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    Project: The great enhancement debate
    Stanford Report, April 1, 2009
    Molecules key to immune system also play role in brain


    Carla Shatz

    Molecules assumed to be in the exclusive employ of the immune system have been caught moonlighting in the brain—with a job description apparently quite distinct from their role in immunity.

    Carla Shatz, PhD, professor of neurobiology and of biology, and her colleagues at the School of Medicine have shown that members of a large family of proteins critical to immune function (collectively known as HLA molecules in humans and MHC molecules in mice) also play a role in the brain. "We think that this family of molecules has an important role in learning and memory," Shatz said. Surprisingly, the absence of one or another of them in the brain can trigger improved motor learning, though perhaps at the expense of other learning ability. The study was published online March 30 in the Proceedings of the National Academy of Sciences.

    The proteins in question sit like jewel cases on the outer surfaces of most cells in the body, displaying fragments of the cell's innards, called peptides, to best advantage for window-shopping by roving inspectors called T-cells. When a T-cell "sees" a peptide with an aberrant chemical sequence—a sign of possible infection or cancer—it can attack the aberrant cell directly or alert the immune system, which responds with a vengeance.

    It was long thought that MHC molecules are found on the surfaces of brain cells only when the brain suffers injury or infection. But that picture was altered several years ago when a group led by Shatz compared gene expression in normally reared mice with another group that had been deprived of visual stimuli. In particular, they looked at a region of the brain that processes visual input. "Completely unexpectedly, we found that one of the genes needing input from the eye in order to be expressed encodes an MHC molecule," said Shatz.

    She and her colleagues then showed that knocking out the expression of most MHC molecules in a brain region that processes visual stimuli caused developmental abnormalities in the circuitry of the mouse's visual system. "That implied indirectly that at least some MHC molecules were needed" for normal tuning up of brain circuits needed for vision, Shatz said, "but which ones?" There are about 60 in the mouse genome—and even more in the human genome.

    The researchers found that two of those molecules in particular—called "K" and "D"—were expressed in the cerebellum, a brain structure critical to motor learning. It's believed that by detecting and reporting differences between intended and executed acts, cerebellar circuitry guides the body toward ever better piano recitals or tennis games. Practice makes perfect.

    A key element in these circuits is a cell type called the Purkinje cell. Motor skills are perfected via the strengthening and weakening of connections, called synapses, between Purkinje cells and other cells supplying inputs to them.

    In the new study, the Shatz laboratory looked at mice's ability to learn how to keep from falling off a rotating rod called a rotarod. "It's like a circus trick," said Shatz. First author Mike McConnell, PhD, a postdoctoral researcher now at the Salk Institute in La Jolla, Calif., put two batches of mice—normal ones and bioengineered mice that lacked the "K" and "D" proteins—through their paces on the rotarod without knowing which batch was which. He noticed that one batch was consistently superior at learning the task. Two weeks later he retested them, with the same results. After another three-month rest, the early winners continued to excel while the slower group had to relearn the rotarod routine pretty much from scratch.

    When the mice were identified, it turned out that the good learners were the mutants. Looking at the mice's cerebellar circuitry, the researchers also discovered that contacts between Purkinje cells and the cells feeding them inputs were altered more easily in the K- and D-deficient mice than in the normal ones.

    "This proves that changes in levels of these two MHC molecules is enough to account for both changes in motor learning and the ease of strengthening or weakening connections in the cerebellum," Shatz said. "It implies that, normally, these molecules are putting a brake on the nervous system's ability to alter its circuitry in response to changing experiences. When you take the MHC molecules away, you remove the brake."

    In the wild state, motor performance—running from predators, chasing down meat—is a nice thing to have. If the K- and D-deficient mice learn and retain motor skills better, why doesn't evolution select for the deficient mice? Said Shatz: "Several other forms of learning besides motor learning—cognitive learning, spatial learning, recognition—don't take place in the cerebellum. There may be tradeoffs between one kind of learning and another—you're better able to escape but don't know exactly what to do in the next environment you encounter after running away—as well as between learning ability and circuit stability. More easily altered circuitry might also be more prone to epilepsy."

    The researchers have found other MHC molecules expressed in other types of neurons in other parts of the brain. "These molecules keep showing themselves to be important in limiting how much circuits can change by strengthening or weakening connections between nerve cells. We think they're going to figure as important players in many neurological disorders," Shatz said, noting a tantalizing if still controversial link between immune function and developmental brain disorders such as autism and schizophrenia.

