Brain Cells
Seen Recycling Rapidly To Speed Communications
The tiny spheres
inside brain cells that ferry chemical messengers into the synapse make their rounds much more expeditiously than once assumed,
National Institute of Mental Health (NIMH) - funded researchers have discovered. They used a dye to track the behavior of
such synaptic vesicles in real time, in rat brain cells. Rather than fusing completely with the cell membrane and disgorging
their dye contents all at once, brain vesicles more often remained intact, secreting only part of the tracer cargo in each
of several repeated, fleeting contacts with the membrane, report Richard Tsien, D.Phil., Stanford University, and colleagues
Alex Aravanis and Jason Pyle, in the June 5, 2003 Nature. Dubbed "kiss-and-run"
recycling, this allows for more efficient communication between brain cells, suggest the researchers.
Brain cells
communicate in a process that begins with an electrical signal and ends with a neurotransmitter binding to a receptor on the
receiving neuron. It lasts less than a thousandth of a second, and is repeated billions of times daily in each of the human
brain's 100 billion neurons. Much of the action is happening inside the secreting cell. There, electrical impulses propel
vesicles into the cell wall to spray the neurotransmitter into the synapse. Likened to soap bubbles merging, or bubbles bursting
at the surface of boiling water, this process of membrane fusion may hold clues about what goes wrong in disorders of thinking,
learning and memory, including schizophrenia and other mental illnesses thought to involve disturbances in neuronal communication.
Neurons must
recycle a finite number of vesicles. In "classical" membrane fusion, the vesicle totally collapses and mixes with the cell
membrane, requiring a complex and time-consuming and retrieval and recycling process. Yet, Tsien and colleagues point out
that this process was discovered in huge neurons, such as those in squid giant synapses, with tens or hundreds of thousands
of vesicles per nerve terminal. By contrast, they find that the comparatively tiny nerve terminals of the mammalian brain
must make do with only about 30 functional vesicles – hardly enough to keep up with the split-second demands of synaptic
communication if vesicles can only be replenished via the, one-shot classical process, they argue. Hence, the "kiss-and-run"
hypothesis.
To observe single
vesicles in action, Tsien and colleagues put a fluorescent dye into nerve terminals in cultured neurons from the rat hippocampus,
a key memory hub involved in learning. The dye was later washed out of neuronal membranes, but it remained trapped in the
vesicles, enabling the researchers to take snapshots of their activity at synapses following electrical stimulation, using
a microscope, pulses of fluorescent light, and a CCD imaging device.
When they tracked
single vesicles following stimulation, they usually observed a series of abrupt and lasting -- albeit partial -- decreases
in fluorescence, indicating multiple fusion events.
Yet, only rarely
was there a full loss of fluorescence, indicating full classical collapse.
"A likely explanation
is that most fusion events were simply too brief to permit dye to escape completely," noted Tsien and colleagues. "After rapid
retrieval by a process that maintained vesicle integrity, vesicles remained available for repeated fusion, supporting their
repeated re-use for neurotransmitter release. Vesicles are readily refilled with neurotransmitter so each fusion can send
a meaningful signal. Together, brief fusion, rapid retrieval and re-use would enable small nerve terminals of the central
nervous system to get full mileage from their limited set of vesicles."
Only at times
of "all-out vesicular mobilization" would most of the hippocampal neuron vesicles likely shift to the classical mode of membrane
fusion, they concluded.
Another study
published in the same issue of Nature by Dr. Charles Stevens, The Salk Institute, and colleagues, also found evidence in support
of "kiss-and-run."
NIMH is part
of the National Institutes of Health (NIH), the Federal Government's primary agency for biomedical and behavioral research.
NIH is a component of the U.S. Department of Health and Human Services.
Neurons transmit
chemical signals in a fleeting "kiss-and-run" process, which in large part determines how quickly neurons can fire, according
to new studies by Howard Hughes Medical Institute researchers.
'Kiss-and-run'
Rules The Inner Lives Of Neurons
The transfer
of information between nerve cells occurs when chemicals called neurotransmitters are released into the synapse, the junction
between neurons. Electrical impulses in the neuron cause tiny vesicles loaded with neurotransmitters to move to the tip of
the nerve terminal where they are released.
In an article
published in the June 5,
2003, issue of the journal Nature, HHMI investigator Charles
F. Stevens and Sunil Gandhi, both at The Salk Institute, reported that they have devised a technique that permits them to
visualize individual vesicles after they have released their cargo. The new findings are significant, said the researchers,
because they answer questions about the rate at which synaptic vesicles can be recycled. This rate determines how much information
nerve cells can transmit.
Stevens and
Gandhi have identified three distinct ways in which a used vesicle can be retrieved from the surface of the nerve cell once
it has released its cargo. The fastest of these, called the "kiss-and-run" mode, takes less than a second; the slower "compensatory"
mode takes up to 21 seconds; and the "stranded" mode leaves the vesicle stuck at the surface until the next nerve impulse
triggers its retrieval.
According to
Stevens, the latest findings settle lingering questions about how vesicle retrieval occurs. Early electron microscopy images
of vesicles in synapses were interpreted as either a kiss-and-run model or one in which the vesicle is completely incorporated
into the cell membrane, to be drawn back into the cell.
"The advance
that we have made is to figure out a way of imaging individual vesicles so that we can measure the time course of single vesicle
events and immediately answer these questions," said Stevens.
The optical
recording technique devised by Stevens and Gandhi involves genetically modifying a gene for one type of vesicle protein to
incorporate a special form of green fluorescent protein. This modified fluorescent protein, developed by other researchers,
does not fluoresce under acidic conditions normally present in vesicles fully loaded with neurotransmitter. However, when
the vesicle releases its payload, the interior becomes less acidic and the vesicle glows a bright green.
Thus, said Stevens,
by imaging individual vesicles in cell cultures of neurons, it is now possible to detect how and when vesicles release their
cargo at the synaptic membrane.
"Among the minor
observations we made was that vesicles can re-acidify themselves in less than half a second," said Stevens. "We also observed
that the proteins in the vesicle are maintained together, so that when a vesicle is taken back in from the membrane, the same
proteins are still there, even if the vesicle had been fused with the membrane for quite a while.
"And the third
thing that was surprising is that all vesicles across different preparations have basically the same number of these tagged
protein molecules," said Stevens. "This means that they are either saturated or there is some mechanism for counting the proteins."
The major observations
from their studies, said Stevens, are that are three modes of vesicle release and retrieval from the membrane. "One is what
you could call classical, when the vesicle opens to the outside world, stays open for about eight seconds, and then is taken
back in at random times extending out to twelve or fourteen seconds," he said. This finding confirms previous theories about
modes of vesicle recycling, he said.
"However, sometimes
if the vesicle failed to be re-internalized to be reused again by about fourteen or fifteen milliseconds, sometimes it got
stuck there," said Stevens. In this "stranded" mode, the vesicle remained stuck until another nerve impulse caused it to be
zipped into the interior of the neuron to be recycled. Presumably, stranding occurs because vesicle recycling depends somehow
on the level of calcium in the nerve cell, which rises precipitously during a nerve impulse, and drops afterward, said Stevens.
"The third recycling
mode we observed was a kiss-and run-mode that happened very rapidly, in less than half a second," said Stevens. "Also, we
showed experimentally that in this mode there was a 'fusion pore' formed where the vesicle contacted the membrane," he said.
Stevens and
Gandhi also found that vesicles appear to adjust their mode of recycling based on the probability that a given synapse will
trigger the release of a vesicle's cargo. Vesicles in synapses with a low-release probability are more likely to use the rapid
kiss-and-run mode, he said, while those vesicles in a higher-probability synapse use the slower compensatory mode.
Future studies
will seek to determine the molecules responsible for recycling and how structures such as the fusion pore form. The researchers
will also explore the role of calcium in recycling, as well as the advantages to the nerve cell of using the kiss-and-run
recycling mode.
Editor's Note:
The original news release can be found here.
Protein Stimulates
Key Link Between Nerve Cells, Suggesting Possible Target For Mental Retardation And Nerve Regeneration Therapies
UCSF researchers
have exposed a single protein that can stimulate the maturation of the synapses, or junctures, through which nerve cells communicate
a key signal to one another. The discovery reveals a mechanism critical for supporting brain development, learning and memory
and a possible target for treating mental retardation and nerve damage following stroke and spinal cord injury.
The
finding, reported in the November 17 issue of Science, indicates that the protein, PSD-95, helps build the physical scaffolding of the synapse that cells
use to transmit the chemical messenger, or neurotransmitter, known as glutamate, to a target cell. The
protein also matures other aspects of the synapse -- enhancing the clustering of glutamate receptors on the target cells receiving
the chemical messenger, increasing the number and size of the dendritic spines that hold glutamate receptors, and increasing
the number of glutamate neurotransmitters emitted from the releasing cell.
The results,
says senior author David S. Bredt, MD, PhD, UCSF professor of physiology, indicate that the protein is the cornerstone of
physical maturation for both the pre- and post- synaptic structures that allow glutamate to signal from one neuron to another.
The findings are provocative, for glutamate, the major excitatory neurotransmitter in the brain, is the engine behind cellular
learning -- including brain development and mental and physical processes.
Glutamate is
also thought to be the key to plasticity, the brain's ability to relearn mental and physical skills following injury and to
adjust to new circumstances. The neurotransmitter acts by stimulating a receptor on target cells containing a protein known
as the NMDA receptor, which serves to strengthen, or reinforce, the neural circuits between nerve cells that store memory.
Glutamate enables
the brain to develop, language to be learned, a new math equation to be grasped, tennis to be mastered and walking to be relearned
following a stroke. But without the synapses that allow the chemical signal's transmission from one nerve cell to the next,
glutamate has no more luck in communicating its messages than a train has luck in reaching its destination without tracks
to follow.
During synaptic
transmission, nerve cells release thousands of neurotransmitters from their nerve terminals at once. The messengers diffuse
across a synaptic cleft to corresponding receptors on a target cell, and prompt a response in that cell that is then transmitted
to another cell and yet another, ultimately causing a wave of reaction in the brain.
Some neurotransmitters,
such as GABA, carry inhibitory signals, reducing excitation and anxiety in the brain, and others, such as dopamine and serotonin,
modulate the activity of neural circuits to influence mood and sleep. The millisecond relay of glutamate to thousands of nerve
cells sparks the brain into high activity.
Mental retardation is associated with a loss of the dendritic spines on post-synaptic
neurons that play a role in receiving glutamate messages. As the study shows that PSD-95 increases the number and size of these spines, gene therapy could prove effective
in stimulating the growth of the spines and thus treating the disease. Likewise, using PSD-95 gene therapy to stimulate the maturation of glutamate receptors could be used to regenerate nerves
following stroke or spinal cord injury.
On the flip
side, when nerve cell receptors that receive glutamate become overactive and thus receive too much glutamate - as occurs following
stroke and in such neurodegenerative diseases as Alzheimer's disease -- brain damage occurs.
Much
research is aimed at treating this so-called excito-toxicity by blocking the glutamate receptor. But identifying a way to
disrupt the synapses that allow communication of glutamate from one nerve cell to another could provide an alternative way
of treating these diseases and, again, the PSD-95 protein might prove an effective target.
The
UCSF researchers conducted their study in cultured neurons of the hippocampus, a brain structure involved in learning and
memory. They over-expressed the PSD-95 protein
in their normal location, the post-synaptic membrane of neurons, at an early stage of glutamate synapse development.
They detected
enhanced clustering and activity of glutamate synapse development, enhanced clustering and activity of glutamate receptors
at the post-synaptic sites and an increase in the number and size of dendritic spines, which contain the receptors that respond
to glutamate neurotransmitters.
More
surprisingly, they discovered that PDS-95 stimulates maturation of the pre-synaptic terminal, which emits
neurotransmitters, presumably by reaching across the synaptic cleft. They also determined the protein increases the release
of glutamate neurotransmitters from the pre-synaptic terminal of the emitting neuron.
The
findings suggest, says Bredt, that during normal conditions clustering of the protein at the post-synaptic site, which would
cause maturation of the glutamate synapse, may be regulated during development and during learning processes and plasticity.
The next step in the research, he says, is to try to understand at the molecular level what the PSD-95
protein targets to promote synaptic maturity and plasticity.
Co-authors of
the study were Alaa El-Din El-Husseini, PhD, UCSF postdoctoral fellow in physiology, Eric Schnell, BS, a UCSF graduate student
in cellular and molecular pharmacology, Dane M. Chetkovich, MD, PhD, clinical instructor in neurology and Roger A. Nicoll,
PhD, UCSF professor of cellular and molecular pharmacology. The study was funded by the National Institutes of Health, the
Howard Hughes Medical Institute and the National Association for Research on Schizophrenia and Depression.
No. 4
: J Cell Biol.
1998 Apr 20;141(2):431-41.
Defect
in synaptic vesicle precursor transport and neuronal cell death in KIF1A motor protein-deficient mice.
Yonekawa
Y, Harada A, Okada Y, Funakoshi T, Kanai Y, Takei Y, Terada S, Noda T, Hirokawa N.
Department of Cell Biology and Anatomy,
GraduateSchool of Medicine, University of Tokyo, Tokyo 113, Japan.
