2002.

Astrocytic Connectivity in the Hippocampus. Jai-Yoon Sul, George Orosz, Richard S. Givens, and Philip G. Haydon in Neuron Glia Biology, Vol. 1, pages 3-11; 2004.

Also see the journal Neuron Glia Biology:



• For decades, neuroscientists thought neurons did all the communicating in the brain and nervous system, and glial cells merely nurtured them, even though glia outnumber neurons nine to one.

• Improved imaging and listening instruments now show that glia communicate with neurons and with one another about messages traveling among neurons. Glia have the power to alter those signals at the synaptic gaps between neurons and can even influence where synapses are formed.

• Given such prowess, glia may be critical to learning and to forming memories, as well as repairing nerve damage. Experiments are getting under way to find out.

PHOTO (COLOR): GLIAL CELLS outnumber neurons nine to one in the brain and the rest of the nervous system.

PHOTO (COLOR): GLIA AND NEURONS work together in the brain and spinal cord. A neuron sends a message down a long axon and across a synaptic gap to a dend- rite on another neuron. Astrocyte gila bring nutrients to neurons as well as surround and regulate synapses. Oligodendrocyte gila produce myelin that insulates axons. When a neuron's electrical message [action potential] reaches the axon terminal [inset], the message induces vesicles to move to the membrane and open, releasing neurotransmitters [signaling molecules] that diffuse across a narrow synaptic cleft to the dendrite's receptors. Similar principles apply in the body's peripheral nervous system, where Schwann cells perform myelination duties.

PHOTO (COLOR): ASTROCYTES REGULATE SIGNALING across synapses in va- rious ways. An axon transmits a signal to a dendrite by releasing a neurotransmitter (green) -- here,glutamate. It also releases the chemical ATP [gold].These compounds then trigger an influx of calcium (purple) into astrocytes, which prompts the astrocytes to communicate among themselves by releasing their own ATP. Astrocytes may strengthen the signaling by secreting the same neurotransmitter, or they may weaken the signal by absorbing the neurotransmitter or secreting proteins that bind to it (blue), thereby preventing it from reaching its target. Astrocytes can also release sig- naling molecules I red) that cause the axon to increase or decrease the amount of neurotransmitter it releases when it fires again. Modifying the connections among neurons is one way the brain revises its responses to stimuli as it accumulates expe- rience -- how it learns. In the peripheral nervous system, Schwann cells surround synapses.

PHOTO (COLOR): MOVIE MADE using scanning-laser confocal microscopy [later colorized] shows that glial cells respond to chattering neurons. Sensory neurons [two large bodies, 20 microns in diameter] [al and Schwann glial cells [smaller bodies] were mixed in a lab culture containing calcium ions [invisible J. Dye that would fluo- resce if calcium ions bound to it was introduced into the cells.A slight voltage applied to the neurons prompted them to fire action potentials down axons [long lines], and the neurons immediately lit up [bl,indicating they had opened channels on their mem- branes to allow calcium to flow inside. Twelve seconds later [c}, as the neurons conti- nued to fire, Schwann cells began to light up, indicating they had begun taking in cal. cium in response to the signals traveling down axons/Eighteen seconds after that [d], more gila had lit up, because they had sensed the signals. The series shows that gila tap into neuronal messages all along the lines of communication,not just at synapses where neurotransmitters are present.

PHOTO (COLOR): HOW DO GLIA communicate? Gila called astrocytes [a] and sen- sory neurons [not shown] were mixed in a lab culture containing calcium ions. After a neuron was stimulated to fire action potentials down long axons [lightning bolts] [b], gila began to light up, indicating they sensed the message by beginning to absorb calcium. After 10 and 12.5 seconds [c and d], huge waves of calcium flux were swee- ping across the region, carrying signals among many astrocytes. Green to yellow to red depicts higher calcium concentration.

Lisää ko. mekanismista: valkean aineen välitilaneuronit (intermediate neurons):

Tästä viestistä alkoi Vaparien keskustelusivujen alasajo. Mode Kari P. vastasi seu- raavalla "viestillä", ja uhkasi hävittää ketjun, koska siinä on liikaa minun viestejäni:

Re: Einsteinin aivojen ainoa erikoisuus johti aivojen toimintateorian jäljille

Kirjoitti: Kari P (IP rekisteröity)
Päiväys: 16. elokuuta 2008 09.03


"Kyky suunnitella, eli "toimia ensin päässään ja sitten vasta objektimaailmassa" on ihmisten taito."

Tarkoitat, että "vain ihmisten taito". Uutinen ja siinä viitattu tutkimus ovat toista mieltä.

Väitteesi on muodoltaan negatiivinen väite, joten sitä ei voi todistaa oikeaksi, vain vääräksi osoittamalla, että on olemassa eläinlajeja, joilla on kykyä suunnitella. Näin on tehty.

"Sitä vastoin KAIKKI EHDOLLISTUMINENhan perustuu nimenomaan kokemukselle, joten se on ominaista kaikille AIVOKUORELLISILLE nisäkkäille ja linnuille, ei suinkaan "pelkästään ihmiselle"!"

Uutinen ei koskenut ehdollistumista, joten et voine esittää, että se kyseenalaisti noita väitteitäsi.

"Mitähän hörhöilyä siellä oikein taas on..."

Sanot näin tietysti lukematta koko uutista vaikka eihän se sinun mielipidettäsi missään tapauksessa muuttaisi. Pistin uutisen tänne ihan sinun kiusaksesi arvaten suhtautumisesi siihen etukäteen.

Ei ole hyvää foorumikäyttäytymistä laittaa pitkiä artikkelilainauksia kommentoimatta niitä mitenkään. Sinun pitäisi osoittaa niistä jokin "pointti", josta jo on ollut erimieli-syyttä tai joka muuten voisi herättää keskustelua. Tämä foorumi on keskustelu-, ei julistuspalsta. "

Viseti, jokoh mode kari P. tuossa viittaa, on tämä:

"Sunnittelua sumpanssilla?

Kirjoitti: RK (IP rekisteröity)

Kari P kirjoitti:
> Uusi Tiede-lehti (8/2008) julkaisi uutisen otsikolla "Uniikit kykymme hupenivat
> taas": "Kyky suunnitella tulevia ja kyky soveltaa koeteltua tietoa uusiin tilanteisiin
> ovat olleet vain meidän ihmisten taitoja. Eivät ole enää. Lundin yliopiston
> kognitiotutkijat Mathias ja Helena Osvath ovat osoittaneet, että simpanssi ja oranki
> hallitsevat tällaisen kaavailun, ja jos ne, miksei myös gorilla, vaikka sitä ei nyt
> testattukaan."

