Despite more than a century of research on inhibitory neurons, very little is known about how this small population (10-20% of brain neurons) exerts its controlling effect on the brain.

Inhibitory neurons are pivotal for normal brain development, learning, and memory, so it is not surprising that they are involved in most neurological disorders. A recent Weizmann study, published in the January 2000 issue of Science, reveals key principles underlying the design and function of this inhibitory system.

By repressing the level of activity in neighboring neurons, inhibitory neurons (I-neurons) prevent the brain from quickly spinning out of control into hyperexcited states or full-blown epilepsy. One of the signs in children with autism and attention deficit hyperactivity disorder (ADHD) is I-neuron malfunction: their inhibitory system does not effectively suppress unwanted information, impeding their ability to make choices. I-neuron malfunction is involved in the majority of neurological disorders: Alzheimer's disease, neural trauma, addictions, and a wide range of psychiatric problems such as depression, obsessive-compulsive behavior, and schizophrenia.

In the past, researchers basically thought that I-neurons just spray an inhibitory neurotransmitter called GABA onto their neighbors. But this did not explain how they inhibit the right neurons at exactly the right time and to the right degree. The new study carried out in the laboratory of Prof. Henry Markram of the Neurobiology Department shows how this is achieved.

The research team found new types of I-neurons, revealing that this tiny population is much more diverse than previously thought. Further, using new methods that they developed, the researchers succeeded in recording directly how individual inhibitory neurons control their neighbors. They found that I-neurons build complex synapses (connections) onto their target neurons. The synapses selectively filter inhibitory messages, enabling I-neurons to shut down the activity in neighbors as required. These synapses act as fast-switching "if-then" filtering gates that allow inhibition to be applied only at the exact millisecond and only to the extent necessary.

Each I-neuron fixes complex if-then gates on thousands of neighboring neurons and is therefore "in charge" of controlling their activity. The gates allow I-neurons to rapidly switch their focus onto any neuron to which they are connected. This ingenious design principle is what enables the small group of I-neurons to exert such a sophisticated effect, simultaneously giving personal attention to the activity of each of the neurons to which they are linked.

The researchers showed that a "discussion" between I-neurons and target neurons is involved in deciding which type of if-then gate should be set up to filter the inhibitory message. This decision-making process could allow each neuron in the brain to be inhibited in a unique way. Dubbed the "interaction principle," this process generates maximal diversity of if-then gates, allowing more complex and more refined control over large numbers of neurons.

The researchers went on to reveal a remarkable ability of I-neurons: they can sense neurons that share the same functions in the brain. I-neurons "select" groups of target neurons to construct the same type of if-then gates, possibly enabling the I-neurons to control groups of neurons collectively. It also means that I-neurons can "sniff out" brain neurons that collaborate in the most elementary functions even if they seem different in almost every other way (i.e., they can identify neurons descended from the same "ancestors").

"I-neurons can trace the family trees of neurons. In other words, they could help us to work out how neurons are related to one another. This could one day enable us to map the functional aspect of the brain according to the genealogy of its neurons  an organizing principle we never dreamed would be possible, says Markram. The researchers believe that the ability to detect functionally related groups in the brain, called "the homogeneity principle," results from common signal molecules released by target cells. I-neurons may use the signal molecules to determine what kind of if-then gates to build. Future research designed to identify the nature of these molecules could yield a potent tool for mapping the functional structure of the brain.

Prof. Markram's research is supported by the Minna James Heineman Stiftung, Germany; the Abramson Family Foundation, North Bethesda, Maryland, and the Nella and Leon Benoziyo Center for Neurosciences.

 

 

While crucial to warding off disease, immune cells have traditionally been thought to be potentially damaging to the central nervous system (CNS) - the brain and the spinal cord. However, a team of Weizmann Institute scientists has now found that immune cells can be recruited to treat partial spinal cord injuries.

Severing the spinal cord causes complete paralysis of the organs innervated by the central nervous system, from the point of injury downward. In fact, even a partial injury of the spinal cord may cause complete paralysis, due to the "hostile environment" created by damaged fibers causing harm to the undamaged fibers. As a result, even in cases of partial spinal cord injury, the damage continues to spread, intensifying the paralysis. Blocking the spread of damage may therefore save the nerve cells undamaged by the initial trauma - and with them, at least some of the patient's motor activity.

Several years ago, a team of Weizmann researchers led by Prof. Michal Schwartz of the Neurobiology Department found that following neuronal injury, immune cells known as macrophages may be recruited to encourage repair and renewed growth of damaged nerve fibers. Schwartz now hopes to take this research one step further. In a study recently published in The Lancet, she proposes adding additional immune cells, known as T-cells, to the damage-control battalion aimed at blocking the spread of damage.

At first glance, this idea seems to oppose the widespread view of immune cells as potentially damaging to the central nervous system. Indeed, while macrophages normally help to heal damaged tissue, previous research by Schwartz revealed that the mammalian CNS actually suppresses an immune response following injury. This suppression may be the result of an evolutionary trade-off. In contrast to fish and other lower life forms capable of repairing damaged CNS fibers, humans and other mammals can repair only peripheral nerves, while injuries to the brain or spine leave them permanently paralyzed or otherwise handicapped.