The nerve axon is a good model system for studying
the molecular mechanism of organelle transport in cells. Recently, the new kinesin superfamily proteins (KIFs) have been identified
as candidate motor proteins involved in organelle transport. Among them KIF1A, a murine homologue of unc-104 gene of Caenorhabditis
elegans, is a unique monomeric neuron- specific microtubule plus end-directed motor and has been proposed as a transporter
of synaptic vesicle precursors (Okada, Y., H. Yamazaki, Y. Sekine-Aizawa, and N. Hirokawa. 1995. Cell. 81:769-780). To elucidate
the function of KIF1A in vivo, we disrupted the KIF1A gene in mice. KIF1A mutants died mostly within a day after birth showing
motor and sensory disturbances. In the nervous systems of these mutants, the transport of synaptic vesicle precursors showed
a specific and significant decrease. Consequently, synaptic vesicle density decreased dramatically, and clusters of clear
small vesicles accumulated in the cell bodies. Furthermore, marked neuronal degeneration and death occurred both in KIF1A
mutant mice and in cultures of mutant neurons. The neuronal death in cultures was blocked by coculture with wild-type neurons
or exposure to a low concentration of glutamate. These results in cultures suggested that the mutant neurons might not sufficiently
receive afferent stimulation, such as neuronal contacts or neurotransmission, resulting in cell death. Thus, our results demonstrate
that KIF1A transports a synaptic vesicle precursor and that KIF1A-mediated axonal transport plays a critical role in viability,
maintenance, and function of neurons, particularly mature neurons.
PMID: 9548721 [PubMed
- indexed for MEDLINE]
No. 5
Tuesday, 26 August, 2003, 14:24 GMT15:24UK
Dyslexia 'caused by faulty
gene'
Dyslexia may be
caused by a fault in a single gene, scientists have suggested.
Researchers in Finland
say their finding may explain why the condition seems to run in families. Dyslexia
affects about one in 10 people. It is the most common learning disorder in children. Many find it difficult to recognise and
read words.
Writing in the Proceedings
of the National Academy of Sciences, scientists said a flaw in a gene called DYXC1 may cause the condition. Previous studies have suggested that people with dyslexia process information in a different area of the
brain than the average person does, even though they are often of average or above-average intelligence.
Other studies have
suggested they use the right side of the brain for reading instead of the left side, which is better set up for processing
words.
Scientists have
also suspected that the condition may also have a genetic component.
Finnish families
Researchers at the
University of Helsinki carried out tests
on 20 Finnish families, many of whom had several cases of dyslexia.They found
that the DYXC1 gene was disrupted in a number of these families. The scientists were unable to say exactly what role this
gene has but they do believe it could play a role in determining who is at risk of dyslexia.
They suggested it may
be involved in helping cells cope with stress but they acknowledged that much more study is needed. They added that faults
in other genes may also cause dyslexia.
But writing in the
PNAS, they said: "We conclude that DYXC1 should be regarded as a candidate gene for developmental dyslexia."
They added: "There is
overwhelming evidence that dyslexia is a genetically complex condition."
If their findings are
backed up in other studies, it could allow doctors to test children for this particular genetic fault.This, in turn, could enable these children to get the additional help they need to make sure they no longer
fall behind in their studies. In the longer term, it could enable scientists
to start working on drugs to treat the condition.
No. 6
The Brain Starts
to Change at Age 40
By Cheryl Simon Silver Posted:
June
10, 2004
If you’re
middle aged, there’s a good reason why you can’t beat your child at games like “Memory” and “Concentration.”
Scientists report that after age 40, brain tissue shows genetic changes that may contribute to the aging process, including
cognitive decline.
Researchers at Children’s
Hospital in Boston and at HarvardMedicalSchool report a genetic signature revealed in post mortem tissues of individuals
between 26 and 106 years old. They looked at tissue from the prefrontal region of the brain, the locus of higher level functions
such as long-term planning and executive function.
Bruce Yankner, lead author
of the study, says aging brains show significant differences in the behavior of several groups of genes that are important
for brain function and that may contribute to the aging process. One group of the genes plays a role in what researchers call
synaptic plasticity—the ability of the brain to make new connections so critical to learning and memory.
Another group of genes,
involved in processes such as responses to stresses and defense against damaging oxidants such as free radicals, are turned
on in the aging brain. The researchers found that regions of particular genes are quite vulnerable to DNA
damage in the aging brain.
“These regions appear
to be quite vulnerable to DNA damage—they are chemically sensitive, and they are
not repaired easily,” Yankner says. The findings appear this week as an advance online publication in Nature.
The research team performed
a statistical analysis to 11,000 genes for the study, and compared the rates of change over time. The changes in genes of
individuals younger than 40 years were quite similar, and the genes of the oldest individuals were also similar. However,
the individuals between ages 40 and 73—the middle years—aged at strikingly different rates, with some gene patterns
resembling those of the young group, while others had gene patterns more like those of the older group.
Once they zeroed in on
the groups of genes, the researchers conducted laboratory tests in which they exposed brain cells to agents such as free radicals
and environmental toxins. The results mimic the changes seen in the tissue of aging brains.
On the bright side, when
the researchers duplicated the scenario in the lab, and genetically manipulated the cells to produce proteins to repair the
damage, the function of the damaged genes was restored, and more copies were made.
“It may be
that DNA damage, once it occurs in the brain, is reversible,” Yankner says.
Once the damage is reversed,
it might be possible to extend the duration of cognitive function, or to delay the onset of age-related diseases such as Alzheimer’s
disease or Parkinson’s. This will be a goal of future research.
“There is certainly
evidence that DNA damage can underlie a large part of the aging process in humans,”
Yankner says. “My feeling is that the process of maintaining the integrity of the genome is going to be very important
in understanding the aging process. Whether it explains the entire spectrum of the aging process, or a part of it, remains
to be seen.”
Lu, T. et al. Gene regulation
and DNA damage in the ageing human brain. Published online in Nature (June 9, 2004).
Last Updated: Saturday, 12 June,
2004, 23:05 GMT00:05UK
Gene loss linked to Alzheimer's
Genes which play a key
role in keeping our minds sharp gradually begin to turn off as we age, research has found. Scientists
at the Children's Hospital in Boston hope the discovery could lead to new ways
to preserve brain function and ward off Alzheimer's disease. They used a sophisticated
screening technique to analyse brain samples from 30 people aged 26 to 106 at post-mortem.
The research is published
in the journal Nature.
Lead researcher
Professor Bruce Yankner said: "We found that genes that play a role in learning and memory were among those most significantly
reduced in the ageing human cortex. "These include genes that are required for
communication between neurons."
Varied results
Gene activity was
assessed by measuring the amount of proteins that they produce.
Protein levels were reduced
in older individuals - and changes seemed to start for some in their 40s.
However, the rate
of deterioration seemed to vary between individuals.
Compared with the gene
patterns of young brains, those of people aged from 40 to 70 were much more variable. Some
middle-aged individuals had "young" genes while others were old before their time.
The researchers believe
brain genes are particularly vulnerable to toxins in the environment, and to charged oxygen molecules called free radicals
which are released by chemical reactions in the body.
In addition to a reduction
in activity in genes important for thought processes, they found evidence of greater activity among genes associated with
stress and repair mechanisms and genes linked to inflammation and immune responses. This
suggests that the ageing brain has to try to cope with increasing levels of damage. Professor
Yankner said: "The brain's ability to cope with these toxic insults and repair these genes declines with age.
"It will now be important
to learn how to prevent this damage, and to understand precisely how it impacts brain function in the elderly." Dr Yankner said it had already proved possible to repair ageing genes in the laboratory - but he stressed
much more work was required to achieving the same effect in a living human brain.
Great potential
Rebecca Wood, chief executive
of the Alzheimer's Research Trust, described the research as producing "some potentially very important results". She said: "The genes which the researchers found to be damaged may give us valuable insights into the mechanisms
of ageing.
"The evidence of
varied rates of ageing between different people in middle age is also exciting as it may suggest means of postponing or slowing
the process."
However, she said the
techniques used in the study were relatively new, and more work was needed to assess the validity of the findings.
"Not enough is yet
known about the multiple functions of the genes they have picked out.
"Further studies should
also include cases of Alzheimer's to see if the same or different genes are affected in ageing to those in the disease.
"However, this is
an exciting step which could lead to real progress in understanding the ageing of the brain and of its degeneration in the
tragic disease of Alzheimer's."
Professor Clive Ballard,
director of research, Alzheimer's Society, said: "This work is likely to initiate a variety of productive research strategies,
including approaches to look at the protection of gene function.
"It also provides
a scientific framework to reinforce the potential therapeutic value of antioxidants such as vitamin C, green tea and red wine
that 'mop-up' free radicals."
No. 8
Schizophrenia
Gene Variant Linked to Risk Traits
Kansas City infoZine
Monday August 23, 2004
Monday August 23, 2004 :: posted by
Researchers
at the NIH's National Institute of Mental Health (NIMH) have identified a relationship between a small section of one gene,
the brain chemical messenger glutamate, and a collection of traits known to be associated with schizophrenia.
The
finding confirms the gene responsible for management of glutamate is a promising candidate in determining risk for schizophrenia.
The study, conducted by Michael Egan, M.D., Daniel Weinberger, M.D., and colleagues, is in the August 24th issue of the Proceedings
of the National Academy of Sciences, published online the week of August 9, 2004.
Glutamate
is a key neurotransmitter long thought to play a role in schizophrenia. The gene identified in this study makes the glutamate
receptor (GRM3), which is responsible for regulating glutamate in synapses—spaces in between brain cells—where
chemicals like glutamate transfer information from cell to cell. The amount of glutamate remaining in the synapse may have
a downstream impact on cognition.
"Because of the small effects of individual genes in complex genetic disorders like
schizophrenia, it is difficult to make significant associations with any one particular marker. However, this study brings
us closer to unlocking the genetic clues that increase the risk for schizophrenia," said NIMH Director Thomas R. Insel, M.D.
Researchers
know that schizophrenia affects several regions in the front part of the brain that are involved in higher order thinking
and decision-making and neurotransmitter systems like glutamate. Many of the genes already identified as likely candidates
for the disorder have been thought to affect the glutamate system. The study implicates the GRM3 gene as well.
GRM3
alters glutamate transmission, brain physiology and cognition, increasing the risk for schizophrenia. To pinpoint the section
of the gene responsible for these changes, scientists are exploring a region where the gene may differ by one letter at a
location called SNP4. The normal variation is spelled with either an 'A'-the more common of the two-or a 'G'. Patients with
schizophrenia are more likely to inherit an 'A' from either parent, indicating the 'A' variant slightly increases risk. The
'A' variant is also associated with the pattern of traits linked with the disorder. This was true in patients, their healthy
siblings, and normal volunteers.
In
the study, people with an 'A' variant have differences in measures of brain glutamate. In a postmortem study of brain tissue,
the 'A' variant was associated with lower levels of the chemical that promotes gene expression for the protein responsible
for regulating the level of glutamate in the cell. N-acetylaspartate, a measure of cell health evaluated through the use of
MRI spectroscopy, was lower in 'A' participants. 'A' carriers had poorer performance
on several cognitive tests of prefrontal and hippocampal function than people with the 'G' variant. The 'G' marker was associated
with relatively more 'efficient' processing in the prefrontal cortex. Those who inherit the 'G' variant scored higher on verbal
and cognitive tests than those who have two of the 'A' variant. Scientists think the less common 'G' variant may exert a protective
effect against the disease.
People with schizophrenia and their healthy siblings share the inefficient brain physiology,
and cognition patterns, which suggests a link to genetic risk, though the disease itself is most likely caused by a combination
of genetic and environmental factors. The gene seems to affect the mechanism of memory encoding only as there was no genotype
effect seen during retrieval in the memory tests.
Although scientists could not be certain that the 'A/G' difference
accounts for all the affects on brain function, there may be yet undiscovered variations located near SNP4 on the GRM3 gene.
It is unclear as to why the higher-risk 'A' variant is more common in humans. Researchers speculate that it may provide a
counterbalancing advantage, perhaps related to reduced glutamate in the cells.
Also participating in the research were:
Drs. Richard Straub, Terry Goldberg, Joseph Callicott, Ahmad Hariri, Venkata Mattay, Thomas Hyde, Cynthia Shannon-Weickert,
Mayada Akil, Radha Krishna Vakkalanka, Rishi Balkissoon, Joel Kleinman; Alessandro Bertolino, NIMH and Universita Study Bari,
Italy; Jeremy Crook, NIMH and ES Cell International; Imtiaz Yakub, and Richard Gibbs, Baylor College of Medicine.
No. 9
Supercharging the brain
Sep 16th 2004 From The Economist print edition
Biotechnology: New drugs
promise to improve memory and sharpen mental response. Who should be allowed to take them?
DO YOU have an important meeting tomorrow, or perhaps
an examination, for which you would like your mental powers to be at their peak? Within a few years, you may have the option
of taking a “cognitive enhancer”—a drug that sharpens your mental faculties. During the 1990s—declared
“decade of the brain” by America's Congress and the National Institutes of Health—much progress was made
in understanding the processes of memory and cognition. Advances in genetics, molecular biology and brain-imaging technologies
allowed researchers to scrutinise the brain's workings and gave them the potential to create drugs to enhance aspects of its
performance. Though there are very few products on the market that reflect this increased understanding, that may soon change.
At least 40 potential cognitive enhancers are currently
in clinical development, says Harry Tracy, publisher of NeuroInvestment, an industry newsletter based in Rye, New Hampshire.