Kas kun löysinkin tuon "uutisen", kun ostin tapojeni vastaisesti lehden. Kyseinen koe todistaa ihan muuta kuin miten "TIEDE" ja "Animal Cognition" "tulkitsevat":

Kerrassaan erinominen esimerkki nimenomaan instumentaalisesta ehdollisesta re- fleksistä ja siitä miten sellainen voi mennä ärsykehierarkiassa yli välittömään tar- peentyydytykseen liittyvästä klassisesta ehdollisesta refleksistä, tuossa tapauksessa syömisestä, oli TIEDE 8/2008:n "uutinen" muka "suunnittelusta simpanssilla":

Simpanssi sai ruoakseen joko miten kuten kelpaavia hedelmiä, tai sitten erittäin her- kullista hedelmäsoppaa, jota se oli opetettu imemään letkulla. Kun se sai tilaisuuden valita joko käsillä olevia hedelmiä syödäkseen, tai pelkän imuletkun, joka vain viittasi huomattavasti mieleisempään ruokaan, se valitsi letkun (ja jäi odottamaan hedelmä-soppaa, ainakin niin kauan kunnes huutava nälkä kääntäisi kuitenkin ärsykehierarkian hedelmien puoleen, jos soppaa ei kuulukaan...).

Tämän "TIEDE" katsoi "todistavan simpanssin ajattelun puolesta reagointia vas- taan": simpanssi olisi ikään kuin ajatellut "en syö paskaa, en syö paskaa, kun kerran parempaakin saa, parempaakin saa..."

Kuitenkin tuo koe todistaa kahden ehdollisen refleksin, klassisen (heti syöminen) ja instrumentaalisen KILPAILUA ärsykehierarkiassa,aivan erityisesti jos kokeen taholta EI OLE ESTETTY VALITSEMASTA MOLEMPIA, kuten AJATTELEVA simpanssi olisi ainakin yrittänyt tehdä: jemmata hedelmätkin itselleen siltä varalta, ettei saakaan soppaa!

Kokeessa ilmennyt käyttäysyminen oli täysin odotetteua lukuisten kokeiden perusteella, joita on tehty simpanssien, koirien jne. huomattavan monimutkaisiksi kehitettävissä olevilla instrumentaalisilla ehdollisilla reflekseillä.

Sikäli koe on kyllä ajattelun ja/eli suunnittelun jäljillä, että juuri tuollaisten instrumen-taalisten ehdollisten refleksien pohjalta se ja symbolinen kommunikaatio muodostu- vat, ja tuollaiset mainitut seikat kuten "kyky tinkiä välittömästä tarpeentyydytyksestä" (vaikkei se reflekseillä ole kaan tietoista!) ovat molempien edellytyksiä.

Koe on myös sikäli kuvaava ihmistymisen kannalta olennaisille piirteille, että siinä esiintyy "käyttäytymisinstrumentin" lisäksi fysikaalinen instrumentti, työkalu, eli juuri se sopanimuputki joka samalla toimii sillä suorittevan instrumentaalisen operaation SIGNAALINA ("merkkinä").

Tuollainen työkalu ei siis ole instrumentaaliselle ehdolliselle refleksille välttämättö- myys, mutta kun sellainen sattuu olemaan, se on myös erittäin tehokas keino välittää kyseinen refleksi laumassa muille, esimerkiksi pennuille.

On muuten huomattava,että "toiminnassa oleva" ehdollinen refleksi näkyy aina taval- la tai toisella esimerkiksi simpanssin ulkoisesta toiminnasta,mutta TAJUNNAN, ihmi- sen ajattelun, EI TARVITSE NÄKYÄ TOIMIASSA MILLÄÄN TAVALLA ULOSPÄIN. "


Tämä tarkoittaa, kuten akateemikko Mikko Korhonenkin eräässä kirjassaan toteaa (Noam Chomskyn "kielielimestä"), että AVARUUSARAKENTIN SUUNNITTELUNKIN PITÄISI OLLA KEENISTÄ!!!



(Ja sitten vielä haukutaan Pavlovin teoriaa "uskonnolliseksi", helvetin helvetin helvetti!)

Viesti väärässä paikassa
Kirjoitti: RK (IP rekisteröity)
Päiväys: 16. elokuuta 2008 21.43
Kari P kirjoitti:
> RK,

> "Kyky suunnitella, eli "toimia ensin päässään ja sitten vasta objketimaailmassa" on ihmisten taito."

> Tarkoitat, että "vain ihmisten taito".

Kyllä. Vain ihminen sanan psykokologisessa merkityksessä ylipäätään "toimii", muut lajit simpanssi mukaan lukien REAGOIVAT, vaikka sitten kuinka kattavalta osin opituin, ei-geneettisin ehdollistunein malleinkin.

> Uutinen ja siinä viitattu tutkimus ovat toista mieltä.

MITÄ uutista tarkoitat? Tätäkö, johon olet kommenttisi liittänyt?

Ellet tarkoita tätä, on "kommenttisi" tässä AIVAN JÄRJETÖN.

> Väitteesi on muodoltaan negatiivinen väite, joten sitä ei voi todistaa oikeaksi, vain
> vääräksi osoittamalla, että on olemassa eläinlajeja, joilla on kykyä suunnitella. >Näin on tehty.

Voi tämän osoittaa todeksi, kun vain on kunnon tosi ajatteluteoria, että miten se ajattelu/suunnittelu (ne ovat lopultakin aivan samaa) eroaa elänten reagoinnista, ja millaiset edellytykset tällainen ero vaatii.

Teorioiden ja käsitteiden totuus on ensisijaista erllisten lauseiden totuuteen verrattu- na, mm. koska kaikenlainen TEOREETTINEN todostaminen aina tapahtuu jonkin TEORIAN SISÄLLÄ.

> "Sitä vastoin KAIKKI EHDOLLISTUMINENhan perustuu nimenomaan
> kokemukselle, joten se onominaista kaikille AIVOKUORELLISILLE nisäkkäille ja >linnuille, ei suinkaan "pelkästään ihmiselle"!"

> Uutinen ei koskenut ehdollistumista, joten et voine esittää, että se kyseenalaisti >noita väitteitäsi.

MIKÄ uutinen?Tuoko,että ehdollistamisen biokemiallinen mekanismi löydettiin Einsteinin aivojen avulla? Jos taas jokin muu uutinen, jonka vain sinä tiedät, niin käsittele, sitten siellä, missä se on näkösällä!

> "Mitähän hörhöilyä siellä oikein taas on..."

> Sanot näin tietysti lukematta koko uutista vaikka eihän se sinun mielipidettäsi
> missään tapauksessamuuttaisi. Pistin uutisen tänne ihan sinun kiusaksesi arvaten >suhtautumisesi siihen etukäteen.

MINKÄ uutisen? En löydä sinun vietistäsi ENSIMMÄISTÄKÄÄN UUTISTA! Kirjoitat ihan kuin koko maailmassa olisi vain yksi "Uutinen"!

Sinä terrorisoit keskustelupalstaa.

>Ei ole hyvää foorumikäyttäytymistä laittaa pitkiä artikkelilainauksia kommentoimatta >niitä mitenkään.

Tuo oli liitelinkki, jota useimpien lukijoiden on vaikea saada käsiinsä, edellisen viestin juttuun, jonka kommentit sitten koskevat molempia.

> Sinun pitäisi osoittaa niistä jokin "pointti", josta jo on ollut erimielisyyttä tai joka
> muuten voisi herättää keskustelua. Tämä foorumi on keskustelu-, ei julistuspalsta.

Te jotkut olette olleet "erimileisiä" tieteen ja siinä ohessa myös minun kanssani koko ehsollistumismekanismin OLEMASSAOLOSTA, ettekä pelkästään sen biokemiallisesta mekanismista!

