MEDIA CONTACT: Mitch Leslie, (650) 725-5371 or 723-6911 (mleslie@leland)
FOR COMMENT: Dr. David Prince, (650) 723-5522 (daprince@leland.stanford.edu)
EDITORS, REPORTERS PLEASE NOTE: This release coincides with publication
in the Aug. 14 issue of Science.
Directing traffic in the brain
STANFORD -- A single brain chemical can switch the direction of nerve messages
in the brain's cerebral cortex, Stanford researchers have found. The chemical,
called acetylcholine, acts through inhibitory circuits to turn on nerve
cells that send messages horizontally across the cortex and to turn off
nerve cells that send messages vertically.
"Acetylcholine is acting like a traffic cop in the cortex, directing
the flow of information -- the nerve signals -- along the cortical highways,"
said Dr. David Prince, a professor of neurology and neurological sciences
at Stanford University School of Medicine.
Prince is the senior author of a research report in the Aug. 14 issue of
Science. His co-authors are John Huguenard, associate professor of neurology
and neurological sciences, and postdoctoral fellow Zixiu Xiang.
Acetylcholine is important in memory acquisition. In people with Alzheimer's
disease, cells that make this chemical are among the first to be lost. These
cells are located deep within the brain, but they send the acetylcholine
signal to the cortex, nearer the surface.
The cerebral cortex does higher-level processing, such as that involved
in vision, memory and emotion. In their studies, the Stanford researchers
looked at a part of the cortex used for processing vision.
Their findings explain acetylcholine's effect on a network of nerve cells,
although the connection to behavior and disease remains to be established,
said Prince.
"The behavioral significance of these results is not very clear, because
we are doing experiments on rat brain slices, not live animals," he
said. "But integration of information requires that messages spread
horizontally across the cortex, and acetylcholine would facilitate that
spread."
Potential consequences
Information integration is needed because different parts of the body are
represented at different sites in the cortex. The cerebral cortex is organized
into vertical building blocks called columns. Horizontal communication links
the columns, allowing the brain to coordinate the movements of different
body parts, such as the individual fingers of a pianist.
Too much horizontal information flow can, however, lead to epileptic seizures,
in which uncontrolled electrical activity spreads across the cortex. It
is known that excess acetylcholine in the cortex can induce epileptic activity.
The potential effects of reducing vertical communication within a column
are even less clear, said Prince. Information from distant brain areas and
from the sense organs (such as the eyes, ears and skin) is processed as
it flows vertically within cortical columns. So one possibility is that
acetylcholine, by increasing vertical inhibition, may act as a filter for
messages coming from outside of the cortex. This could, for example, keep
a painful sensation or a noisy environment from disrupting ongoing computations.
The situation is further complicated because some nerve cells have both
vertical and horizontal connections, Prince said. And the researchers did
not test the effects of acetylcholine on other types of nerve cells, some
of which are known to respond to acetylcholine. Some of these nerve cells
release messengers with opposite effects.
Molecules and circuits
Many nerve messengers such as acetylcholine can attach to more than one
type of protein, or receptor, on the outside of nerve cells. Through these
different receptors, a single messenger can produce opposite effects in
different cell types -- for example, turning one cell type on while turning
another off. It is just this sort of complexity that makes it difficult
to predict the likely effects of different chemical messengers.
The Stanford researchers found that acetylcholine's ability to do two things
at once -- increase horizontal communication and decrease vertical communication
-- can be explained by a two-receptor model.
After confirming the orientation of the cells by filling them with dye and
studying their anatomy, the researchers found that the two cell types have
two different receptors. The "basket" cells communicate horizontally
and have muscarinic acetylcholine receptors (mAChR), whereas the "bipolar"
cells communicate vertically and have nicotinic acetylcholine receptors
(nAChR). Acetylcholine attaches to both receptors, but has different effects
on the different cell types.
Acetylcholine increases horizontal communication by reducing nerve cell
inhibition. In the basket cells, the researchers found that acetylcholine
attaches to the mAChR and causes the cell to release less of the messenger
gamma-aminobutyric acid (GABA), which normally turns off nerve communication.
Less GABA means more horizontal communication.
But in the bipolar cells, they found that acetylcholine attaches to the
nAChR and causes the cells to release more GABA, which turns off vertical
communication.
Integrated approach
The new study is distinctive in that it considers the behavior of a large
number of interacting nerve cells, rather than the response of a single
cell type in a dish.
"Detailed observations of the effects of nerve messengers on single
cell types are an important part of neuroscience today, but it is hard to
translate these observations to understand the operation of a particular
brain circuit or region," said Prince. "Effort has to be made
to put molecular information together with that gathered from studies of
anatomy and cell responses to neurotransmitters. Only then can we can begin
to think about how large chunks of the nervous system work.
"These experiments are an attempt to take such an integrated approach,"
he said.
Scientists will need to study entire brain regions in order to understand
the effects of nerve messengers such as acetylcholine, serotonin and norepinephrine,
said Prince. Whereas many nerve messengers act only between two adjacent
cells, these "neuromodulatory" messengers can affect whole regions
of the brain. For example, changing serotonin levels in large brain regions
affects depression; this is how drugs such as Prozac work.
Although Prozac is used for depression and other drugs are used to boost
acetylcholine levels to help Alzheimer's patients, "we really don't
know how these neurotransmitter systems alter the way the brain works,"
said Prince. "Our discovery that acetylcholine can act selectively
on different groups of inhibitory cells in cortical circuits may provide
a model for the actions of other neuromodulatory messengers in the cortex."
Funding for the research came from the National Institute of Neurological
Disorders and Stroke, and from the Morris and Pimley Research Funds.