Some could reach the market within a few years. For millions, these breakthroughs could turn out to be lifesavers or, at the
very least, postpone the development of a devastating disease. In America alone, there are currently about 4.5m people suffering
from Alzheimer's disease, and their ranks are expected to grow to 6m by 2020. Mild Cognitive Impairment (MCI), defined as
memory loss without any significant functional impairment, is estimated to afflict at least another 4.5m people. Because the
majority of MCI patients will eventually develop Alzheimer's, many doctors believe that intervening in the early stages of
the disease could significantly delay its onset.
But there is a fine line between curing the ill and enhancing
the well. The gradual deterioration of mental faculties is part of the natural process of ageing. There are now about 85m
people aged 50 and over in America, many of whom may already fit the definition of “age-related cognitive decline”,
a category so vague it includes people who become distressed over such mild glitches as forgetting their keys or glasses.
Should they be offered “cognitive enhancers” too?
And the interest in such drugs will not stop there, predicts
James McGaugh, who directs the Centre for the Neurobiology of Learning and Memory at the University of California at Irvine.
Next in line could be executives who want to keep the names of customers at the tips of their tongues, or students cramming
for exams. “There's an awful lot of sales potential,” says Dr McGaugh. That is putting it mildly. But are such
drugs really feasible—and if they are, who should be allowed to take them?
A handful of small companies are at the forefront of
the fledgling field of cognitive enhancement. Among them is six-year-old Memory Pharmaceuticals, based in Montvale, New Jersey,
which has two compounds in early-stage clinical trials and recently went public. The company's visionary and Nobel prize-winning
co-founder, Eric Kandel, has been unravelling the processes of learning and memory for more than four decades with the help
of Aplysia, a type of colossal sea slug that grows up to a foot in length. While it has only about 20,000 neurons (humans
have 100 billion), individual neurons are large enough to be distinguished by eye—making them easy to study.
When a shock is applied to Aplysia's tail or head,
messages travel around a circuit of neurons, causing it to retract its gill for protection. The same fundamental process occurs
in humans too: neurons “talk” to each other across a gap, the synapse, via chemicals called neurotransmitters,
which bind to receptors at the receiving end. One shock in Aplysia creates a memory that lasts for minutes; several
shocks spaced out over time will be remembered for days or longer. Dr Kandel showed that the process of acquiring long-term
memories does not change the basic circuitry of nerve cells. Rather, it creates new synaptic connections between them, and
solidifies existing ones.
In 1990, Dr Kandel's laboratory at Columbia University
found the first clue to one of the key elements underlying that process—“cyclic AMP response element binding protein”,
or CREB. It turns out that CREB functions like a molecular switch that can turn genes off or on, thus manipulating the production
of proteins that bring on lasting structural changes between neurons. Lowering the threshold for turning on that switch causes
memories to be consolidated more easily. After creating compounds that successfully manipulated the CREB pathway in rodents,
the company signed a partnership with Swiss pharmaceutical giant Hoffmann-La Roche worth up to $106m.
Helicon Therapeutics of Farmingdale, New York, is pursuing
the same target, with competing patents, albeit more slowly. In the mid-1990s the firm's co-founder, Tim Tully, a neuroscientist
at Cold Spring Harbor Laboratory of Long Island, New York, performed his own groundbreaking CREB studies in fruit flies. In
one particular experiment, Dr Tully and his colleagues compared normal flies with those that had been genetically engineered
so that the CREB switch was permanently turned on. While crawling in a small tunnel in the presence of an odour, the insects
received an electric shock. Just one such jarring experience was enough to teach the enhanced flies to run away from the same
odour in future: they had, in effect, perfect recall, or what is sometimes called “photographic memory” in humans.
The normal flies, however, required a total of ten training sessions to learn the same lesson. By the end of this year, Helicon
hopes to move one particularly promising compound into clinical trials.
Not everyone believes CREB-enhancers will boost human
mental performance, however. Among the sceptics is Joe Tsien, director of the Centre for Systems Neurobiology at Boston University,
who created a buzz a few years ago when he engineered “Doogie,” a strain of intelligent mice. Dr Tsien points
to a study published in the Journal of Neuroscience last year, which found that mice with CREB “deleted”
from a part of the brain called the hippocampus showed little impairment of long-term memory formation. Moreover, he notes,
CREB is not a brain-specific molecule, but is present throughout the body. “That doesn't bode well for the notion that
it's a memory switch,” argues Dr Tsien. Even if the drugs work, he adds, nasty side-effects could appear—one of
the main reasons promising compounds never make it to the market.
Saegis Pharmaceuticals, based in Half Moon Bay, California,
is taking a different approach—three of them, in fact. The company has licensed in three compounds, each one acting
on a different pathway in the brain. Moreover, all of them have already demonstrated efficacy in animals, and two of them
safety in humans. The company's lead candidate, SGS742, which has just entered a mid-stage clinical trial for Alzheimer's
disease, appears to alter brain chemistry in several distinct ways. Most importantly, the drug binds to GABA B receptors,
which act as pre-synaptic gatekeepers for various neurotransmitters. By docking on to these receptors, SGS742 blocks their
inhibitory actions. This enables many more neurotransmitter messengers to travel from one nerve cell to another.
Besides pursuing compounds that originated elsewhere,
Saegis is busy developing its own drug pipeline. The firm enlisted Michela Gallagher, a research psychologist at Johns Hopkins
University, to help identify new drug targets in animal models. Dr Gallagher, who has studied the ageing brains of rats for
more than a decade, has developed an elaborate system with which she grades the rats based on their ability to master a variety
of cognitive challenges, such as memorising a specific location in a maze. Interestingly, she has found that both humans and
rats develop age-related memory loss gradually and in similar proportion. By comparing the gene-expression profiles of rats
of different ages and abilities, she has been able to pinpoint over 300 genes that play a part in the process. Because people
share those genes, Dr Gallagher reckons her research will hasten the development of memory drugs.
Currently only a handful of drugs to treat Alzheimer's
are approved in America, and none for MCI. Most of them prevent the breakdown of acetylcholine, a neurotransmitter. Unfortunately,
these medications are not that effective. While patients show small gains on tests, many doctors doubt that the scores translate
into meaningful lifestyle improvements, such as the ability to continue living at home. Moreover, the drugs often have unpleasant
side-effects, such as nausea and vomiting, which may be why they have failed to interest healthy people. But that could change
with the next generation of drugs. Because of their huge market potential, any drug approved for MCI will have to show an
immaculate safety profile, predicts Dr Tracy.
For an indication of what might happen if a safe and
effective cognitive enhancer were to reach the market, consider the example of modafinil. Manufactured by Cephalon, a biotech
company based in West Chester, Pennsylvania, and sold under the names “Provigil” and “Alertec”, the
drug is a stimulant that vastly improves alertness in patients with narcolepsy, shift-work sleep disorder and sleep apnea.
Since it first reached the market in America in 1999, sales have shot through the roof, reaching $290m in 2003 and expected
to grow by at least 30% this year.
Much of the sales growth of modafinil has been driven
by its off-label use, which accounts for as much as 90% of consumption. With its amazing safety profile—the side-effects
generally do not go beyond mild headache or nausea—the drug is increasingly used to alleviate sleepiness resulting from
all sorts of causes, including depression, jet lag or simply working long hours with too little sleep. Cephalon itself is
now focusing on moving the drug through late-stage clinical trials for attention deficit hyperactivity disorder in children.
Ritalin, an amphetamine now widely used to treat this disorder, is in the same category as morphine for its addictive potential.
Most experts believe that modafinil, by contrast, is far less likely to be abused.
While there are those who scoff at the idea of using
a brain-boosting drug, Arthur Caplan, a bioethicist at the University of Pennsylvania in Philadelphia, does not think it would
be particularly new, or inherently wrong, to do so. “It's human nature to find things to improve ourselves,” he
says. Indeed, for thousands of years, people have chewed, brewed or smoked substances in the hopes of boosting their mental
abilities as well as their stamina. Since coffee first became popular in the Arab world during the 16th century, the drink
has become a widely and cheaply available cognitive enhancer. The average American coffee drinker sips more than three cups
a day (and may also consume caffeine-laced soft drinks).
Prescription drugs, though never intended for widespread
use, have followed suit. Ritalin, for example, is used by some college students to increase their ability to study for long
hours. Not surprisingly, some worry about the use of such drugs to gain an unfair advantage. Modafinil has already surfaced
in doping scandals. Kelli White, an American sprinter who took first place in the 100-metre and 200-metre competitions at
last year's World Championships in Paris, later tested positive for the drug. Initially she insisted that it had been prescribed
to treat narcolepsy, but subsequently admitted to using other banned substances as well. As a result, she was forced to return
the medals she won last year and, along with a handful of other American athletes, was barred from competitions for two years.
Nonetheless, such performance-enhancing properties are
exactly why the armed forces have taken an interest in brain-boosting drugs. For soldiers on the battlefield, who may sleep
only four hours a night for weeks, a boost in alertness could mean the difference between life and death. Pilots on long missions
are also at risk: fatigue means they have slower reaction times and impaired attention spans, says John Caldwell, a research
psychologist at the US Air Force Fatigue Countermeasures Branch, who has been studying the effects of sleep deprivation in
pilots for a decade. Worst of all, pilots are prone to “microsleeps”—short, involuntary naps that can last
up to 30 seconds. Since the second world war, pilots of American fighter jets have been known to use amphetamines, known as
“go pills”, to stop them dozing off at the controls.
But there are drawbacks to amphetamines. Besides their
addictive potential, they are strong stimulants, which can prevent soldiers from sleeping when a legitimate opportunity arises.
But with modafinil, which has a much more subtle effect on the nervous system, napping is an option, says Dr Caldwell. Last
December, America's air force authorised the use of modafinil as an alternative to dextroamphetamine for two-seater bomber
missions lasting more than 12 hours. While the drug has not yet been approved for use by solo fighter pilots, approval is
expected soon.
Last year, Nancy Jo Wesensten, a research psychologist
at the Walter Reed Army Institute of Research in Silver Spring, Maryland, compared the effects of three popular alertness
drugs—modafinil, dextroamphetamine and caffeine—head to head, using equally potent doses. Forty-eight subjects
received one of the drugs, or a placebo, after being awake for 65 hours. The researchers then administered a battery of tests.
All of the drugs did a good job restoring wakefulness for six to eight hours. After that, says Dr Wesensten, the performance
of the subjects on caffeine declined because of its short half-life (a fact that could be easily remedied by consuming another
dose, she points out). The other two groups reached their operational limit after 20 hours—staying awake for a total
of 85 hours.
When the researchers looked at the drugs' effects on
higher cognitive functions, such as planning and decision-making, they found each drug showed strengths and weaknesses in
different areas. Caffeine was particularly effective in boosting a person's ability to estimate unknown quantities. When asked
20 questions that required a specific numeric answer—such as “how high off a trampoline can a person jump?”—92%
of volunteers on caffeine and 75% on modafinil showed good estimation skills. But only 42% on dextroamphetamine did so—the
same proportion as the sleep-deprived subjects who had received a placebo.
The Defence Advanced Research Projects Agency (DARPA),
the research arm of America's defence department, is funding an initiative to find new and better ways to sustain performance
during sleep deprivation. Among its collaborators are Yaakov Stern, a neuroscientist, and Sarah Lisanby, a psychiatrist, both
of Columbia University. Using functional magnetic-resonance imaging, Dr Stern has been observing the brains of healthy volunteers
before and after forgoing sleep.
In the process, he has discovered a neural circuit that
is linked to prolonged periods of wakefulness while performing memory tasks. Interestingly, its areas of activation vary from
person to person, depending on the ability to tolerate sleep deprivation. Dr Lisanby is an expert in transcranial magnetic
stimulation, the use of strong magnetic fields to facilitate or impede the communication of nerve cells using a coil held
close to the head. She now plans to test stimulating the very regions in the brain that appear to correspond to better cognitive
performance during long hours of wakefulness.
DARPA is also supporting the research of Samuel Deadwyler,
a neuroscientist at Wake Forest University in Winston-Salem, North Carolina, who is studying the effects of ampakines, so
called because they bind to AMPA receptors. There, they amplify the actions of glutamate, a neurotransmitter involved in two-thirds
of all brain communications. Roger Stoll, the boss of Cortex Pharmaceuticals, which has been developing the compounds, has
called them “a hearing aid for the brain”.
According to Dr Deadwyler's tests in primates,
Cortex's new drug candidate, CX717, which just entered human clinical trials, appears to eliminate the cognitive deficits
that go hand in hand with sleep loss. Monkeys deprived of sleep for 30 hours and then given an injection of the compound even
do slightly better in short-term memory tests than well-rested monkeys without the drug. And unlike amphetamines, which put
theis humanity's most widely consumed drug—there is
little reason to object to this state of affairs, provided no laws are broken and the risks of side-effects or addiction are
minimal.
Besides, cognitive enhancers merely improve the working
of the brain: they cannot help people remember something they never learned in the first place. No single pill will make you
a genius, says Fred Gage, a neuroscientist at the Salk Institute in California, as there is no pharmaceutical substitute for
a rich learning environment. In experiments with genetically identical mice, he found that the ones brought up with lots of
toys and space had 15% more neurons in an area of the brain important for memory formation. And the brain had not just created
more cells: fewer of them were dying off. “Any pill coming down the road”, says Dr Gage, “is going to be
taken in the context of how you behave.”
And too much enhancement might even be counter-productive—at
least for healthy people. As Dr Kandel and his colleague Larry Squire, of the University of California, San Diego, point out
in their book “Memory: From Mind to Molecules”, there is a reason why the brain forgets things: to prevent cluttering
up our minds. People with the natural ability to remember all sorts of minute details often get bogged down in them, and are
unable to grasp the larger concepts. So it remains to be seen whether a pill can be any more effective than a good night's
sleep and a strong cup of coffee.