Re: Viesti väärässä paikassa
Kirjoitti: Kari P (IP rekisteröity)
Päiväys: 16. elokuuta 2008 22.19


"MINKÄ uutisen? En löydä sinun viestistäsi ENSIMMÄISTÄKÄÄN UUTISTA!"

Keskusteluketjuun kirjoitetut viestit linkittyvät toisiinsa, aikaisemmin kirjoitettuun. Tarkoitin koko ajan sitä Tiede-lehden uutista, jonka mainitsin viestissäni 15. elokuuta 2008 08.42 ja jonka oleellisen sisällön (ei mitään Einsteinin aivoista!) lainasin siihen. Olisi luullut sinun muistavan sen! Mutta ethän sinä lue edes keskusteluviestejä saati Tiede-lehdeeä. Eikä tosiaankaan ole tarkoitus lainata tänne kokonaisia artikkeleita tai uutisia, joten minäkään en tehnyt niin.

Tiede etenee. Se ei jää siihen, mitä se on ollut joskus 1930-luvulla. Ja viimeaikaiset tutkimukset, joita sinä et halua uskoa, osoittavat vastustamattomasti, että ihmisen ja muun eläimen ero on pieni ja kaventuu koko ajan. Suunnittelu ja ajattelu eivät tieten- kään vaadi asioiden pukemista sanalliseen muotoon, joten puhekielen olemassaolo ei ole ajattelun edellytys vaan ajatteleminen voidaan nähdä eläimen käyttäytymisestä niin kuin tässä tapauksessa oli tehty.

Jumittamalla ajatuksesi siihen, että ihmisen ja (muun) eläimen välillä on laadullinen ero, osoitat uskovaisuutesi. Juuri sellaisen eron uskovaiset näkevät.

Täällä tarvittaisiin moderointia sinunlaisiasi ei-keskustelullisen tekstin suoltajille (ja niin kuin nyt näytti, itsensä kanssa keskustelijalle). "

(Mode siis heitti laakista roskiin kielleisen ajatteluteorian jonkin "Tiede-lehden artik-kelin" perusteella, johon ei edes annettu linnkiä, raivostuneena minun kopioimistani SCIENTIFIC AMERICANIN artikkeleista, jotka kohta olisivat menneet useimmilta lukijoilta muuten tunnuten taakse!)

Re: Viesti väärässä paikassa
Kirjoitti: Kari P (IP rekisteröity)
Päiväys: 17. elokuuta 2008 20.00

Juuri RK yrittää tehdä palstan lukukelvottomaksi.Osallistuisin siihen itsekin,*jos* vas- taisin hänen valheellisiin ja vääristeleviin väitteisiinsä yksitellen. Sitä minä en tee.

RK:n viesti, johon minä ja Sam viittaamme, on poistettu.

Re: Viesti väärässä paikassa
Kirjoitti: RK (IP rekisteröity)
Päiväys: 20. elokuuta 2008 01.14

Kari P kirjoitti:
> Juuri RK yrittää tehdä palstan lukukelvottomaksi. Osallistuisin siihen itsekin, *jos*
> vastaisin hänen valheellisiin ja vääristeleviin väitteisiinsä yksitellen. Sitä minä en >tee.

> RK:n viesti, johon minä ja Sam viittaamme, on poistettu.

Taas te valehtelette.

Tästä ketjusta ei ole ainakaan ihan viime aikoina poistettu allekirjoittaneen viestejä.

Re: Viesti väärässä paikassa
Kirjoitti: Kari P (IP rekisteröity)
Päiväys: 20. elokuuta 2008 08.58
RK valehtelee. Sen todistaa Samin RK:n viestistä ottama lainaus "NO MITÄ HEL- VETTIÄ SINÄ SITTEN SOTKET TUON HYVÄN KÄYTÄNNÖN?!", jota ei löydy mis- tään hänen alkuperäisestä viestistään. Poistettu viesti oli kirjoitettu aamuyöllä 17.8.

(Tuollaista viestiä ei ollut. Ehkä sitten "Sam" oli poistanut "viestinsä"...)

Stories by R. Douglas Fields

" The Hidden Brain

Sitting in a darkened lab at the National Institutes of Health in 1999, my ­colleague Beth Stevens and I prepared to send a mild electric current through fetal mouse neu- rons in a cell culture. We were using a new microscope technique that would let us see ­electrical activity as a bright fluorescence emitted from a dye we had added to the culture, and we were hoping to find out if another kind of cell common in the ner- vous system would react in some way, Schwann cells,odd-looking cells that fabricate insulation around neurons. We didn’t really expect them to; Schwann cells cannot communicate ­electrically. I flipped the switch. The neurons immediately glowed. But then the Schwann cells began to glow as well. It was as if they were talking back.

The most mysterious substance on earth is the stuff between your ears, and much of the intrigue exists because many long-held beliefs about how the brain works have turned out to be wrong. Like medieval astronomers who were shocked to learn that the earth is not the center of the universe, neuroscientists today are facing a similar revelation about neurons.

Until recently, our understanding of the brain was based on a century-old idea called the neuron doctrine. This theory holds that all information in the nervous system is transmitted by electrical impulses over networks of neurons linked through synaptic connections. But this bedrock theorem is deeply flawed. New research proves that some information bypasses the neurons completely, flow­ing without electricity through networks of cells called glia. The studies are upending our understanding of every aspect of brain function in health and disease, bringing answers to long-standing riddles about how we remember and learn.

Glial cells interact with neurons,control them,work alongside them,and the functions of these strange-looking cells are myriad.Star-shaped astrocytes ferry neurotransmit- ters, food and waste. Ceph­alopod-like oligodendrocytes and sausage-shaped Schwann cells wrap themselves around neurons like sheaths, speeding their electri- cal transmissions and helping control muscle contractions throughout the body. Mic- roglia, ranging in form from multibranch to ameboid, are the brain’s first responders to injury and disease, killing invading germ cells and beginning the process of repair.

Especially exciting is new research showing the central role of glia in information processing, neurological disorders and psychiatric illness. Some glial cells speed in- formation between distant regions of the brain, helping us master complex cognitive processes. Others break down as they age and in their failure bring dementia. This research has great implications not only for understanding how the brain works but also for developing new treatments for neurological and psychological illnesses.

And all this comes down to a class of brain cells dismissed for 100 years as mere putty. In the 19th century,when pioneering scientists first trained microscopes on gray matter, they were amazed to find a cell unlike any other in the body:the neuron.At one end of this dazzling cell was a long, wirelike structure called the axon that carried electrical impulses to a cluster of transmission terminals. At the opposite end,the neu- ron sprouted busy, rootlike dendrites that received signals from the axons of other neurons, ferried across the space that separated them, the synapse, by tailor-made chemicals. Neurons were scattered sparsely throughout the brain like juicy raisins, but few cared to examine the seemingly bland dough in which they were embedded.

But, as Sherlock Holmes observed,“There is nothing more deceptive than an obvious fact,” and the fact that scientists were ignoring is that neurons make up only 15 per- cent of our brain cells; the other 85 percent were considered little more than packing material. Indeed, 19th-century German pathologist Rudolf Virchow, one of the first to study glia,likened this brain matter to connective tissue and dubbed it nervenkitt,mea- ning nerve putty or cement, which in English became “neuroglia,” from the Greek root for glue.