To get smart, higher animals may have had to pay a price, Schwartz suggests. Along with the asset of complex brains capable of continuous learning came a disadvantage - loss of the self-healing ability existing in lower vertebrates. "The need to prevent immune cells from "remodeling" the brain may have dictated losing the tissue-repair capacity since the immune cells could disrupt the complex and dynamic neuronal networks that build up during a lifetime," says Schwartz.

T-cells prevent infection by seeking out and destroying pathogenic "enemies" that infiltrate the body. But the body also contains T-cells that are directed against its own components. The accepted notion is that these anti-self T-cells may cause autoimmune diseases, such as multiple sclerosis and diabetes. However, the Institute scientists have shown that a controlled amount of these autoimmune cells, when directed against specific components, can assist in curbing injury-induced neuronal damage.

Following treatment with anti-self T-cells, rats with partial injuries of the spinal cord regained some motor activity in their previously paralyzed legs while untreated rats developed increasing and sometimes even total paralysis. These findings may lead to an innovative clinical treatment for preventing total paralysis after partial spinal cord injury.

Immune cells have a double-edged sword potential in treating neuronal injuries, Schwartz explains. The key to using them effectively is to extract the cells from the patients blood and increase their amount and activity in such a way that their healing effect is maximized while their potential risk is minimized. The cells are then reintroduced into the damaged neuronal area. Schwartz: "The concept is to work together with the body's existing self-repair mechanism, which apparently requires encouragement and monitoring."

Other scientists participating in this study were Weizmann Profs. Irun Cohen of the Immunology Department, Michal Neeman of the Biological Regulation Department, and Prof. Solang Akselrod of Tel Aviv University. Working with Prof. Michal Schwartz were Dr. Eti Yoles, Dr. Eugenia Agranov, Ehud Hauben, Uri Nevo, and Gila Moalem, all of the Neurobiology Department.

Prof. Michal Schwartz holds the Maurice and Ilse Katz Chair of Neuroimmunology. Her research is funded Proneuron Ltd., the Alan T. Brown Foundation to Cure Paralysis, New York, the Glaucoma Research Foundation, San Francisco, California, and the Jerome and Binette Lipper Award.

1. Nerve signals from the brain go down the spine to the front and hind limbs

2. Damage to the spine interrupts the signals to the hind legs, causing their paralysis

3. Immune system cells (red) try to heal the damage, but they are blocked by a protective mechanism of the central nervous system (green )

4. A segment of the peripheral nerve (purple) is incubated with the immune cells and "activates" them 

5. "Activated" immune cells are returned to the damaged site

6. They manage to overcome the protecitve mechanism an partially heal the damage

7. As a result, the paralysis is partially overcome

An article reviewing the development of man's understanding of vision, which recently appeared in the Journal of NIH Research, begins with Plato's theory of "visual fire" and ends with elucidation of functional organization in the visual cortex of the brain by Prof. Amiram Grinvald of the Institute's Department of Neurobiology.

According to the article, the first detailed theory of vision was propounded by early Greek philosophers such as Plato, who held that a ray of visual fire emanated from each eye and mixed with light to produce an invisible structure between the eye and an observed object. Galen, a second-century Roman physician, suggested that the brain is essential for consciousness and perception. In 1490, da Vinci reiterated Galen's concept that the eyes communicate directly with the brain. This long line of research, pursued by many scientists, was followed by the seminal work of Cajal and that of Hubel and Wiesel, who won Nobel Prizes for their contribution to brain research. And the most recent advances, according to the Journal, have been made by Prof. Gary Blasdel of the Harvard Medical School and the Weizmann's Prof. Grinvald.

"Independently," the Journal reports, "since 1986 they have used cameras to measure changes in the activity of neurons in exposed surfaces of the visual cortex as animals view lines of different orientations. They mapped the location of many different orientation columns on the surface of the primary visual cortex in a single test animal, at a higher resolution than is possible with standard methods of labeling."

The optical imaging technique that they used, which allows the direct visualization of electrical activity in the living brain, was developed by Grinvald at the Weizmann Institute in 1984. In enables scientists to visualize the intricate functional architecture of the brain, that is, the layout across the cortical surface of brain cells involved in distinct processing tasks. Optical imaging of functional borders is also being applied by neurosurgeons to minimize damage during tumor removal. The technique grew out of the 1968 pioneering work of Tasaki and Cohen showing that electrical activity of single nerve cells can be monitored by light.

Referring specifically to Grinvald's work, the Journal states: "He showed that the orientation columns are arranged in radially symmetric, fan-like structures he called 'pinwheels'. In this arrangement, a set of orientation columns intersects at the center of the pinwheel." This information sheds new light on the functional organization of the nerve cells responsible for the perception of object shapes. This work was done together with Prof. Tobias Bonhoeffer at Rockefeller University.

Thanks largely to these investigations, the NIH Journal concludes, "researchers currently understand the primary visual cortex better than any other part of the brain."
Prof. Grinvald, who holds the Helen and Norman Asher Chair in Brain Research, is the director of the Grodetsky Center for the Research of Higher Brain Functions.