No. 10
Scientists
Find Storehouse for Memory
Fri Sep 24, 7:03
PM ET
By Karen Pallarito HealthDay
Reporter
FRIDAY, Sept. 24 (HealthDayNews)
-- In a finding that could lead to better insights into how memories are formed, neuroscientists say they have identified
the compartment within nerve cells that stows special receptors that can be deployed to intensify incoming messages.
These compartments, called
recycling endosomes, also carry other molecules and proteins, which may play a role in remodeling nerve cells, or neurons,
to strengthen the connections between them.
The findings provide
important clues to understanding how the brain makes memories, say the researchers from DukeUniversityMedicalCenter
and BrownUniversity.
"The gist of what we're
interested in is how the strength of communication is altered between neurons as the circuitry of the brain adapts, as we
learn and store new memories," explained study leader Dr. Michael Ehlers, an associate professor of neurobiology at Duke.
Having a better understanding
of the machinery of the brain also will help pave the way for new treatments targeting diseases that affect memory and cognition,
such as Alzheimer's, the researchers said.
The study appears in
the Sept. 24 issue of Science.
The brain is a vast communications
network, where some neurons serve as transmitters, firing off messages to other neurons that act as receivers, or antennae.
All of this data exchange occurs across a small gap between neurons, known as a synapse.
Changes in the strength
of a neuron's response to those transmissions depend on the number of receptors that are present. More receptors on the information-receiving
cell, called the post-synaptic neuron, make for a stronger antenna. This strengthening of connections between neurons, which
can last hours or even days, is known as long-term potentiation, believed to be the cellular basis for memory, the researchers
said.
Until now, scientists
hadn't known the exact source of these synaptic-strengthening receptors, named AMPA receptors for the chemical substance that
activates them. "We wanted to see, can we identify a hidden source of receptors within this postsynaptic neuron?" Ehlers explained.
By injecting mutant protein
into rat neurons and into brain tissue, the researchers were able to confirm that the recycling endosomes house those receptors.
But they were surprised to find the compartments also carried more than just AMPA receptors. In additional experiments, they
found that the recycling endosome houses other material that may be used to expand synapses during memory formation.
"These findings indicate that
the molecules for memory are close by to all of our synapses," said neuroscientist Dr. Roberto Malinow, whose research lab
at Cold Spring Harbor Laboratory in New York investigates learning and memory
by studying synaptic transmission in rodent brain slices. "We just need a way to move them into the right synapses."
In practical terms, these discoveries
could lead to a better understanding of normal cognitive decline and memory diseases such as Alzheimer's. It may be that such
conditions reflect impairments of synaptic plasticity, an inability of the synapses to change their properties, Ehlers suggested.
"It tells us where in the cell
to look for molecular targets to improve or reverse synaptic dysfunction," he said.
"Unfortunately," added
Malinow, "so little is currently known regarding the basic cause of neurological diseases that any finding significantly advances
our knowledge."
More information:
Check with the National Institute
of Neurological Disorders and Stroke to learn about the life and death of a neuron.
No. 11
Dopamine AndBrain Circuitry
HowardHughesMedicalCenter
March 03, 2005
A Rewarding
Discovery Shows How Dopamine Activates Brain Circuitry
Researchers have discovered
how dopamine — a molecule important for communication between neurons in the brain — stimulates the synthesis
of proteins in neuronal processes. This local stimulation of protein synthesis may modify synapses in the brain during learning,
said the researchers.
The new findings add
to the understanding of dopamine's influence on the brain's reward circuitry that appears to be altered by addictive drugs.
The research team, led by Erin M. Schuman, a Howard Hughes Medical Institute investigator at the California Institute of Technology,
published its findings in the March 3, 2005, issue of the journal
Neuron. Lead author on the paper was Bryan Smith in Schuman's laboratory.
“This raises
the possibility that some of the signaling that goes awry during addiction may have to do with local protein synthesis.” Erin
M. Schuman
Neurons trigger nerve
impulses in their neighbors by launching bursts of neurotransmitters, such as glutamate and dopamine, across junctions called
synapses. The neurotransmitter receiving stations on neurons are tiny spines that festoon the surfaces of dendrites, which
are small branches that extend from neurons.
“Dopamine and
regulation of dopamine signaling is important for reward circuits in the brain, including those responsible for our ability
to learn about the positive or negative consequences of environmental stimuli including drugs of abuse,” said Schuman.
Dopamine-triggered
neuronal signaling is also involved in regulating motivation, and in such diseases as Parkinson's disease and schizophrenia,
she said.
According to Schuman,
it was known that dopamine influenced the strengthening of synaptic connections among neurons. It was also known that such
strengthening, or plasticity, involved activation of protein synthesis in the dendrites, which somehow led to enhanced activity
of other kinds of neurotransmitter receptors. However, she said, the mechanism by which dopamine influenced such local protein
synthesis and triggered plasticity was not known.
In their studies, Schuman
and her colleagues introduced the gene for a fluorescent “reporter” molecule into cultured rat neurons, such that
when protein synthesis was activated, the neurons would emit a telltale glow. When the researchers activated dopamine receptors
on the dendrites, they detected the glow in the dendrites, revealing that dopamine did activate local protein synthesis and,
thus, promoted plasticity. In a more targeted experiment, they introduced molecules directly into the dendrites that would
tag newly synthesized endogenous proteins fluorescently. Those experiments also revealed local protein synthesis due to activation
of dopamine receptors.
The researchers' measurements
indicated that dopamine receptor activation triggered immediate enhancement of protein-synthesis-sensitive synaptic transmission
among the neurons. “That's a result that people have been seeking for years,” said Schuman. “It's a very
rapid effect on synaptic transmission that is protein-synthesis-sensitive.”
Schuman and her colleagues
also identified a specific neurotransmitter receptor subunit whose synthesis was switched on by dopamine-triggered plasticity.
That subunit, called GluR1, is part of another class of neurotransmitter receptors, called AMPA receptors — which play
a key role in normal synaptic transmission and the plasticity associated with learning and memory. The researchers demonstrated
that dopamine caused an increase in the GluR1 subunit delivery to the cell membrane, where it would be expected to play a
role in enhancing responsiveness to transmitter.
“This evidence
is consistent with the concept of the `silent synapse,'” said Schuman. “That idea holds that such synapses are
functionally silent because they do not possess functional AMPA-type receptors. Rather, these silent synapses possess only
receptors known as NMDA-type receptors, which are thought to be inactive. However, when AMPA-type receptors are inserted into
the membrane, according to this theory, a silent synapse converts to an active one.”
The researchers also
demonstrated a link between dopamine-related plasticity and NMDA receptor activity. They found that when they blocked NMDA
receptors, the dopamine-regulated synthesis of GluR1, as well as enhanced synaptic transmission, were blocked. “This
experiment showed that there may be some specificity to dopamine's actions, at least in how it stimulated local protein synthesis,”
said Schuman. “You may need both dopamine release and functional NMDA receptors to trigger protein synthesis and plasticity.”
According to
Schuman, their findings could have implications for understanding drug addiction and its treatment. “Over the past few
years, investigators have begun to focus on the dendrite and its spines as potential sites that are altered during reward
and addiction,” she said. “This raises the possibility that some of the signaling that goes awry during addiction
may have to do with local protein synthesis.”
Biological clock
may shut down long-term memory at night
If you crammed for
tests by pulling 'all nighters' in school, ever wonder why your memory is now a bit foggy on what you learned? A University
of Houston professor may have the answer with his research on the role of circadian
rhythms in long-term learning and memory. Arnold Eskin, the John and Rebecca Moores Professor of Biology and Biochemistry
at UH, was recently awarded two grants totaling $2,472,528 from the National Institutes of Health (NIH) to continue pursuing
his investigations of memory formation and the impact of the biological clock on learning and memory.
Scientists have known
for a while that the brain's biological (or circadian) clock influences natural body cycles, such as sleep and wakefulness,
metabolic rate and body temperature. New research from Eskin suggests the circadian clock also may regulate the formation
of memory at night. This new research focuses on "Circadian Modulation of Long-term Memory Formation" and "Long-term Regulation
of Glutamate Uptake in Aplysia," with NIH funding to be disbursed over four years.
"There is a lot of
research going on in memory," Eskin said. "How do we remember things given that we don't have a camera in our brain to record
events? What changes take place in our brains that allow us to remember? These grants are about fundamental learning and memory
and about modulation of memory."
For the grant on circadian
modulation of long-term memory formation, Eskin will continue studies based on his data that reveal the circadian clock modulates
several forms of long-term memory in the marine snail Aplysia.
These studies
involved experiments on the defensive reflexes and feeding responses of Aplysia. Eskin's results showed that Aplysia form
long-term memory when they are trained during the day but not when they are trained at night. However, short-term memory of
the same behaviors is formed equally well during the day and night, which might explain why all-night cram sessions may have
helped you get through certain classes in school, but did not leave you with enough of a lasting impression to become part
of your long-term store of knowledge.
"Somewhere in the molecular
circuit, in the neural circuit in the brain, the biological clock is shutting that circuit off at a particular time of night.
It's shutting molecules down so that long-term memory can't happen," Eskin said.
Lisa Lyons, a research
assistant professor at UH, is the primary investigator on this grant and is already investigating molecules involved in memory
formation that might be activated during the day but not at night. NIH funding will help advance the pursuit of this line
of research.
For the grant
on long-term regulation of glutamate uptake in Aplysia, Eskin will focus on the transmitter substance glutamate, which is
involved in memory formation.
"The formation of memory
happens at places in the brain called synapses, where cells 'talk' to one another through the release of chemicals called
transmitter substances," Eskin said. "In order for transmitters to work, once they are released they have got to be cleared
away so that others can subsequently act. So, there are not only important mechanisms to release the transmitters, but also
mechanisms to get rid of them, and these are called reuptake systems."
Eskin is studying glutamate
reuptake and glutamate transport to understand the mechanism or change that takes place at the synapses of nerve cells (or
neurons) that enables people to remember. In previous research, Eskin found that glutamate transport molecules, which act
as the brain's cleaning crew during learning and memory formation, actually increase once the long-term memory-forming process
begins. Deficiencies in these glutamate transporters that affect the strength of connections among the neurons associated
with memory may explain why memory lapses such as forgetting where you last set down your keys occur.
"This research will
provide significant information toward understanding memory and thus diseases that affect memory," Eskin said.
With the potential
to shed light upon neurodegenerative diseases such as Alzheimer's – marked by a loss of brain function due to the deterioration
of neurons – studying these nerve cells could one day take this research from helping you be better able to find your
glasses to providing relief from a debilitating illness.
"At the end of
the day, we can't make memory better or improve it unless we understand how memory works and is modulated," he said. "That's
what this research is all about."
He is currently completing
the last year of another NIH-funded grant on "Glutamate Transport Regulation and Synaptic Plasticity" that complements these
two new grants, but investigates the role of glutamate uptake in associative learning in mammals. This research project on
mammals represents a great example of traslational research in which basic findings in a simple system (i.e. Aplysia) were
quickly applied to a higher organism (i.e. mammals). They found that glutamate transport increased in the brains of mammals
during learning as also found in Aplysia. (See related release at http://www.uh.edu/admin/media/nr/2002/032002/eskinlearning.html.)
Coming to UH more than
25 years ago, Eskin guided the merger of two departments into what is now the Department of Biology and Biochemistry in the
College of Natural Sciences and Mathematics.
As department chair from 1994 to 2000, Eskin tripled research grants to approximately $6 million per year and developed the
department's research foci of neuroscience, the biological clocks and infectious disease. The author or co-author of more
than 150 publications, he has received numerous honors, including the Esther Farfel Award, the university's highest faculty
honor. He is the only faculty member to receive both the Farfel Award and the Moores Professorship in the same year. Eskin
earned his bachelor's degree in physics from VanderbiltUniversity
and his doctorate in zoology from the University of Texas.
UH's Biological
Clocks Program is one of the world's leading centers for circadian rhythms research, with five laboratories and a team of
more than 30 scholars. In addition to Eskin, the group is led by four other tenured faculty members in the biology and biochemistry
department – Associate Professor Gregory M. Cahill, Professor Stuart Dryer, Professor Paul Hardin and Professor Michael
Rea.
No.12
Researchers Uncover
Key Step In Manufacture Of Memory Protein
The protein is known
as mBDNF, which stands for mature brain-derived neurotrophic factor. In an earlier study, another team of NICHD researchers
had shown that mBDNF is essential for the formation of long-term memory, the ability to remember things for longer than a
day.
“Understanding
how BDNF is made may help us to better understand the learning process, perhaps leading to better treatments for disorders
of learning and memory,” said Duane Alexander, M.D., Director of the National Institute of Child Health and Human Development.
The research
team was led by Y.Peng Loh Ph.D, of NICHD’s Section on Cellular Neurobiology. The researchers published their work in
the January 20 issue of Neuron.
Specifically, the researchers
discovered that the enzyme carboxypeptidase E, (CPE) is needed to deliver the early, or
inactive, form of BDNF — proBDNF — to a special compartment in the neuron (nerve cell.) Once in the compartment,
proBDNF is chemically converted into active mBDNF. After mBDNF is formed, it is released to the outside of the neuron, where
it binds to receptors on other neurons and stimulates them to form long-term memory.