Few scientists are drawn to brain research to study glue. We still have no singular noun equivalent to neuron when we speak about an individual glial cell. Virchow barely distinguished between the different sorts of glia. And none of this mishmash of bizarre-looking cells had any of the telltale features essential for neuronal communi-cation, such as axons, dendrites or synapses, so scientists had no reason to suspect that glia might be communicating in secret and doing so in an unexpected way.

A Language of Their Own

Neurons use both electricity and chemistry to convey information, with electricity transmitting impulses along the wirelike axon and chemicals carrying those signals across the synapse to another neuron. The recipient neuron then fires an electrical impulse and relays the signal to the next neuron in the chain.

Only in the past few years have scientists come to realize that the glial cells called astrocytes can control synaptic communication. So named because early anatomists thought they resembled stars, astrocytes were at first thought to be responsible only for housekeeping functions such as transporting nutrients from the bloodstream to the neurons and carrying waste in the opposite direction. These functions were surmised from the way many astrocytes cling to blood vessels with some of their arms and reach deep into brain tissue with others, tightly grasping neurons and their synapses. Only later did scientists come to see that neurons are utterly dependent on glia to fire their electrical impulses and to pass messages to one another across synapses. A clue that this dependency might be the case was the discovery of the same neuro-transmitter receptors on glia as on neurons. As it happens, glia were listening to neurons and talking among themselves without using electricity at all.

This discovery awaited the invention of new tools allowing electrical activity to be seen as flashes of light. The microelectrodes that neuroscientists typically use to probe neuronal function are deaf to glial communication. But video and laser-illumi- nated microscopes developed in the 1980s and 1990s let researchers monitor neuro- nal firing by adding tracer dyes to the cells. Like the fluorescent fluid in a glow stick, these dyes shone when ions such as calcium entered neurons as their axons carried a signal, causing the dye to generate light. Very quickly those of us using these new methods saw that when we stimulated a neuron to fire an impulse, the neuroglia, hid- den in plain sight,flashed back. Glia had sensed the electrical activity in neurons, and somehow calcium ions had flooded into them as well, producing the same green glow.

The new technique also revealed that glia communicate with one another in the same way. Scientists observed that when neurotransmitters released by neurons stimulated receptors on glia, the glia released neurotransmitters as well. And the re- lease stimulated a chain reaction as the message was passed to other glia. The glial communication is stunningly evident as a wave of fluorescent light sweeping from one glial cell to the next after a neuron has fired and released a neurotransmitter.

This finding led to a bigger question: whether glial networks use the information gleaned about neuronal communication at a synapse to manage neuronal signaling at synapses in distant parts of the brain. If so, glia might have a central part in information processing itself.

Recent research provides tantalizing evidence of such a role. Using a laser to stimu- late a calcium wave in an astrocyte next to an axon, a team led by neurobiologist No- rio Matsuki of the University of Tokyo reported earlier this year that neurotransmitters released from the astrocyte boosted the strength of an electrical impulse in the axon. A 2005 study led by neurobiologist Philip Haydon, now at Tufts University , showed that astrocytes provide a nonelectrical pathway for communication between synap- ses in a brain area governing memory,the hippocampus. After responding to the neu- rotransmitter glutamate released from one synapse, astrocytes released a different neurotransmitter, adenosine, affecting the strength not only of its neuronal neighbor but of distant synapses as well. By controlling data processing at synapses, glia participate in aspects of vision, memory, muscle contraction and unconscious brain functions such as sleep and thirst.

The pace and breadth of glial communication provide another bit of evidence that glia play a part in information processing.Unlike neurons,which communicate serially across chains of synapses, glia broadcast their signals widely, like cell phones. Neu- rons’ electrical communication is quite rapid,zipping through neural networks in mere thousandths of a second, but the chemical communication of glia is very slow, sprea- ding as a tidal wave through neural tissue at a pace of seconds or tens of seconds. Rapid response is critical for certain functions — reflexive recoil from a pain stimulus, for example — but many important processes in the brain occur over longer periods.

Not the least important of these is learning. New human brain-imaging techniques have revealed that after learning to play a musical instrument or to read or to juggle, structural changes occur in brain areas that control these cognitive functions. Remar- kably the changes are seen in regions where there are no complete neurons: the “white matter” areas, formed from bundles of axons coated with myelin, a white elect- rical insulator. Previously all theories of learning held that we incorporate new infor-mation solely by strengthening synaptic connections, but there are few synapses in white matter. Clearly, something else is happening.

Findings from my lab in the past 10 years concern two different types of glial cells that cling to axons and coat them with myelin insulation — oligodendrocytes in the brain and Schwann cells in the body. Like an octopus, each cellular tentacle of an oligodendrocyte cell grips an individual segment of an axon and wraps up to 150 layers of compacted cell membrane around it in the way an electrician wraps tape around a wire. This insulation changes how impulses travel through axons, increasing the transmission speed by up to 50 times.

And much like astrocytes at synapses, these myelinforming glia could sense the im- pulses transmitted through axons. This capability was a puzzle at first, because such glia are far from the synapses where neurotransmitters are released. But my lab re- cently discovered that axons also release neurotransmitters through channels in their membrane that open when the axon fires. I was able to see the release of one such neurotransmitter — adenosine triphosphate, or ATP — by fitting my microscope with an extremely high-gain night-scope image intensifier that can detect single photons. For my experiment,I exploited the chemical reaction that produces a firefly’s telltale green flash. I took the protein and enzyme from the tail of a firefly and added them to cultures containing mouse neurons. The firefly proteins require one more ingredient before they can glow:ATP,normally supplied by firefly cells.When I stimulated the mouse axons with a mild electric shock, they released ATP, eliciting a burst of photons.

The formation of myelin in response to stimuli likely means that early life experience plays a big role in brain development. By increasing the speed of information transfer between parts of the brain involved in mastering complex cognitive tasks, these glial cells are essential to learning, too.

How the Brain Goes Awry

Glial cells have also emerged as major actors in a host of neurological and psycho-logical illnesses ranging from epilepsy to chronic pain to depression. Indeed, recent research has found that many neurological disorders are in fact disorders of the glia, in particular a class of cells called the microglia, which serve as the brain’s defense against disease. These specialists seek out and kill invading germs and promote re- covery from injury, clearing away diseased tissue and releasing powerful compounds that stimulate repair. And their function is a factor in every aspect of neurological illness.

New research suggests to some scientists that the dementia of Alzheimer’s disease could be a direct outcome of microglia that have lost the ability to clear waste. Alois Alzheimer first noted that microglia surround the amyloid plaques that are the hallmark of the disease. Normally microglia digest the toxic proteins that form these plaques.But recent studies led by neuroscientist Wolfgang J.Streit of the University of Florida College of Medicine and others suggest that microglia become weaker with age and begin to degenerate. The atrophy is visible under a microscope. Senescent microglia in aged brain tissue become fragmented, losing many of their cellular branches.

The way Alzheimer’s courses through the brain is one more sign of microglial in- volvement. Tissue damage spreads in a predetermined manner, beginning near the hippocampus and eventually reaching the frontal cortex. Streit’s observations show that microglial degeneration follows the same pattern—and in advance of neuronal degeneration, suggesting that senescence of microglia is a cause of Alzheimer’s dementia and not a response to neuron damage, as Alzheimer and most experts had presumed. This discovery may lead to new treatments for dementia,once researchers determine why microglia become senescent with age in some people but not in others.

