Directing Traffic in the Brain

MEDIA CONTACT: Mitch Leslie, (650) 725-5371 or 723-6911 ([email protected])

FOR COMMENT: Dr. David Prince, (650) 723-5522 ([email protected])

EMBARGOED FOR RELEASE 4 p.m. U.S. Eastern Time on Thursday, Aug. 13, to coincide 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 brainís 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.

ìAcetylcholine is acting like a traffic cop in the cortex, directing the flow of information -- the nerve signals -- along the cortical highways,î 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 Alzheimerís 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 acetylcholineís effect on a network of nerve cells, although the connection to behavior and disease remains to be established, said Prince.

ìThe behavioral significance of these results is not very clear, because we are doing experiments on rat brain slices, not live animals,î he said. ìBut integration of information requires that messages spread horizontally across the cortex, and acetylcholine would facilitate that spread.î

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 acetylcholineís 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 ìbasketî cells communicate horizontally and have muscarinic acetylcholine receptors (mAChR), whereas the ìbipolarî 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.

ìDetailed 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,î said Prince. ìEffort 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.

ìThese experiments are an attempt to take such an integrated approach,î 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 ìneuromodulatoryî 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 Alzheimerís patients, ìwe really donít know how these neurotransmitter systems alter the way the brain works,î said Prince. ìOur 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.î

Funding for the research came from the National Institute of Neurological Disorders and Stroke, and from the Morris and Pimley Research Funds.

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