Dr. Loh explained that,
like other proteins, proBDNF is made inside the endoplasmic reticulum, a convoluted network of tubes and channels inside the
cell. The proBDNF winds through the endoplasmic reticulum until it reaches another structure within the cell, the golgi apparatus.
There, the proBDNF binds to CPE, which protrudes from special rafts of fatty, cholesterol-rich
molecules known as lipids. If this binding process does not take place, proBDNF cannot be converted to its active form. Dr.
Loh explained that the proBDNF molecule has four projections, resembling prongs. These prongs fit into a corresponding indentation
on CPE, analogous to the way a plug for an electric appliance fits into an electric wall
outlet, Dr. Loh said.
The golgi apparatus
then encases the lipid rafts — along with proBDNF — in bubble-like structures known as vesicles. Within these
vesicles, proBDNF is converted to mBDNF by other enzymes. The vesicles are then transported to the cell’s outer membrane,
where they remain until they are ready to be secreted. Once the cell receives an electrical signal from another neuron, these
vesicles fuse with the cell’s outer membrane, open up, and release mBDNF.
During their research,
Dr. Loh and her colleagues observed mice genetically incapable of producing CPE. In these
mice, proBDNF could not be delivered into the lipid raft-rich vesicles for conversion to mBDNF. Instead, it appeared to leak
out of the golgi apparatus, where it leached through the cell membrane without first having been converted to active mBDNF.
Because they cannot make mBDNF, CPE-deficient mice have poor long-term memory.
Dr. Loh added that,
in the near future, an understanding of the chemical mechanism she and her colleagues deciphered in the current study may
provide insight into long-term memory deficits. She explained that other researchers have learned that some human beings lack
normal CPE due to mutations in the CPE gene. Future
research may determine if the CPE mutation affects these individuals’ long-term memory.
The NICHD is
part of the National Institutes of Health (NIH), the biomedical research arm of the federal government. NIH is an agency of
the U.S. Department of Health and Human Services. The NICHD sponsors research on development, before and after birth; maternal,
child, and family health; reproductive biology and population issues; and medical rehabilitation.
No.13
Mechanism
of RNA recoding: New twists in brain protein production
17 Mar 2005
RNA loops and knots guide genetic modifications -
University of Connecticut Health Center
scientist, Robert Reenan, has uncovered new rules of RNA recoding--a genetic editing method cells use to expand the number
of proteins assembled from a single DNA code. According to his work, the shape a particular RNA adopts solely determines how editing enzymes
modify the information molecule inside cells. The study may help explain the remarkable adaptability and evolution of animal
nervous systems--including the human brain.
The work appears in the March 17 issue of Nature.
DNA sequences spell out the instructions for making protein but they aren't always followed
to the letter. Sometimes, the genetic recipe gets edited after cells copy DNA to RNA--a close chemical relative--during transcription. Think of DNA as an unalterable "read only" copy of the genetic code and the RNA as a "writable"
working copy that cells can edit extensively--adding, deleting, and modifying the molecular letters and words that guide protein
assembly. Often, even simple editing such as changing one letter in an RNA molecule affects the resulting protein's function.
There are many different types of RNA editing.
Reenan's group studies one particular method called A-to-I RNA recoding.
It occurs when an enzyme chemically "retypes" RNA letters at specific locations, changing adenosine (A) to inosine (I). Proteins
responsible for fast chemical and electrical signaling in animal nervous systems are the main targets of this process. In
a prior study, Reenan's group identified species-specific patterns of RNA recoding on such targets, but didn't explain how
they were determined or how they may have evolved. His new study does both.
By comparing the same highly edited RNA
from over 30 insects, Reenan uncovered some general rules of A-to-I recoding. He observed that the RNA of different insects
folds into unique structures. These shapes single-handedly determine the species-specific RNA editing patterns that Reenan
previously observed. For example, part of the RNA molecule he focused on--the code for the protein synaptotagmin, a key player
in neuronal chemical signaling--looks like a knot in fruit flies, but a loop in butterflies. These molecular knots and loops
bring regulatory regions of the RNA together with sites destined for recoding, guiding editing enzymes to act there. As proof,
Reenan coaxed fruit fly RNA to adopt a "mosquito-like" structure by making small changes in the molecule--a procedure he dubbed
"guided evolution." Predictably, cells edited the reconfigured fly RNA in the mosquito-like pattern.
In all species
Reenan studied, the RNA region that regulates folding is located within an intron--a string of non-protein coding letters
that cells cut out or "splice" from the molecule during processing. RNA recoding can't occur without introns, so cells must
have a way of slowing down splicing long enough for editing enzymes to do their job. "The structures imply a really strong
interaction between splicing and editing," according to Reenan, who notes that, "these complicated structures actually tie
up--literally--splicing signals." By making small alterations in introns during evolution, different insects conserved the
basic RNA code for making important proteins, but developed a way to tweak the resulting nerve cell protein's function in
a species-specific manner. The species-specific editing may give insects different abilities by modifying behaviors.
According
to Joanne Tornow, the National Science Foundation program manager who oversees Reenan's work, "These findings provide dramatic
evidence that intron sequences, which were once thought to serve little purpose of their own, are functionally important in
the accurate expression and regulation of these genes. What's more," she adds, "this work is revealing a new type of genetic
code, which incorporates both sequence and structural signals." She anticipates this work, also funded in part by the National
Institutes of Health, will "greatly increase our ability to interpret the information encoded in the genome."
Researchers
still don't know why editing occurs, but posit that organisms use it to increase protein variety. RNA recoding lets cells
generate an array of proteins from a single DNA sequence, each
with a slightly different function. Producing different proteins in a cell at once could let organisms fine tune biological
processes with extreme precision--a level of flexibility the DNA code doesn't afford. "Genetics is digital," says Reenan, adding "Editing changes
digital to analog," letting cells "dial up" the exact amounts of altered proteins required at any given time or place.
No
matter why organisms do it, one thing is clear--serious problems can occur when RNA editing goes awry. RNA recoding defects
cause neurological problems in all of the animals examined to date.
NSF-05-041
The National Science Foundation
(NSF) is an independent federal agency that supports fundamental research and education across all fields of science and engineering,
with an annual budget of nearly $5.47 billion. NSF funds reach all 50 states through grants to nearly 2,000 universities and
institutions. Each year, NSF receives about 40,000 competitive requests for funding, and makes about 11,000 new funding awards.
The NSF also awards over $200 million in professional and service contracts yearly.
Receive official NSF news electronically
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Contact: Nicole Mahoney nmahoney@nsf.gov 703-292-5321 National
Science Foundation http://www.nsf.gov
No. 14 :
Some Brain Cells "Change
Channels" To Fine-Tune The Message
26 Mar 2005
Johns Hopkins researchers have
identified the proteins that allow specific brain cells to "change channels," a rare ability that tweaks what can come into
the cell. The findings, described in the March 24 issue of Neuron, might let researchers harness the process, perhaps one
day using it to protect cells that die in Lou Gehrig's disease.
Much as turning the television dial changes what comes
into the living room, these brain cells are able to change what they allow in by swapping one kind of channel, or membrane
opening, for another. Doing so lets the cells fine-tune their messages and adjust connections within the cerebellum, the brain
region that controls fine motor skills.
Although the cells' channel-changing ability has been recognized for a few
years, the key players controlling it hadn't been identified. Now, by studying mice, the Hopkins team has identified two proteins,
called PICK1 and NSF for short, that help replace channels that let charged calcium ions in with another kind of channel that
keeps calcium out. If muscle-controlling nerve cells can do the same thing, forcing the swap might help protect them from
a calcium overdose that can kill them in Lou Gehrig's disease.
"We don't know yet whether this happens in muscle-controlling
nerve cells, but we're looking into it," says Richard Huganir, Ph.D., professor of neuroscience and a Howard Hughes Medical
Institute investigator in Johns Hopkins' Institute for Basic Biomedical Sciences.
So far, no one has really looked
for the channel changing in other cells in the brain, he says, in part because the swapped channels are most common in these
particular cells in the cerebellum (so-called stellate cells). But Huganir thinks the channel changing is going to be relatively
common in the brain.
Whether through channel changing or other, more well-understood ways of fine-tuning its responsiveness,
a brain cell's activity level depends on its neighbors, the nerves and other cells that connect to it. Although they don't
physically touch, the cell and its neighbor are so close to one another at these connection points, called synapses, that
molecules released from one cell travel immediately to the next.
These molecules dock at specific places, or receptors,
on the cell and trigger "channels" in the cell's membrane to open. Depending on the receptor and the channel, in will flow
sodium, calcium, chloride or other charged atoms that then keep the communication process going.
In the cells in the
cerebellum, a channel made of proteins called AMPA receptors, built from subunits called GluR3 and GluR4, is usually found
at the synapse. If the cells are shocked with an electric current, within minutes the channels are replaced by ones made of
GluR2 and GluR3. After the swap, sodium can still get in, but calcium is kept out.
To learn more about how this takes
place, the Hopkins researchers studied brain cells from genetically engineered
mice. Through their experiments, the researchers determined that the PICK1 and NSF proteins are both required for the calcium-forbidding
channel to move into place at the synapse. Exactly how they help the channels move is still unknown, as is why the cells change
their channels.
Part of the answer is likely to be self-preservation: Too much calcium inside nerve cells can kill
them. But Huganir points out that calcium does a lot of things inside cells, suggesting that the channel swap might be accomplishing
more than just keeping the cell alive.
"Calcium turns some processes on, and it turns others off," he says. "My personal
belief is that the cells might be doing more than just protecting themselves by keeping calcium out."
In some cases,
protection might be enough of a goal. In people with Lou Gehrig's disease, or amyotrophic lateral sclerosis (ALS),
some muscle-controlling nerve cells die because too much of the brain chemical glutamate binds to the cells' AMPA receptors,
and so too much calcium gets inside. If these threatened nerve cells can swap their calcium-allowing channels for the kind
that keeps calcium out, it might be possible to harness that switch to prevent the cells from dying.
"But that's a
big 'if' at this point," says Huganir.
The researchers were funded by the RobertPackardCenter for ALS
Research at Johns Hopkins, the National Institute of Neurological Disease and Stroke, and the Howard Hughes Medical Institute.
Authors on the paper are Huganir,
Stephanie Gardner, Kogo Takamiya, Jun-Gyo Suh, Richard Johnson, Sandy Yum and Jun Xia, all of Johns Hopkins. Suh is now at
the Hallym [sic] University College of Medicine, Chuncheon, Gangwondo, South
Korea, and Xia is now at the Hong Kong University of Science and Technology.
Under
a licensing agreement between Upstate Group Inc. and The Johns Hopkins University, Huganir is entitled to a share of royalty
received by the University on sales of products used in this research. Huganir is a paid consultant to Upstate Group Inc.
The terms of this arrangement are being managed by The Johns Hopkins University in accordance with its conflict of interest
policies.
Search
for body's 'repair kit' is medicine's Holy Grail
By Steve
Connor, Science Editor
14 June 2005
The importance
of the latest study into brain repair is the power it gives scientists to pin-point the vital stem cells that are capable
of developing into mature nerve cells.
If scientists
can harness stem cells in the brain it offers the prospect of regenerating nerve tissues that would otherwise remain damaged
for life. It could lead to effective treatments and even cures for chronic debilitating conditions from inherited disorders
such as Huntington's chorea to severe brain damage resulting from traffic accidents.
Stem
cells, especially those in the brain, are one of the most enigmatic elements of the body. Scientists know they must exist
but they do not have an easy way of finding and harnessing them.
Neuroscientists
have also come to realise that the brain has an in-built mechanism of regeneration which uses stem cells. They hope to exploit
this natural repair kit in future to mend damaged nerves.
For more
than 20 years, stem cells have been the Holy Grail of medicine because of their ability to replicate almost indefinitely before
they develop into one of the 200 or so specialised tissues of the body, from blood to nerves.
Yet it
was only in 1998 that researchers published the first studies showing that it was possible to extract stem cells from human
embryos and grow them in the laboratory.
Stem
cells derived from early embryos are known to have the greatest ability to develop or "differentiate" into any of the specialised
tissues of the body.
The stem
cells found in adults have a somewhat similar though muted power of development. Those in the brain for instance are believed
to be primarily programmed to turn into brain cells, while those in the bone marrow are designed to develop into blood cells.
If stem
cells can be isolated and grown in the laboratory it offers hope of stimulating them with growth factors so they become the
mature cells needed for transplant surgery, whether for treating a damaged heart or a defective brain.
However,
one of the potential difficulties in using stem cells for transplant medicine is the possibility of tissue rejection. One
way around this would be to clone an embryo from a skin cell and use the embryonic stem cells from this cloned embryo.
Work
in this area is severely curtailed in many countries, including the US, which has banned the use of government funds for such research. This is one of the reasons why there
is such interest in adult stem cells.
Neuron "Assembly Line" Created
Method
holds promise for producing limitless supplies of cells to treat such conditions as Parkinson's
[Betterhumans] | 06.13.2005 @06:05 PM
A method
of generating neurons in a lab dish has been developed that could provide a limitless supply of brain cells for treating such
conditions as Parkinson's.
"It's
like an assembly line to manufacture and increase the number of brain cells," says Bjorn Scheffler of the University of Florida. "We can basically take these cells and freeze them until we need them. Then we thaw them, begin a cell-generating process,
and produce a ton of new neurons."
Previous
attempts to produce brain cells aren't thought to mimic the natural process, nor have they allowed researchers to watch development
of cells from primitive states to functional neurons.
For their
study, Scheffler and colleagues collected cells from mice and used chemicals to make them to differentiate. They took images
of the cells every five minutes for up to 30 hours and compiled these into movies.