The functions of the glial cells also account for why some people develop horrible chronic pain that does not relent after an injury has healed and sometimes even worsens. Doctors must use powerful narcotics such as morphine and other opiates to blunt the unrelenting pain in such patients. These drugs lose their strength over time, necessitating higher doses for the same effects, which can lead to drug dependence [see “When Pain Lingers,” by Frank Porreca and Theodore Price; Scientific American Mind, September/October 2009].

We now know that malfunctions of glial cells may account for both persistent pain and the diminishing power of some pain-relieving drugs. Research by Linda Watkins of the University of Colorado at Boulder, Kazuhide Inoue of Kyu­shu University in Fu- kuoka, Japan, and Joyce DeLeo of Dartmouth Medical School, among many others, reveals that microglia and astrocytes respond to the hyperactivity in pain circuits after injury by releasing compounds that initiate the healing process. These substances also stimulate neurons. Initially this heightened sensitivity is beneficial, because the pain forces us to protect the injury from further damage. With chronic pain, microglia do not stop releasing these substances even when healing is complete. But in recent studies pain in experimental animals was sharply reduced when the researchers blocked either the signals from neurons to glia or the signals that glia release. Scientists are now developing painkillers that target glia rather than neurons.

Glial cells also account for the ancient mystery of why spinal cord injury results in permanent paralysis.Martin Schwab of the University of Zurich and others have found that proteins in the myelin insulation that oligodendrocytes wrap around axons stop injured axons from sprouting and repairing damaged ­circuits. Blocking these proteins allows damaged axons to regrow in experimental ­animals. Clinical trials on patients with spinal cord injury are now under way.

That glia would play a central role in neurological illness is easy to understand be- cause astrocytes and microglia are the first responders to disease.We have also long known that demyelinating disorders such as multiple sclerosis, which strips the mye- lin insulation from axons, cause severe disability. But it came as a recent surprise to find glia implicated in psychiatric illness. Recent work has linked chemicals called cytokines, which are released by immune system cells and microglia, to obsessive-compulsive disorder.In 2002 molecular geneticist Mario Capecchi and his colleagues in the department of human genetics at the University of Utah reported that mice with a mutation in the Hoxb8 gene exhibited compulsive grooming and hair removal be- havior similar to humans with obsessive-compulsive disorder. The only cells in the brain that have this gene are microglia. Then, in a 2010 study, the researchers har- vested immature immune cells that will develop into microglia from normal mice and transplanted them into the mutants. The mice were cured of their compulsive groo- ming behavior. Presumably cytokines released from microglia excite brain circuits responsible for habit formation. [For more about habits, see “Obsessions Revisited,” by Melinda Wenner Moyer.]

Analysis of postmortem brain tissue has also linked oligodendrocytes and astrocytes to depression and schizophrenia by revealing reduced numbers of these cells. So have MRI examinations of people with schizophrenia, which show anomalies in sub- cortical white matter regions of the brain. Although psychiatric illnesses are likely to have many different causes, schizophrenia and several other mental illnesses have a strong genetic basis. If an identical twin develops schizophrenia, there is a 50–50 chance that the sibling will as well.

Some of the genes implicated in these mental illnesses are found only in oligodend-rocytes; others control development of these myelin-forming glia. An analysis of 6000 genes in tissue from the prefrontal cortex of people with schizophrenia by Yaron Hakak, then at the Genomics Institute of the Novartis Research Foundation in San Diego, revealed that 89 genes were abnormal; remarkably 35 of them are involved in myelination. Presumably these genetic abnormalities upset such processes as synaptic function and myelin insulation, which in turn could disrupt information transmission in the higher-level cognitive circuits affected in psychiatric illnesses.

Roots of Mental Illness

Investigators have set out to learn why glial cells would cause these synaptic snafus. Consider that the biological basis for most mental illness is an imbalance in neuro­transmitter chemicals in circuits controlling perception,emotion and thought. All drugs used to treat mental illness and most neurological diseases work by regulating the balance of neurotransmitters. The selective serotonin reuptake inhibitors (SSRIs) used to treat chronic depression and many other psychiatric conditions work by im- pairing removal of serotonin and dopamine from synapses, allowing these neuro- transmitters to build up and in effect boosting the signal. In a similar way, all halluci-nogenic drugs, from LSD to PCP, produce their mind-bending effects by altering the levels of neurotransmitters in specific neurological circuits. Regulating neurotransmitter levels at synapses is precisely what astrocytes do.

In theory, then, astrocytes are in a position to control the balance between mental health and madness. In a strange and largely forgotten coincidence, glia were the inspiration for the revolutionary idea that mental illness could have a biological cause and that psychiatric illness could be corrected with medical treatment, albeit a very peculiar one. In the 1930s Hungarian psychopathologist Ladislas von Meduna no- ticed during autopsies that the number of astrocytes was abnormally low in the cereb- ral cortex of people who had suffered from chronic depression and schizophrenia. Von Meduna and other pathologists also knew from examination of brain tissue ob- tained by biopsy that the number of astrocytes increases after epilepsy, presumably to regulate electrical activity when it spins wildly out of control.

Von Meduna observed as well that people with epilepsy rarely suffered schizophre- nia. He surmised that a deficiency in astrocytes was the biological reason for schizo-phrenia and chronic depression. By inducing a seizure in such people, he could co- rrect the imbalance in astrocytes and cure patients suffering from these illnesses. He later wrote in his autobiography: “I published this work in 1932 without knowing that this would become the origin of shock treatment.” How it works is still unclear, but electroshock therapy remains the most effective treatment for chronic depression in people who are not responsive to drugs.

The new awareness of glia in brain function suggests that drugs targeting glia might help treat mental and neurological illnesses. “Epilepsy is a prime candidate for glial- based therapeutics,” says Haydon of Tufts.Recent studies by Haydon,Maiken Neder- gaard of the University of Rochester Medical Center, Giorgio Carmig­noto of the Uni- versity of Padua in Italy, and many others are using calcium imaging and electrophy-siology to show that when neuronal activity is heightened, glia release neurotransmit- ters that can either contribute to seizure activity or suppress it. New research also implicates glia in sleep disorders, a component of many mental illnesses. Haydon demonstrated the link in experiments on mice genetically altered to prevent their astrocytes from releasing neurotransmitters, disrupting sleep regulation.

Transformational moments are legendary in scientific history, but it is rare to witness one. Until quite recently,we neuroscientists had dismissed more than half of the brain as uninteresting — a humbling realization. We see only now that the glial and neuro- nal brains work differently, and it is their intimate association that accounts for the astonishing abilities of the brain. Neurons are elegant cells, the brain’s information specialists. But the workhorses? Those are the glia.

Kuvat: []

" Oligodendrocytes lay down multiple layers of myelin around axons, increasing signal speed up to 50-fold. Recent work suggests that neural impulses can ­stimulate myelination. "

"The Other Brain: From Dementia to Schizophrenia, How New Discoveries about teh Brain are revolutionizig Science and Medicine".