    "Traditionally, there's been a kind of provincialism about molecules," she said. "You know, 'Some molecules are used only by the immune system, other ones only by neurons.' But I think the assumption that the immune system would have sole ownership over these molecules is pretty naïve.

    "We could have ignored this finding. We could have said, 'Well, MHC isn't supposed to be there, so it must be an artifact.' And we would have missed one of the most exciting aspects of doing research, which is the unexpected."

    Other co-authors include postdoctoral scholars Yanhua Huang and Akash Datwani. McConnell and Huang, currently a postdoctoral researcher at Washington State University, contributed equally to the work.

    The study was funded by grants from the National Institutes of Health and the Dana Foundation. 

    Wed, Apr 1, 2009  Permanent link

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    gamma     Sat, Dec 5, 2009  Permanent link
    The generation of new nerve cells in the brain is regulated by a peptide known as C3a, which directly affects the stem cells' maturation into nerve cells and is also important for the migration of new nerve cells through the brain tissue, reveals new research from the Sahlgrenska Academy published in the journal Stem Cells.

    Although the research has been carried out using mice and cultured cells, it could lead to a new medicine for human beings, which could be given to patients who have had a stroke or other disorders that damage or destroy the nerve cells.
    "Our research findings show that it could be possible to use molecules that are similar to the peptide C3a to boost the formation of nerve cells and stimulate the replacement of nerve cells lost due to injury or illness," says senior lecturer Marcela Pekna who headed the research group at theSahlgrenska Academy.

    The peptide C3a is generated through the activation of the complement system, a group of proteins in the blood that is essential for the body's immune defence.
    "Our research group was the first in the world to show that the complement system also plays an important role in the repair and regeneration of the brain," says Pekna. "This was a surprising discovery that opened up a whole new field of research."

    New Nerve Cells

    New nerve cells are formed in the brain throughout our lives. The brain's stem cells are formed in the hippocampus and the subventricular zone, an area next to the fluid-filled cavities (lateral ventricles). Stem cells from the subventricular zone mature into nerve cells in the olfactory bulb, but can also migrate out into the brain to replace nerve cells that have been damaged or destroyed. By finding out more about how new nerve cells are formed and what controls their migration, stem cell researchers hope to find new ways of treating stroke, Parkinson's disease and other disorders that result from the nerve cells failing to function as they should. 
    gamma     Sun, Oct 17, 2010  Permanent link
    Pericytes crucial to protecting central nervous system
    By Rachel Ehrenberg
    Web edition : Wednesday, October 13th, 2010

    Of all the body’s organs, the brain is the most like Area 51: Entry to the region is severely restricted, thanks to a barricade of cells and molecules known collectively as the blood-brain barrier. Increased surveillance by scientists has now pinpointed the barrier’s senior operatives, cells that are tasked with monitoring the razor wire–like barricade that keeps all but a select few from entering the brain.

    In two papers published online October 13 in Nature, scientists report that specialized cells called perictyes are crucial in the blood-brain barrier’s development and its maintenance in adulthood. A better understanding of how these pericytes function could help elucidate why some people fare especially poorly after traumatic brain injury or get particular neurological diseases such as cerebral palsy, scientists say. And new research could also lead to tricks for selectively opening or closing the blood-brain barrier, letting in medications that might combat diseases such as Alzheimer’s.

    One of the new studies demonstrates that pericytes are necessary for cementing the barrier’s cells into a nearly impenetrable wall surrounding blood vessels in the central nervous system. The work also establishes a timeline: In mice, the blood-brain barrier develops well before birth, researchers from Stanford and the University of California, San Francisco report. Pericytes also appear to keep the barrier’s cells on lockdown, dialing down the activity of genes that, if left to their own devices, would spur the transport of molecules across the barrier and into the brain.

    The second new study establishes that pericytes play a key role in regulating the blood-brain barrier in adult mice and also identifies a drug that appears to slow the transport of molecules across a leaky blood-brain barrier. In mutant mice lacking functional pericytes, the leukemia drug imatinib quickly halted the willy-nilly passage of molecules into the brain, researchers from Sweden and Germany report.

    “We are now doing experiments with imatinib-like substances,” says Christer Betsholtz of the Karolinska Institute in Stockholm, who led the second study. “We would like to understand how imatinib is closing the barrier.”