In the
late 1990s, researchers at the University of Florida recognized similarities between cell development in blood—hematopoiesis—and the brain, which was termed "neuropoiesis."
"The
exciting part is we are actually using methods that researchers involved with hematopoiesis used," Scheffler said. "Those
researchers took primitive cells, put them in a dish and watched them perform. From that, they learned vital information for
clinical applications such as bone marrow transplants. Now we have a tool to do exactly the same thing."
Brains are marvels of diversity: no two look the same -- not even those of otherwise identical
twins. Scientists at the Salk Institute for Biological Studies may have found one explanation for the puzzling variety in
brain organization and function: mobile elements, pieces of DNA that can jump from
one place in the genome to another, randomly changing the genetic information in single brain cells. If enough of these jumps
occur, they could allow individual brains to develop in distinctly different ways.
"This mobility adds an element of
variety and flexibility to neurons in a real Darwinian sense of randomness and selection," says Fred H. Gage, Professor and
co-head of the Laboratory of Genetics at the Salk Institute and the lead author of the study published in this week’s
Nature. This process of creating diversity with the help of mobile elements and then selecting for the fittest is restricted
to the brain and leaves other organs unaffected. "You wouldn’t want that added element of individuality in your heart,"
he adds.
Precursor cells in the embryonic brain, which mature into neurons, look and act more or less the same. Yet,
these precursors ultimately give rise to a panoply of nerve cells that are enormously diverse in form and function and together
form the brain. Identifying the mechanisms that lead to this diversification has been a longstanding challenge. "People have
speculated that there might be a mechanism to create diversity in brain like there is in the immune system, and the immune
system’s diversity is perhaps the closest analogy we have," says Gage.
In the immune system, the genes coding
for antibodies are shuffled to create a wide variety of antibodies capable of recognizing an infinite number of distinct antigens.
In
their study, the researchers closely tracked a single human mobile genetic element, a so-called LINE-1 or L1 element in cultured
neuronal precursor cells from rats. Then they introduced it into mice. Every time the engineered L1 element jumped, the affected
cell started glowing green [WHY?]. "We were very excited when we saw green cells all over the brain in our mice," says research
fellow and co-author M. Carolina N. Marchetto, "because then we knew it happened in vivo and couldn’t be dismissed as
a tissue culture artifact."
Transposable L1 elements, or "jumping genes" as they are often called, make up 17 percent
of our genomic DNA but very little is known about them. Almost all of them
are marooned at a permanent spot by mutations rendering them dysfunctional, but in humans a hundred or so are free to move
via a "copy and paste" mechanism. Long dismissed as useless gibberish or "junk" DNA, the transposable L1 elements were thought to be intracellular parasites or leftovers
from our distant evolutionary past.
It has been known for a long time that L1 elements are active in testis and ovaries,
which explains how they potentially play a role in evolution by passing on new insertions to future generations. "But nobody
has ever demonstrated mobility convincingly in cells other than germ line cells," says Gage.
Apart from their activity
in testis and ovaries, jumping L1 elements are not only unique to the adult brain but appear to happen also during early stages
of the development of nerve cells. The Salk team found insertions only in neuronal precursor cells that had already made their
initial commitment to becoming a neuron. Other cell types found in the brain, such as oligodendrocytes and astrocytes, were
unaffected.
At least in the germ line, copies of L1s appear to plug themselves more or less randomly into the genome
of their host cell. "But in neuronal progenitor cells, these mobile elements seem to look for genes expressed in neurons.
We think that’s because when the cells start to differentiate the cells start to open up genes and expose their DNA to insertions," explains co- author Alysson
R. Muotri. "What we have shown for the first time is that a single insertion can mess up gene expression and influence the
function of individual cells," he adds.
However, it is too early to tell how often endogenous L1 elements move in human
neurons and how tightly this process is regulated or what happens when this process goes awry, cautions Gage. "We only looked
at one L1 element with a marker gene and can only say that motility is likely significantly more for endogenous L1 elements,"
he adds.
No.: 17
June 21, 2005 09:01 AM US Eastern Timezone DARPA to Sponsor Evaluation of the AMPAKINE CX717 in a New Study in Shift Work
IRVINE, Calif.--(BUSINESS WIRE)--June 21, 2005--Cortex Pharmaceuticals,
Inc. (AMEX: COR) announced that the Defense Advanced Research Projects Agency (DARPA) of the U.S. Department of Defense is
sponsoring a new CX717 study. Results from this study could help confirm and extend the positive findings with CX717 from
the recently completed sleep deprivation study.
Rationale for the Study: The new study
will evaluate the cognitive performance and objective alerting effects of CX717 utilizing a simulated night shift work paradigm.
Volunteers will undergo four nights of simulated shift work during which they will be "on shift" (high work load) from 11:00 P.M. to 7:00 A.M. The volunteers will also be restricted to only four hours of recovery sleep on each
of the four study days. Three different doses of CX717 will be compared to placebo in randomized, double-blind, parallel-group
design. The study medication will be given daily prior to the simulated night shift activities. Outcome measures will include
the maintenance of wakefulness test, cognitive performance tests, and polysomnography during the recovery sleep period.
According to Dr. Roger G. Stoll, Chairman,
President and CEO of Cortex, "Cortex will supply CX717 and matching placebos for the study. DARPA will fund a military research
organization to conduct the study. The first volunteers are expected to be enrolled this summer and we expect that the study
should be concluded near the end of the year. Positive results from this study could move CX717 closer toward a marketable
indication, namely to improve wakefulness in patients with Excessive Daytime Sleepiness (EDS), while at the same time provide
the military with a simulated situation that more closely approximates the adverse sleep conditions often faced by soldiers
during military operations."
Cortex announced on May 3, 2005 that CX717, when compared to placebo, increased wakefulness in a dose-related manner and improved performance
in healthy male subjects that became impaired during 27 hours without sleep. The study was performed in the United Kingdom
at the Academic Clinic for Disorders of Sleep and Wakefulness within the Human Psychopharmacology Research Unit at the Medical
Research Centre, School of Biomedical and Molecular Sciences, University of Surrey by Dr. Julia Boyle, Acting Director of
the Research Unit and Professor Anthony N. Nicholson, Medical Director and Visiting Professor of Aviation Medicine, King's
College London.
About Excessive Daytime Sleepiness
(EDS) and Shift Work
There are direct benefits to the broader
civilian population from this AMPAKINE(R) study in EDS. The National Commission on Sleep Disorders estimates that 40 million Americans are
either chronically or intermittently affected with various sleep disorders. In addition to the tremendous personal pain and
suffering they inflict, sleep disorders are a tremendous drain on the productivity and safety of our country: falling asleep
at the wheel is one of the most costly and devastating problems on American highways; accidents in the workplace due to sleep
deprivation are commonplace and damaging to industry; the annual direct cost to society is over $15 billion. AMPAKINE products
may also be useful in the treatment of narcolepsy, jet lag and rotating shift workers in the workplace.
About DARPA
DARPA is the central research and
development organization for the U.S. Department of Defense. Its primary responsibility is to help maintain technological
superiority for the U.S. military and to guard against unforeseen technological advances by potential adversaries.
The Agency was founded in 1958, and, over the years, has been responsible for advances in computer networking (DARPA created
the ARPANET, the predecessor to today's Internet), advanced materials, ballistic missile defense, space launch vehicles, information
processing, advanced computer displays, and many other areas.
About Cortex Pharmaceuticals
Cortex, located in Irvine, California,
is a neuroscience company focused on novel drug therapies for neurological and psychiatric disorders. The Company is pioneering
a class of proprietary pharmaceuticals called AMPAKINE compounds, which act to increase the strength of signals at connections
between brain cells. The loss of these connections is thought to be responsible for memory and behavior problems in Alzheimer's
disease. Many psychiatric diseases, including schizophrenia, occur as a result of imbalances in the brain's neurotransmitter
system. These imbalances may be improved by using the AMPAKINE technology. Cortex has alliances with N.V. Organon for the
treatment of schizophrenia and depression and with Les Laboratoires Servier for the development of AMPAKINE compounds to treat
the neurodegenerative effects associated with aging and disease, including Mild Cognitive Impairment, Alzheimer's disease
and anxiety disorders. (http://www.cortexpharm.com/)
Forward-Looking Statement
Note - This press release contains
forward-looking statements concerning the Company's research and development activities. The success of such activities depends
on a number of factors, including the risks that the Company's proposed compounds may at any time be found to be unsafe or
ineffective for the indications under clinical test and that clinical studies may at any point be suspended or take substantially
longer than anticipated to complete. As discussed in the Company's Securities and Exchange Commission filings, the Company's
proposed products will require additional research, lengthy and costly clinical testing and regulatory approval. AMPAKINE
compounds are investigational drugs and have not been approved for the treatment of any disease.
Contacts
Cortex Pharmaceuticals, Inc. Roger G. Stoll, Ph.D., 949-727-3157 or The Investor Relations Group Damian McIntosh or Dian Griesel, Ph.D., 212-825-3210
No.: 18
Wired awake
Soldiers
in the field go for days without rest. Now, a Guardian investigation discovers that the MoD has been buying a new stimulant
in bulk. Ian Sample reports on the dangers of sleep deprivation
On April 17 2002, an incident
just outside Kandahar in Afghanistan thrust one of the military's least favourite subjects into the media spotlight. Two US
F-16 pilots, Major Harry Schmidt and Major William Umbach mistakenly bombed a Canadian infantry unit, killing four and injuring
eight. But while the "friendly fire" incident was terrible in itself, worse was to come for the military. In the ensuing legal
case, it was claimed that the pilots had been pressured into taking amphetamines - speed - to sharpen their senses.
The authorised use of drugs by military forces is rarely acknowledged by officials,
but despite accidents like the one in Afghanistan, interest in using drugs to improve performance remains high. Yet as money
is directed into the hunt for newer and better pills to squeeze more out of exhausted troops, some military researchers believe
it's time to quit the drugs and try something radically different.
It's not only the American military that is putting its faith in pharmaceuticals.
A Guardian investigation has learned that over the past six years, the Ministry of Defence has bought significant quantities
of a controversial new drug, Provigil, which is designed to help people with specific medical conditions shrug off the effects
of tiredness. Preliminary studies in America show that pilots popping the pills remained alert even after 40 hours without
sleep. Other tests have looked at how troops function after staying awake for 85 hours on the drug.
According to figures released by the Defence Medical Supplies Agency, which
provides medical items "to sustain UK military capability", the MoD has bought more than 24,000 tablets of Provigil since
1998, at prices at least 10% lower than those charged to the NHS. Released under the open government code, the figures show
that orders for the pills peaked in 2001, the year allied forces entered Afghanistan, with the next largest order being delivered
in 2002, the year before troops invaded Iraq. Provigil is licensed in Britain for alleviating daytime tiredness in people
suffering from the rare sleep disorder narcolepsy and a condition called obstructive sleep apnoea. Its introduction into the
UK triggered concern from some groups who believe it will rapidly be abused, becoming a lifestyle drug for a 24/7 society.
Dealing with sleep deprivation is a perennial problem for the military. Troops
are typically fighting in strange time zones, in unfamiliar climates and sleeping in less than five-star hotel accommodation,
if they have a roof over their heads at all. Add to that the fact that even the best planned campaigns can be knocked off
course by surprises, and the demand on troops' time is unpredictable. Opportunities to sleep may come suddenly and unexpectedly,
or in the worst cases, not for a number of days.
The effect of sleep loss is dramatic. "What you see is people's reactions
becoming impaired, their ability to make decisions is affected, and before long they are absolutely no use to you," says Charles
Heyman, an ex-army major and senior consultant with Jane's defence consultancy. Tests by Greg Belenky at the Walter Reed Army
Institute of Research in Silver Spring, Maryland, show that performance, in terms of physical and thinking ability, drops
on average 25% for every 24 hours without sleep. "Once you've been up for three days, you're pretty much useless for anything,"
he says. While drugs to combat sleepiness have their risks, so too does deploying troops who aren't sufficiently rested.
The problems are considered most acute among special forces who may have to
be alert and active in enemy territory for 48 hours, and pilots on long duration sorties. During the conflict in Kosovo, B2
stealth bombers flew from bases on the US mainland, and so concerned were military commanders that the pilots might nod off
en route that they installed garden sun loungers from Wal-Mart (a bargain at $8.88) behind the pilots' seats in case the opportunity
for a rest arose.
With sleep at such a premium, much of the military functions with the help
of simple stimulants such as caffeine, and sleeping pills, referred to as hypnotics by military medics. Because brewing up
is not always an option, new US army "first strike" rations contain caffeine-laced chewing gum, each stick providing the equivalent
of a strong cup of coffee. "We needed something simple, something that everyone's familiar with, that you don't need a medic
to dole out," says Belenky.
Stronger stimulants, namely amphetamine, have been authorised in some countries,
and mostly for pilots. The reasons are simple. Because there are so few pilots relative to other military personnel, each
can receive specific medical prescriptions for set quantities of drugs. There's an added incentive, of course, to keep pilots
sharp: few ground troops are in sole control of multimillion pound machines courtesy of the taxpayer.
But amphetamine has drawbacks that are all too well-known. The danger is that
pilots might be flying before they get anywhere near their jets. "If you take a high dose, you can end up making more errors
than you would have without it," says Sam Deadwyler, who is studying stimulants called Ampakines for the military at Wake
Forest University in North Carolina. As well as possibly distorting people's perceptions, Deadwyler says that in extreme cases,
addiction and withdrawal from speed can also become an issue.