" Tässä video Fieldsin pitämästä luennosta "The Other Brain":

In this talk, Dr. Doug Fields discusses glia, or "glue," which make up 85% of the cells in the human brain. New discoveries about these glial cells are revolutionizing the way that scientists view the brain, and Dr. Fields gives us a glimpse into this burgeoning area of neuroscience. "

" Noin kohdassa 10:54 Fields vihjailee, että aksonien myelinisoituminen on todennä- köisesti Pavlovin "säännön" "Neurons that fire together wire together" mekanismi. (Mainitsee tuon siis suoraan Pavlovin ansiona, kuten kirjassakin).

Fields toteaa suunnilleen seuraavaa: Neuronien A ja B täytyy "tulittua" samaan ai- kaan, jotta ne voisivat "kaapeloitua" yhteen eli niiden synaptinen voimakkuus kasvai- si. Miten tämä ylipäänsä on mahdollista? Jos neuronit A ja B ovat eri etäisyyksien päässä toisistaan, niiden lähettämät pulssit eivät mitenkään voi saapua samaan ai- kaan (siis A:n lähettämä pulssi B:lle ja B:n lähettämä pulssi A:lle, olettaisin). Näiden (aksonien) konduktionopeuksien täytyy vastata toisiaan jokaisessa (neuroni)"piiris- sä". Joko tämä tapahtuu geneettisesti tai sitten sitä kontrolloi jokin funktio, ja myeliini nopeuttaa konduktionopeutta ja siten saattaa parantaa signaalien synkronisaatiota ja informaationvälitystä aivoissa. Tämä taas tarkoittaisi, että myeliinillä on tärkeä rooli oppimisessa.

Eli kyllähän tuo myelinisoituminen aika selkeästi vaikuttaisi olevan ehdollistumisen biokemiallinen mekanismi... "

Ehdollistumisen biokemiallinen mekanismi tarkentuu

Kirjoitti: RK (IP rekisteröity)
Päiväys: 29. huhtikuuta 2008 13.33

RK kirjoitti:

> Peilisoluteorian hypettäjien odotukset ovat vailla äärtä ja rantaa:

> Kalifornian San Diegon yliopiston neurologian professori ja aivo- ja
> kognitiokeskuksen johtajaViliayanur Ramachandran on pukenut odotukset
> sanoiksi: ”Joskus peilisolut vielä osoittautuvatpsykologiassa yhtä tärkeiksi kuin dna >on osoittautunut biologiassa.”

> Tuon tärkeysluokan toistaiseksi ratkaisematon ongelma onkin olemassa, nimittäin
> kysymys ehdollistumisen biokemiallisesta mekanismista. Se saattaa perustua
> hermosolujen pinnanglykosaminoglykaaneihin./3 Niitä eivät geenit x
> hermosolujen pinnan sokereita eivätkä valkuaisasineita.

> 1. > > 2. > > 3. >

> 4. []

Tämän mekanismin toiminnasta on saatu uutta valaistusta:

Uusi Scientific American (March 2008) kertoo oppimisesta, ehdollistumisesta, että se ei ole solutason vaan solujenvälisen tason ilmiö.


Pavlov arvelikin, että ehdollistuneet yhteydet materialisoituvat tavalla tai toisella välit-tömästi aivokuoren alla olevaan kerrokseen, valkoiseen kerrokseen. Itse asiassa ky- seinen kerros "valkenee" vasta kun jotakin opitaan.Valkoisuus johtuu synapsien/ak-sonien myeliinitupesta, hermotupesta (jonka sisällä on se glykosaminoglykaaneista muodostuva hermotuppiverkko, perineuronal net) verkko per kerros, joita on useita. Myeliinitupen paksuus (kerrosluku) määrää synapsin sähkönkulkunopeuden, se voi olla satakertainen tupettomaan synapsiin nähden optimipaksuudella, joilloin synapsi/ aksoni on 60% koko "langan" halkaisijasta. Jos yhä lisätään kerroksia, niin taas impulssin kulku hidastuu, ja impussi "valitsee" helpommin jonkin muun tien.

Nythän on se vanha tulos, että jos glykosamiinit hajotetaan, niin opittu tieto katoaa. Silloin ilmeisesti ne myeliinikerrokset sekoittuvat, ja on kuin yksi kerros, vaikka se onkin tavallista paksumpi. Yli glykosamiini näyttäisi todellakin olevan eriste, kuten Bruce Caterson otaksuu eikä "silloite".

Niin kauan kuin synapseilla ja aksoneilla ei ole riittävän paksua myeliintuppea, ne pyrkivät muodostamaan satunnaisesti muodostuvien okaiden (spine) kautta uusia satunnaisia yhteyksiä muihin neuroneihin ja sitä kautta periaatteessa kaikkialle aivoihin. Nuo yhteudet kuitenkin myös katoavat, jos niitä ei "käytetä". Sen sijaan jos käytetään, niin "linjalle" muodstuu myeliinituppi, ja siitä tule nopeasti sähköä johtava. Tällä tavalla alueet spesialisoituvat ehdollistuneesti. Vahvastikin myelinisoituneet yhteydet voivat kuitenkin myös degeneroitua, jos niitä lakataan tarvitsemasta.


Re: Ehdollistumisen biokemiallinen mekanismi tarkentuu

Kirjoitti: RK (IP rekisteröity)
Päiväys: 15. kesäkuuta 2008 00.37

Minä olen tuosta asiasta keskustellut yksityisesti joidenkuiden maailmalla johtavien esimerkiksi neurobiokemistien kanssa, pistän tähän pari lainausta, jätän kuitenkin nimet pois. Keskustelun aiheena on "The biochemical mechanism of the Pavlovian conditioning is found?" tämän Scientific Americanin kirjoituksen pohjalta:


" qsh2: I suppose that important is that the mechanism on learning (conditioning) is OUTSIDE the neurons, not inside them (like in the "mirror neuron" and adjacent quack "theoties").

NN: I don't think that those that believe in "mirror neurons" believe in learning inside them, They don't believe they are learned at all.

As far as I can tell, apart from soem very few nutters, everybody agrees that learning happens by changing of the strength of connections. But there are many people that believe in unlearned features (like "Mirror neurons"), or simply assume features without considering how they arise.

Do you actually know about that claim learning iside neurons? "

" NN: I am not sure I can see why you think any of that would be of interest for me. My main interest is to actually understand it works, niot debunking bad ideas, specially where they quite far from mainstream neuroscience.

qsh2: But some of them think that in connection with the environment and experience "different genes express themselves", and learning is "changes in the gene ex- pression". I suppose they think that "an active gene (in for instance "mirror neuron") means an active sensation as the expression of that gene.

NN: Possibly, but neuroscientists in general don't think so, or at least they don't express it in the mainstream literature.

qsh2: Finnish "neuroscientist" Antti Revonsuo thinks that this kind of "states of con- sciousness" could be transmissed by (Revonsuo) cable form one brain to another...

NN: I didn't find English papers this page. Looks to me very much a fringe.

qsh2: That "theory" is formed in Matt ("Trofim") Ridleys book "Nature via Nurture".It is not any scientific university research, but some "professors" take it as a such. I have read the book in Finnish.

NN: Matt Ridley is certainly not part of mainstream neuroscience. I wouldn't pay any any attention to anything he would have to say about neuroscience or cognitive science.