    Pericytes are found all over the body: Wherever there are blood vessels, there are pericytes around them. For a long time researchers thought that pericytes’ primary task was to help control flow in blood vessels. But around the blood vessels of the retina and the blood-brain barrier, pericytes are especially plentiful; in the last decade these cells have come under increased scrutiny as regulators of these important barriers.

    The importance of the blood-brain barrier cannot be understated, says Norman Saunders of the University of Melbourne in Australia. Not only does the barrier block access by baddies such as bacteria and parasites, it also prevents the unchaperoned entry of electrically charged molecules called ions. Since brain cells communicate via electrical impulses, the barrier literally keeps the brain from going haywire, Saunders says.

    “If it weren’t for the blood-brain barrier, our sensory experience would be reduced to a series of flashes and bangs,” says Saunders, recalling a quip of his late colleague and blood-brain barrier research giant Hugh Davson.

    While pericytes were definitely on the short list of key regulators of the blood-brain barrier, many researchers were focusing on astrocytes, the star-shaped brain cells that help the brain’s thinking cells, neurons, do their thing. But research suggests that astrocytes don’t develop until after birth, which led some people to erroneously conclude that the blood-brain barrier therefore also doesn’t develop until infancy.

    The new research firmly establishes that the blood-brain barrier is developed before birth, and that pericytes have a lot to do with that development. The cells also keep the barrier operating during adulthood. Mice genetically engineered to have fewer working pericytes have leakier blood-brain barriers, both teams report. This increased permeability seems to be partially due to structural problems — the normally supertight junctions between the barrier’s cells become cocked and crooked.

    But more important than the dysfunctional junctions is the misbehavior of the barrier’s import and export machinery. Without pericytes, the barrier’s cells take up many more molecules from the blood than they should, and dump those molecules into the brain. This includes molecules associated with the immune system — substances that cause swelling and inflammation — a healthy response in most body tissues but not in the brain, says Richard Daneman of the University of California, San Francisco, who led one of the studies.

    “A major function seems to be keeping the immune system out,” he says. “You don’t see immune cells in the brain — but in certain disease scenarios, multiple sclerosis, strokes — you get damage from the immune system in the brain.”

    A malady that strikes people with diabetes may also be related to pericyte problems. After years with the disease, pericytes associated with the blood vessels around the retina start to disappear, says Andrius Kazlauskas of the Schepens Eye Research Institute at Harvard Medical School. Once the cells are gone, immune system molecules can invade, inflammation occurs and a person can’t see, says Kazlauskas. The condition is known as diabetic retinopathy.

    “This work says that keeping the pericytes happy, keeping them alive, is likely to keep the vasculature happy,” he says. “That’s huge; conceptually, that’s a breakthrough. It is really intolerable for vision when the retina swells.”

    Also intriguing is evidence that the leukemia drug imatinib slowed leakage, Kazlauskas says. Perhaps related drugs will eventually have a place in treating diabetic retinopathy.

    In the future, there may even be genetic tests that tell people how healthy their pericyte population is, says neuroscientist Joan Abbott of the blood-brain barrier group at King's College London. “We’ve been puzzled as to why some people after brain trauma do better than others,” Abbott says. If some people are born with fewer or faulty pericytes due to genetics, their blood-brain barriers may be leaky from the start. 
    gamma     Mon, Jan 17, 2011  Permanent link
    FEELING happy? Down in the dumps? Or been behaving strangely lately? Besides the obvious reasons, whether or not you are happy or sad, or prone to depression or other mental illnesses, could be a consequence of an infection - or even down to the diseases that you didn't catch during childhood.

    "It used to be thought that the immune system and the nervous system were worlds apart," says John Bienenstock of McMaster University in Hamilton, Canada. Now it seems the immune system, and infections that stimulate it, can influence our moods, memory and ability to learn. Some strange behaviours, such as obsessive compulsive disorder, may be triggered by infections, and the immune system may even shape our basic personalities, such as how anxious or impulsive we are. The good news is that understanding these links between the brain and immune system could lead to new ways of treating all kinds of disorders, from depression to Tourette's syndrome.

    This is a massive shift in thinking. Not so long ago, the blood-brain barrier was thought to isolate the brain from the immune system. The cells that make up the walls of blood capillaries are joined together more tightly in the brain than elsewhere in the body, preventing proteins and cells getting into the brain. Now, though, it is becoming clear that antibodies, signalling molecules and even immune cells often get through, sometimes with radical effects. In fact, immune cells do not even need to reach the brain to influence it. Here we look at some of the effects they can have...