The concerns over amphetamines have helped to spur research into improved
stimulants. The Ampakines that Deadwyler studies work in a different way from speed, targeting more specific parts of the
brain, rather than "going in and magnifying everything". The hope is that by working in a more subtle manner, they may help
to treat the symptoms of tiredness without producing a high.
Provigil, sold by the Pennsylvania-based company Cephalon, caught the eye
of the military after studies claimed that modest doses could help narcoleptics. Military trials were soon set up to see just
how far the benefits of Provigil could be pushed. Researchers in France were quickly impressed: the French Foreign Legion
took the drug as early as the Gulf war in 1991.
While Britain's largest research and development company, Qinetiq, for merly
owned by the MoD, refuses to discuss work it may have done with Provigil, and has yet to publish any studies on the drug,
US military researchers are more open.
In Maryland, Belenky's team has studied the effects of caffeine, speed and
Provigil (also known as modafinil) on troops kept awake for up to 85 hours. "In short, they all do the same thing. You give
them to someone who's tired and they feel better, but we find modafinil works longer than amphetamine and both work longer
than caffeine," he says.
While the effect of caffeine lasted for around four to six hours and amphetamine
for eight to 10 hours, Provigil lasted typically for 10 to 12 hours. Where the jury remains out, according to Belenky at least,
is whether Provigil is better at helping people regain their ability to perform complex tasks on little sleep.
Some researchers believe that the long-lasting effects of Provigil make it
ideal for use in some operations: the French military recommends it for 24-hour missions. But others see a downside in a drug
that works for so long. "In any combat operation, there may be an unexpected lull and so a chance to sleep, so a short-acting
drug can have benefits. You've a better chance of being able to sleep if the opportunity arises," says Belenky.
As with any drug, Provigil has side effects. According to the Home Office,
the list is substantial, including nervousness, insomnia, excitation, irritability, tremors, dizziness and headaches. It may
also cause "gastrointestinal disturbances", including nausea and abdominal pain, dry mouth, loss of appetite and cardiovascular
effects such as high blood pressure, palpitations and tachycardia - a fast heart beat.
While stimulants, or "go pills" have an almost inevitable place among some
quarters of the military, some researchers are pulling back from the urge to develop new drugs in the hope of finding alternative
ways of dealing with tired troops. "All three of the drugs we've tested are temporary fixes at best," says Belenky. "The thing
that really restores full-on performance is a nap for starters and then decent amounts of sleep."
Jane's consultant Charles Heyman says there are other issues with fostering
a pill-popping culture. "Without pills, we know very well how long people can last and how quickly they deteriorate, and you
can anticipate problems," he says. "When you start filling in with pills, all your planning assumptions go out of the window.
And when the effects of the pills wear off, you've no idea what kind of a zombie you're going to be left with."
The uncertainties that surround stimulants have prompted tentative forays
into radical research which could yield drugs that don't combat the effects of sleep, but remove, at least in part, the need
to sleep at all.
As a starting point, Ruth Benca at the University of Wisconsin in Madison,
is trying to understand how certain animals manage to function perfectly for long periods on a fraction of the sleep they
are used to. Her work, which is funded by the US Department of Defence, focuses on white-crowned sparrows that migrate some
4,300km between California and Alaska twice a year, a feat that can take months. During that period, the birds survive on
just one third of the sleep they are used to, while coping with the physical effort of flying and navigating by night, and
foraging by day. While special forces operatives may beg to differ, Benca says there are significant parallels between troops
on covert missions and migrating birds.
"Special forces that have to go into enemy territory and accomplish a mission
before returning have to do a lot of the same things migrating birds do," says Benca. "Birds have to go into unfamiliar territory
day after day, they have to find food, avoid predators, and at night they have to navigate and cover ground. There are extreme
physical and cognitive demands on them, because they have to solve all these problems as they go."
So far, Benca's group has yet to find any signs that the birds' performance
suffers when they skip on sleep, and intriguingly, they do not appear to need to make up for the lost hours. "They can go
at least a week without taking a night off," she says. "They just seem to be able to cope." Ultimately, Benca hopes to identify
the biological secrets that allow the birds to work so hard on so little sleep. "If we can find the molecular basis for it,
we could try and reproduce the behaviour in humans. In other words, we could develop not simply stimulants that keep you awake,
but drugs that go a long way to removing the need for sleep," she says.
If there was a way to do it, many military officials would like to see drug
use phased out altogether. "The MoD for one is absolutely paranoid about getting sued, pushing pills into people and giving
them injections and then getting sued further down the line," says Heyman. "What if you have a drug and then it reacts with
something else you've been given? A soldier going into an operational theatre might have had half a dozen injections of different
sorts." In keeping with Heyman's suggestions, the MoD has asked Qinetiq researchers to look into new ways of managing sleep.
The plan is to develop procedures so troops get the most sleep they can on a given operation.
At Belenky's lab, efforts are under way to turn sleep into a commodity of
war, much like bullets and fuel. In the next few months, troops will go on exercises wearing wristwatches that carefully monitor
how much sleep they get. The information from each troop will be beamed back to a central command post and fed into a computer
model that will work out when each unit is ready to fight, and when it must rest.
The watches will also give advice on what stimulants, if any, should be taken,
depending on the mission ahead. "The idea is to turn sleep into an item of logistic supply," says Belenky. "We want to treat
it like fuel - how much do people have, how long will it last them, and when do we need to fill them up again," he says.
How the drugs work
· In its pure form, caffeine, or trimethylxanthine, is a bitter-tasting,
white crystalline powder. In the brain, it works by binding to adenosine receptors, preventing adenosine from doing its job,
which is to make us feel sleepy.
· Amphetamine, or methylphenethylamine, is something of a pharmaceutical
sledgehammer, working throughout the brain to boost levels of a range of neurotransmitters. Its broad effect of turning up
everything, helped to earn it the name speed.
· Provigil, or 2-[(diphenylmethyl)sulfinyl] acetamide, is also
a crystalline powder. The precise mechanism by which it works is unknown, leaving medical authorities to describe it vaguely
as a central nervous system stimulant.
No.:19
Health Can Mental Function be Restored
in Alzheimer's Disease? By Ed Edelson HealthDay Reporter
THURSDAY, July 14 (HealthDay News) -- An animal experiment raises the hope
of future treatment that might restore at least a portion of mental function lost to Alzheimer's disease.
Mice genetically engineered to suffer Alzheimer's-like memory loss regained
some of that memory when the disabling gene was turned off, according to a report in the July 15 issue of Science by
researchers at the University of Minnesota.
The restoration of lost cognitive function is a revolutionary idea, the researchers
say, because so far studies have centered on slowing the loss of mental function in Alzheimer's patients, not reversing it.
The mice in the experiment suffered a major loss of neurons, the brain cells
that drive thinking. That loss was not restored, said study author Dr. Karen Ashe, a professor of neurology. However, she
said the mice's memory ability nevertheless improved.
"That implies that the remaining neurons were functioning improperly," Ashe
said. "If we discover a way to remove the molecules affecting the remaining neurons, Alzheimer's patients who have lost neurons
would regain their ability to learn," she speculated.
Ashe pointed to one molecule as a prime suspect -- some abnormal form of tau,
a protein that plays a key role in structuring the brain.
The villainous tau molecule is not the one found in the fibrous tangles
that are one of the two visible features of Alzheimer's disease, Ashe added. Mice recovered their memory even though the number
of tangles in their brains increased, she pointed out.
"These neurofibrillary tangles -- one of the defining features of Alzheimer's
disease -- are not the cause of the memory problems," she said.
Therapy aimed at the other major feature of the disease, toxic deposits of
a protein called beta-amyloid, is just now moving into the clinic, said William Thies, vice president for medical and scientific
affairs at the Alzheimer's Association. That therapy developed from animal experiments similar to the one reported by Ashe
and her colleagues, he noted.
Her team "have produced a tool with which people can begin to explore whether
limiting tau can be a good endpoint," Thies said.
Mice in the study were trained to swim to a submerged platform in a pool of
water. They lost the ability to find the platform when the damaging gene was in action and regained it when the gene was turned
off -- a surprising gain in memory.
"Many of us have thought that the brains of Alzheimer's patients have live
neurons, dead ones and sick ones," Thies said. "If you remove whatever is irritating the sick ones, they can get better."
While the new study centered on tau, "maybe the ultimate treatment is something
that reduces the accumulation of both amyloid and tau," Thies said.
The form of tau that may become a target for treatment is unknown, Ashe said.
"Maybe there are other abnormal forms of tau that have not been found," she said. "After all, these are not even visible under
the microscope."
And the same can be true of amyloid, Ashe said. "The important message here
is that we need to known which forms of beta-amyloid and which forms of tau we want to target," she said.
Common use of drugs to improve the mind poses ethical challenge
Alok Jha, science correspondent Thursday
July 14, 2005 The Guardian
Can't remember phone numbers, worried about an upcoming exam or desperately want
to give up smoking? In future, the answer will be simple: just pop a pill.
The idea that an array of easily available and addiction-free drugs
could be used to improve memory or increase intelligence is the stuff of science fiction dystopia - in Brave New World, Aldous
Huxley created a whole planet under the spell of a pleasure drug called Soma.
But a new report by leading scientists in the fields of psychology and neuroscience argues that, very soon, there really
will be a pill for every ill.
"It is possible that [advances] could usher in a new era of drug
use without addiction," said the report by Foresight, the government's science-based thinktank.
"In a world that is increasingly non-stop and competitive, the individual's
use of such substances may move from the fringe to the norm."
However, the report said the widespread adoption of new brain-enhancing
drugs was not without risks and would raise "significant ethical, social and practical issues."
Drugs that work on the brain are already common - many people can
hardly begin their days without the mind-sharpening effects of caffeine or nicotine.
Launching the report yesterday, the government's chief scientific
adviser, Sir David King, said that brain-enhancing drugs developed to treat diseases such as Alzheimer's were likely to find
increased use among healthy people looking to improve their perception, memory, planning or judgment.
Ritalin, prescribed to children with attention deficit hyperactivity
disorder, is sometimes used by healthy people to enhance their mental performance. Modafinil, a drug developed to treat narcolepsy,
has been shown to reduce impulsiveness and help people focus on problems.
"It improves working memory - your ability to remember telephone
numbers - it gives you an extra digit or two," said Trevor Robbins, an experimental psychologist at CambridgeUniversity and an author of the Foresight report.
"It also improves your planning when you're doing complex, chess-like
problems. It makes you more reflective about a problem: you take a bit longer but you get it right."
Modafinil has already been used by the US military to keep soldiers awake and
alert and some scientists are considering its usefulness in helping shift workers deal with erratic working hours. It has
also been tested for cocaine users. "It produces some of the subjective effects of cocaine without the chronic dependence,"
said Prof Robbins. Other drugs are being touted as "vaccinations" against substances such as nicotine, alcohol and cocaine.
The treatment would work by causing the immune system to produce antibodies against the drug being abused - these antibodies
would render the drug impotent when taken and prevent it from having any effect on the brain.
"How [the vaccinations are] used depends on clinical judgments,"
said Prof Robbins. "Informed consent is important."
But he cautioned against any plan to pre-vaccinate people against
narcotics. "One would be very careful indeed about trying to sign one's children up for such treatment," he said. "That, to
me, sounds reprehensible."
In the long term, drugs that can delete painful memories could also
be used routinely. "We are now looking 20-25 years ahead," said Prof Robbins. "Very basic science is showing that it is possible
to call up a memory, knock it on the head and produce selective amnesia."
That has obvious uses for people suffering from post-traumatic stress
disorder, but there is also the tantalising possibility that it could be used to treat harmful addictions.
"Drug addiction can be understood very much as an aberrant learning
process," said Prof Robbins.
"Many of these drugs hijack the learning processes of the brain
and produce aberrant habits, which dominate behaviour.
"Clearly the possibility exists that you can call up a drugrelated
memory and produce amnesia for it, thus removing craving for that particular drug."
As drug research improves, the harmful effects of today's recreational
drugs could even be engineered out.
"It may be that one could design out the harmful effects of existing
drugs," said Professor Gerry Stimson of ImperialCollege. "So, alcohol analogues, drugs which produce similar effects to alcohol without some of the side-effects."
Society must decide how to use the new drugs, the scientists said.
For example, if drugs to improve exam performance become widespread,
schoolchildren might find themselves being tested for drugs before exams, they suggested.
"It's a new twist on drug-testing," said Prof Stimson. "Is it a
fair advantage or an unfair advantage?"
On the menu: range of treatments
·
Ritalin (methylphenidate) is used by a small number of students in an attempt to improve exam results and by business people
to improve performance in the boardroom
·
D-amphetamine also improves memory but only for people of a certain genetic make-up
·
Rimonabant is used as an antidote to the intoxicant effects of cannabis and a treatment for heroin relapse. But it is sometimes
also used to enhance the high produced by these drugs by reducing their side-effects
·
Naltrexone is already used to treat chronic alcoholism and narcotic abuse. It works by blocking the pleasure receptors that
are normally activated in the brain when people use the drugs
·
Propranolol, a beta-blocker, is used to treat high blood pressure, angina, and abnormal heart rhythms. It is also used sometimes
by snooker players to calm their nerves
·
Modafinil, a stimulant developed to treat narcolepsy, has been used by soldiers to improve memory and judgment. It is also
used in treatment of cocaine addiction
A British research team from the Autism Research Centre at the University of Cambridge has recently
embarked upon the first-ever rigorous search for a maths gene. The scientists intend to search the DNA of 200 pairs of siblings for clues as to what makes a good mathematician.