I read this and it doesn't give me reason why I sould pay attention to the book.

qsh2: A supporter of the "theory" in scientific institutions is professor of "neuro-science"/"neurobiology" (not neurology, not neurophysiology...) Kai ("From-the-
Genes-la-la-laa", in Finnish "Keenistä-lallaa") Kaila.

NN: Their publications look like pretty solid neurophisiology, though I didn't check the details. I didn't anything that is really controversail in the publications list.

Maybe he support some nonsense thoeries, but he put publications on his page and don't mention it then I am not going to bother about it. "

Tässä esiintyy tuo sana "mainstream", jota niin "maailman" kun suomalaisetkin tutki- jat mielellään jankuttavat, ja joka hienommin tieteenfilosofisesti sanottuna tarkoittaisi "valitsevan tietellisen ihmiskuva/paradigman mukaista".(Noita paradigmaoja VOI toki olla useita tietellisiäkin,samaan aikaan,mutta niiden "voima" ei määräydy huutamalla eikä äänestämällä, vaan siitä, miten ne OHJAAVAT OIKEISIIN TULOKSIIN jotka tulevat kaikin puolin asianmukaisesti tieteellisesti vahvitetuiksi.

Nuo ulkomallaiset sanovat, kuten tässä NN, että "suomalaiset ovat mainstreamin ulkopuolella", ainakin "peilisolut" ja "Revonsuon kaapelit", ja myös Matt Ridley seuraajineen on siellä, kuten ohesta ilmenee.

Mutta (tietyt) suomalaiset ovat sitä mieltä, että HE OVAT "MAINSTREAM" ja KAIKKI MUUT "ovat sen ulkopuolella"...

He eivät ole saaneet tiedeyhteisöjä vakuuttuneiksi, mutta sitäkin paremmin ilmeisesti eurobyrokraattiyhiteisön...

Re: Maailmalta uutta tietoa autismin todellisista syistä

Kirjoitti: RK (IP rekisteröity)
Päiväys: 30. maaliskuuta 2007 13.47

RK kirjoitti:

> Maailmalla tutkitaan autismia nyt allergia- ja autoimmuunireaktioiden kontekstissa

> " The devastating derangements of autism also show up in the gut and in the
> immune system. That unexpected discovery is sparking new treatments that target >the body in addition to the brain. "

> eli samojen ilmiöiden joukosta, jossa ilmeisimmin vaikuttavat myös
> immunijärjestelmän ja ehdollistumisjärjestelmän mekanismit, luonnollisesti:


> Ei tavuakaan "peilisoluista" eikä "cortexmoduleistakaan".

Neuronien sijasta immunihäiriöteoria sijoitta autismin todennäköisen meknismin kokonaan toiseen aivosolutyyppiin, neurogliasoluihin:

" Could white matter become chronically inflamed? It may well be, according to new research from Carlos Pardo, a neurologist at Johns Hopkins. In a 2005 study in the Annals of Neurology, he found inflammation in immune-responsive brain cells of au- tistic patients. “Patients with autism report lots of immunological problems. We looked for the fingerprints of those problems in the brain,” says Pardo. “We had brain tissue from autistic individuals as young as 5 and as old as 45 and we found neuroglial in- flammation in all of them. Neuroglia are a group of brain cells that are important in the brain’s immune response. This inflammatory reaction appears to happen both early and late in the course of the disorder.If it happens early,it could dramatically influence brain development. We’re very excited about this research because one potential treatment approach, then, is to downregulate the brain’s immune response.” To study that approach, Pardo is collaborating on a pilot study funded by the NIH to test mino- cycline,an anti-inflammatory antibiotic drug, on autistic children.“Minocycline is a very selective downregulator of microglial inflammation,” he says. “Neurologists already use it in multiple sclerosis and Parkinson’s.”

“What we’ve got here is a far more comprehensive set of characteristics for autism,” says Herbert, “one that can include behavior, cognition, sensorimotor, gut, immune, brain, and endocrine abnormalities.These are ongoing problems,and they’re not con- fined just to the brain. I can’t think of it as a coincidence anymore that so many autis- tic kids have a history of food and airborne allergies, or 20 or 30 ear infections, or eczema, or chronic diarrhea.”

All this marks a Copernican-scale shift in our approach to the disorder. "

Tämä tukee sitä olettamusta, että ehdollistumisen mekanismi pelaisi neuronien pinnan kemikaaleilla.

Selkärangattomillla ei ole lainkaan Fieldsin mekanismia
Kirjoitti: RK (IP rekisteröity)
Päiväys: 15. marraskuuta 2010 12.35

... eikä siten myöskään PAVLOVILAISTA(/FIELDSILÄISTÄ) ehdollistumista, ilmenee tästä DUODECIM-lehden artikkelista

Kärpänen aivosairauksien tutkimusmallina

" Tautien mallintaminen yksinkertaisissa eläimissä, esimerkiksi banaanikärpäsessä, on kehittynyt nopeasti merkittäväksi menetelmäksi sairauksien syntymekanismien tutkimuksessa. Useita neurodegeneratiivisten sairauksien kärpäsmalleja on kehitetty, ja niissä on kyetty toistamaan tautien keskeisiä piirteitä. "

"Ihmisen genomin täydellinen sekvensoiminen ja tauteihin kytkeytyvien geenilokus- ten paikantaminen ovat olleet keskeisiä edistysaskeleita perinnöllisten sairauksien tutkimuksessa. Viime aikoina on löydetty monia geenivirheitä, jotka aiheuttavat taute- ja,mutta useimpien tautigeenien koodittamien valkuaisaineiden toiminnasta ja niiden osuudesta tautien patogeneesissä tiedetään edelleen varsin vähän. Näiden keskeis- ten kysymysten selvittäminen vaatii useiden eri menetelmien käyttöä, mm. mallintamista eri organismeissa.

Erityisesti hiirimalleja on kehitetty runsaasti eri sairauksille. Vaihtoehdon tavanomai- sille eläinmalleille tarjoaa tautien mallintaminen yksinkertaisemmissa ja pienikokoi-semmissa eläimissä, esimerkiksi banaanikärpäsessä (Drosophila melanogaster) tai seeprakalassa (Danio rerio). Yksinkertaisuutensa vuoksi näillä tautimalleilla on monenlaisia etuja tavanomaisempiin hiirimalleihin verrattuna "

Hiirimalleille nuo eivät siis suinkaan aina kuitenkaan voi toimia "vaihtoehtoina",mutta noilla erottaa tehokkaasti FIEDSIN MEKANISMIIN LIITYVÄT ja ne MUUT genettiset ongelmat hermostossa.

Kirjoittajilla ei ole ollut tiedossaan Fieldsin mekanismi.

Eikä hiirikään aina käy IHMISEN esimerkiksi myeliiniogelmien malliksi, sillä myös tuossa välissä on kemikaaleilla suuria eroja. Näin on erityisesti aksonien myelinisoi-tumista "vastustavan" sialiinin kohdalla (jota sitäkin on Suomessa tutkittu mm. Oulus- sa, mutta julkisuudessa ei kauheasti ole valitettavasti näkyneet nämä tutkimukset.

" Kärpäsen keskushermosto muodostuu päässä sijaitsevista parillisista aivolohkois- ta, jotka ovat kiinnittyneet hermostojänteeseen, joka ulottuu keski- ja takaruumiiseen (kuva 1A). Hermostojänteen jaokkeinen rakenne muistuttaa tikapuita. Se koostuu pa- rillisista ganglioista, jotka ovat kiinnittyneet toisiinsa liitoshermokimpuin. Varsinaiset aivot muodostuvat kahdesta pääosasta, supra- ja subesofageaalisesta gangliosta (kuva 1.) "

Yleensä kärpäsen kohdalla ei kuitenkaan puhuta "aivoista", vaan gangliosta, joita on pää-, siipi- ja peräganglio.

" Kärpäsen keskushermostossa on noin 100 000 ja perifeerisessä hermostossa noin 6 000-8 000 neuronia (Dambly-Chaudiere ja Ghysen 2001). Aivoissa hermosolujen soomaosat sijaitsevat pääosin aivokuoressa,joka ympäröi kauttaaltaan hermosolujen ulokkeista koostuvaa aivojen osaa, neuropiiliä. "

Sanaa "aivokuori" käyeteän myös väärin, sillä se tarkoittaa vakiintuneesti cortexia, jonka kanssa tuolla kärpästen ganglioiden suojakerroksella ei ole mitään tekemistä...

Ja tässä se varsinanen pääasia tältä, aivojen toimintamekanismin kannalta:

"Hermosolujen lisäksi kärpäsen aivoissa on gliasoluja, mutta niiden lukumäärä on huomattavasti pienempi kuin nisäkkäillä.

Kärpäsen aksonikimput eivät ole myeliinin ympäröimiä kuten selkärankaisilla, vaan niitä ympäröivät perineuraaliset gliasolut.

" Sen verran pitää korjata sanontaa tämän suunnattoman tärkeän tiedon suhteen,että

selkärankaisilla ja erityisesti aivokuorella (cortex) myeliinin ympäröimiä eivät ole "aksokimput", vaan kukin aksoni erikaseen,

mikä on varsinkin aivokuoren funtionaalisen toiminnan a ja o, kuten Fields osoitti.

" Sekä perifeerisessä että keskushermostossa on runsaasti erilaisia hermosolutyyp- pejä. Esimerkiksi kolinergisia, dopaminergisia, GABAergisia, serotoninergisia ja neuropeptidejä tuottavia hermosoluja on tutkittu runsaasti.

Kärpäsen ja hiiren hermoston yhteistä alkuperää tukee homologisten geenien osal- listuminen hermoston kaavoittumistapahtumiin (patterning) (Reichert ja Simeone 2001). "

Geenien osallistumisesta "aavoittumistapahtumiin"?? (Kärpäsen ja hiiren hermoston yhteisestä evolutionaaristsa alkuperätä matojen gangliohermoston. )

Onneksi on tuo lähde: Reichert H, Simeone A. Developmental genetic evidence for a monophyletic origin of the bilaterian brain.Phil Trans R Soc Lond B 2001;356: 1533 - 44.

Tähän palataan.

" Kärpäsmallin kehittäminen

Tautien mallinnuksessa voidaan käyttää kolmea tapaa muokata kärpäsgenomia.

Klassisen tavan mukaan (»forward genetics») kärpäsgenomiin aiheutetaan sattu-manvaraisia mutaatioita. Tutkimalla ja seulomalla suuri määrä tietyn ilmiasun suhteen mutantteja kärpäsiä voidaan tunnistaa haluttu, vaikkapa neurodege-neratiivinen fenotyyppi, minkä jälkeen sitä aiheuttava mutaatio on mahdollista paikantaa.

Nykyisin useiden ihmisen tautimutaatioiden selvittyä ja koko kärpäsgenomin sekvenssin valmistuttua käytetympi tapa on »reverse genetics».

Siinä kohdistetaan mielenkiinto ihmisen tietyn tautigeenin homologiin ja muokataan homologigeenin ilmentymistasoa estämällä tai vähentämällä geenituotteen muodos-tumista tai lisäämällä sitä (ja "homologia" määräytyy siis SAMAN GEENITUOTTEEN eli sen koodaaman proteiininperuteella, RK) Ilmentymistason (eli ko. proteiinin määrän, suom. huom., RK) muutoksen vaikutusta ilmiasuun tutkitaan.

Molekyylibiologisten menetelmien kehitys on mahdollistanut myös siirtogeenien il- mentämisen kärpäs- kudoksissa. Paljon käytetty UAS-GAL4-systeemi (kuva 2) tekee mahdolliseksi siirtogeenin - esimerkiksi tietyn taudin aiheuttavan ihmisgeenin mutantin muodon - ilmentymisen halutussa kärpäskudoksessa.

Tämä menetelmä on käyttökelpoinen erityisesti sellaisten tautien mallintamisessa, jotka johtuvat geenituotteen yli-ilmentymisestä (= liiallisesta määrästä, suom. huom., RK, joka lisäksi yleensä KERTYY JONNEKIN, mitä odottamattomiinkin paikkoihin, perosessi ei ole HOMEOSTATTINEN, jolloin geenistä vain korvataan jä'lkikäteen prosessissa kuluneen proteiinin vajausta) tai mutantin valkuaisaineen toiminnasta (gain-of-function). "

" Kärpäsmallin keskeisin heikkous selkärankaismalleihin verrattuna on kärpäsen hermoston yksinkertaisempi rakenne. Joidenkin neurodegeneratiivisten sairauksien - esimerkiksi amyotrofisen lateraali- skleroosin - mallintamisyritykset kärpäsessä ovat- kin ainakin toistaiseksi tuottaneet pettymyksen,kun ihmisen tautia aiheuttavan geenin ilmentäminen kärpäsessä ei ole aiheuttanut lainkaan neurodegeneraatiota (Feany 2000).

Tämä voi johtua siitä, että joihinkin neurodegeneraation mekanismeihin osallistuu keskeisenä osana proteiineja, jotka ovat kärpäsellä erilaisia tai puuttuvat siltä kokonaan.

Kärpäsmalli on myös joissain tapauksissa (esimerkkinä parkiinimalli) poikennut ilmiasultaan huomattavasti ihmisen taudin ilmiasusta.

Tästä huolimatta malli voi kuitenkin osoittautua varsin käyttökelpoiseksi,sillä erilaiset ilmiasut saattavat olla seurausta häiriöstä samassa biologisessa tapahtumasarjassa, joka on säilynyt evoluutiossa (Bier 2005), ja genominlaajuinen seulonta kärpäsmallissa voi auttaa selvittämään tämän tapahtumasarjan molekyylitasolla.

Toisaalta joitakin tauteihin liittyviä kysymyksiä voi olla syytä tutkia vielä yksinkertai-semmissa eliöissä, esimerkiksi hiivassa, silloin kun se on mahdollista. Tällaisia koh- teita voivat olla esimerkiksi solunsisäisiin tapahtumiin liittyvät mekanismit, joita esiin- tyy myös yksisoluisissa organismeissa. Hedelmällisin tapa tutkia tautimekanismeja tulee epäilemättä olemaan eritasoisten tautimallien tutkimuksesta saatujen tulosten yhdistäminen. "

"Unohtamatta" niitä kaikkien "korkeimpia", vain aivokuorellisilla, ja myös vain ihmisellä esiintyviä malleja....