Mathematical ability
is commonly thought of as an innate gift that some people are born with. Moreover, this gift, which often runs in the family,
is coupled in many cases with other peculiar characteristics such as musical ability, spatial awareness and a lack of social
skills. People with autism are not only challenged in terms of social skills, but can also show extremely high mathematical
ability.
The question remains as to whether this connection is due to genetics or due to nurture rather than nature.
Mathematically minded families are more likely to foster the attraction of their children to this field by playing maths puzzles
and games. Also, being a solitary business, maths is more likely to attract introverted individuals when they are still young.
Trying
to establish whether such a genetic link does exist, the Cambridge team of scientists, lead by Professor Baron-Cohen, intends
to consider the genes of pairs of siblings who have both obtained an A grade at maths A level - the exams taken in the UK
at the age of 18. Candidates will be asked to perform an online maths test and to send in a cheek swab by post.
On
average, siblings share 50 per cent of their genes. If the scientists find along the way a significantly higher number of
genes that are shared, those genes would be candidates for being responsible for the common maths ability of the siblings.
These candidate genes could then be subjected to further tests in order to see whether they really are connected to mathematical
ability, or autism, or both.
Understanding mathematical ability, and its origins, can help improve maths education
and support those unable to get to grips with basic maths - a huge handicap for some people. Early identification of those
that are likely to struggle, would allow provisions to be made so that they do not get left behind at school. Besides, knowledge
of a maths gene, if it exists, may provide insights into how mathematically gifted people see the world, and may help scientist
to pierce the mysteries of autism.
The project team is asking for volunteers. They are particularly interested in brothers
and sisters who both have an A grade in A Level maths.
Category: Miscellaneous Data Source Provider: Autism Research Centre (CambridgeUniversity) Document Reference: Based on information from the Autism Research
Centre, CambridgeUniversity, and press sources Programme or Service
Acronym:MS-UK C Subject Index : Medicine, Health; Education, Training; Scientific Research
No. 22
Salk scientists overturn a dogma of nerve
cell communication
July 14, 2005
La Jolla, CA — Every neurobiology textbook invariably states that
nerve cells communicate with each other through synapses, the specialized cell-cell contacts found at the end of the cells'
threadlike extensions. In this week's journal Science, researchers at the Salk Institute for Biological Sciences and
the University of California at San Diego report that nerve cells, or neurons, may not have to rely on traditionally defined
synapses to "talk" to each other.
The new study indicates that nerve cells can also release neurotransmitters outside
of synapses. Neurotransmitters are the chemical messengers that nerve cells use to shuttle outgoing signals to adjacent neurons.
Salk scientists refer to the release of neurotransmitters outside of synapses as "ectopic neurotransmission".
Cell-cell
communications in other parts of the nervous system may also rely on ectopic neurotransmission, the new study suggests. This
finding is an additional challenge to the descriptions of neuronal signal transmission found in neurobiology textbooks.
"Our
results opened up the possibility that neurons can communicate many other ways not just at the traditional places that are
defined by their anatomy," says lead investigator Terrence J. Sejnowski, who heads the Crick-Jacobs Center for Computational and Theoretical Biology
at the Salk Institute. To investigate cell-to-cell communication in the nervous system, Sejnowski and his colleagues developed
a computer model simulating signal transmission at a particular synapse in chick embryos. The computer model convinced Sejnowski
and his collaborators that it may be time to rethink cell-to-cell communication in the nervous system.
In the past,
the suggestion that neurotransmitters could be released and find their targets outside of clearly defined synapses, was considered
an almost heretical notion.
A unique collaboration between anatomists and physiologists at the University of California
in San Diego and theoretical neurobiologists at the Salk Institute was needed to rethink the standard model of neurotransmission.
Darwin Berg in the Biology Department provided the physiological data upon which the model was based and Mark Ellisman in
the Department of Neuroscience created a high-resolution reconstruction of the structure using high-voltage electron microscopy.
"In addition to the discovery of ectopic transmission this is the very first time that all these elements have been
brought together," says Sejnowski. "Combining mathematical modeling with physiological, anatomical and behavioral data is
the future of neurobiology. It allows us to draw conclusions that we could not have reached in any other way."
According
to textbooks, nerve signals are transmitted from cell to cell only via specialized junctions. The transmitting neuron has
a slightly swollen terminal point, which houses small vesicles that are filled with neurotransmitter. Upon arrival of a nerve
signal, the vesicles spill their content into the narrow space between two cells. The released neurotransmitter molecules
flow across the gap to the adjacent nerve cell and bind to specific receptor proteins on the receiving cell's membrane. If
the receiving cell is a neuron, the binding of the neurotransmitter will generate an electrical impulse that travels along
the length of the cell. If the receiving cell is a muscle cell, it will be stimulated to contract.
Based on high-resolution
electron microscope images, research fellow Jay S. Coggan and scientist Thomas M. Bartol, the co-first authors of the Science
paper, created a highly accurate computer model simulation of the giant chick embryo synapse that connects nerve fibers originating
in the brain with the neuron that controls the size of the pupil and the shape of the eye lens. This particular synapse is
a favorite model for the study of synaptic transmission since the neurons forming what is known as the ciliary ganglion are
rather simple, easily accessible and nerve impulses can be recorded from either the presynaptic or the postsynaptic element
or both.
Such recordings of nerve signals tipped off the researchers to the possibility that receptors outside of
the synapse were routinely activated. But where did the necessary neurotransmitter molecules come from?
Coggan and
Bartol then simulated the release of neurotransmitter from single vesicles located within synapses as well as from vesicles
located outside traditional synaptic junctions in what they called "ectopic release". Next they compared their predictions
with actual recordings from living cells. "We could only match the physiological results when we allowed 90 per cent of the
release to occur outside of synapses," says Bartol who remarks in a philosophical aside: "Ectopic release is an interesting
term because it means 'out of place', but of course in nature nothing is out of place."
"I think it challenges how
we define synapses. There might still be synapses that fit the old definition but that might not be the only way that cells
communicate," adds Coggan.
The necessary machinery, for one, has always been there. Scientists had known for a long
time that all over the nervous system neurotransmitter-filled vesicles, SNARE-complexes responsible for fusing vesicles with
cell membranes and neurotransmitter receptors were sitting outside of synapses but nobody knew what their function was. "A
lot of the signals we recorded from the ganglion indicated that receptors that were considered perisynaptical were being activated
in large numbers," remembers Coggan. "For me it was very gratifying when the computer model verified our suspicions."
Coggan
points out that traditional and ectopic neurotransmission might simply serve different functions since acetylcholine, the
neurotransmitter bridging the synaptic gap in the ciliary ganglion, activates two different types of nicotinic receptors:
Alpha7-acetylcholine receptors (alpha7-AchR) and alpha3- acetylcholine receptors (alpha3-AchR) that differ in their biophysical
properties and their spatial distribution. alpha3-AchRs cluster at synaptic sites on the cell body whereas alpha7-AchRs are
found in perisynaptic areas. Ectopic transmission activates almost exclusively the latter.
"We are just beginning
to appreciate the diversity and complexity of signaling in the brain. In the past we have been guided by very simple model
systems like the neuromuscular junction. But in the brain there is an enormously more complex set of connections and demands
that the system has to be able to perform. Evolution could have created entirely new possibilities," says Sejnowski.
The
Crick-Jacobs Center for Computational and Theoretical Biology, funded by a generous gift from Joan and Irwin Jacobs, uses
computer-based computational methods to mine the enormous amount of data on the composition of genes and proteins in the brain
as well as the neural networks that regulate information processing. The ultimate goal is to generate theoretical models that
explain how the brain works.
The Salk Institute for Biological Studies in La Jolla, California, is an independent
nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and the
training of future generations of researchers. Jonas Salk, M.D., whose polio vaccine all but eradicated the crippling disease
poliomyelitis in 1955, opened the Institute in 1965 with a gift of land from the City of San Diego and the financial support
of the March of Dimes.
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Item No:
November 18, 2005 Loss of Fear Factor Makes Timid Mouse Bold
Researchers have identified a fear factor - a protein the brain uses to
generate one of the most powerful emotions in humans and animals. The molecule is essential for triggering both the innate
fears that animals are born with - such as the shadow of an approaching predator - as well as fears that arise later in life
due to individual experiences. Eliminating the gene that encodes this factor makes a fearful mouse courageous. The finding,
the researchers say, suggests new approaches for drugs designed to treat conditions such as phobias, post-traumatic stress
disorder, and anxiety.
Working in mice, the scientists, led by Howard Hughes Medical Institute
investigator Eric R. Kandel at Columbia University, found that the protein stathmin is critical for both innate and learned
fear. Mice without stathmin boldly explore environments where normal mice would be hesitant, and, unlike their normal counterparts,
fail to develop a fear of cues that have been associated with electric shock. The scientists also found physiological changes
in the brains of mice lacking stathmin that correlate to the behavioral changes they observed.
“It was localized not only in the pathway of the learning process, but also in the pathway
of instinctive fear.” Eric R. Kandel
The work, published in the November 18, 2005 issue of the journal Cell,
was carried out by lead author Gleb Shumyatsky, a postdoctoral fellow from Kandel's lab who is now at Rutgers University,
and other scientists from Columbia, Rutgers, Harvard Medical School, and Albert Einstein College of Medicine.
Both humans and animals are born with an innate fear of certain threatening
stimuli. As an example, Kandel said, “If you see a train heading right at you, you get scared and run away. This is
built into the genome - the capability to respond to natural threat.” Furthermore, when researchers pair a naturally
frightening stimulus, such as an electric shock, with a neutral signal, such as a tone, animals develop fear of the neutral
tone. “That is called learned fear - that's acquired, it's a form of learning,” Kandel explained. In humans, stage
fright, phobias, and post traumatic stress disorders are examples of learned fear.
In previous work, Kandel and his colleagues set out to determine the underlying
mechanisms that encode fear in the brain. “We knew from other people's work about the neural pathways involved,”
Kandel said, “but there was little knowledge of the key genes or the detailed neural circuitry involved. So we thought
we would tackle that problem.”
The researchers began their studies by searching for genes that were particularly
active in the amygdala, a region deep within the brain known to contribute to fear and other emotions. They zeroed in on the
lateral nucleus, the portion of the amygdala that receives information from the rest of the body about fearful stimuli. They
dissected out individual pyramidal cells, the principal cells in the lateral nucleus, and found two genes, known as gastrin-releasing
peptide (GRP) and stathmin, that were much more active in the lateral nucleus than in a part of the brain not thought to be
involved in fear, which the researchers analyzed for comparison.
Several years ago, Kandel, Shumyatsky, and their colleagues studied the
first of these genes, GRP, in detail and found that it encodes a protein that inhibits the fear-learning circuitry in the
brain. GRP does not, however, play a role in innate fear — demonstrating that the two fear pathways are genetically
distinct.
When the scientists moved on to study stathmin, they had few clues as to
what role it might play in fear - if it was involved at all. “When you go after a gene like this, you have no idea what
behavior or biological process it may be involved in,” Kandel said. “I think it's the mystery of the thing that
creates part of the excitement. Except for thinking that the amygdala was very likely to be involved, we had no way of knowing
what the outcome would be.”
An indication that stathmin might contribute to fear came when they mapped
the parts of the brain where the gene was most active. They found that stathmin was highly expressed not only in the amygdala,
but also in other parts of the brain's fear circuitry. “It was localized not only in the pathway of the learning process,
but also in the pathway of instinctive fear,” Kandel noted.
To investigate stathmin's role in more detail, the researchers created
mice lacking that gene, and examined the brain activity in the lateral nucleus of their amygdalas. Recent work from other
labs had shown that during fear learning, the connections between the neurons in this part of the brain strengthen. In stathmin-deficient
mice, however, the connections between these neurons remained virtually unchanged, despite repeated stimulation.
These results were good indications that stathmin might play a role in
learned fear. To determine whether a lack of stathmin actually altered animals' behavior in situations likely to trigger fear,
the scientists used several standard laboratory tests. Mice were trained to associate an electric shock with either an auditory
tone or a particular location in a cage. After the training period, normal mice would freeze when they encountered the tone
or location that they'd learned was likely to accompany a shock. Stathmin-deficient mice, on the other hand, seemed unnerved
by those stimuli, carrying on their normal activities boldly, without fear.
From these experiments, it was clear to the scientists that stathmin was
needed for fear learning. To find out whether it might also contributed to innate fear, the scientists took advantage of mice's
natural fear of open spaces. Unlike normal mice, which cower on the edges of an open field and stay near the center of a plus-shaped
maze, mice without stathmin were much more adventurous, readily exploring exposed areas.
The authors concluded from their experiments that stathmin is required
for both innate and learned fear. Together with his lab's previous work on GRP, Kandel said, the work advances the understanding
or learned fear versus instinctive fear in several ways. “It shows genetically there's a fundamental difference between
the two; it gives you some insight into the neural circuitry; it shows that there's an inhibitory constraint to fear; and
it gives you the potential of thinking of therapeutic targets.”
As drug targets, Kandel said, GRP and stathmin each present unique opportunities.
“One would be for learned anxiety, the other would be for instinctive. They both, I think, are reasonable - no one has
worked on those as targets before.” While drugs targeting stathmin would likely affect both types of fear, Kandel expects
that with further work, researchers should also be able to identify genes that act exclusively on instinctive fear.
