(iv)Development of an understanding of how anaesthetics work, and how venoms and toxins cause their effects.

Over the past 50 years, neurobiologists have, with a considerable investment of public and private money, shown that the building blocks of brains, the nerve cells or neurons, are fundamentally similar all across the animal kingdom in terms of their electrical and chemical properties. This fact means that scientists are not forced always to solve human brain problems the "hard way", i.e. using human or even other mammalian brains. The magnitude of the difficulties of studying brains in general, and mammalian brains in particular at the cellular level can be better appreciated if a few numbers are compared:

The message in these numbers is clear enough. Over a half million human brain cells would fit nicely inside a single large nerve cell from a slug. Where a nervous system problem involves study of cellular-level questions with the need to visualize cells, measure chemical reactions, or record from electrodes in cells, then there are real advantages in simple model systems amongst the lower animals.

One of the useful developments of recent years is the discovery that there are simple model systems in which these questions can be studied directly, all the way from the behavioral level down to the cells, membranes and molecules, in the same animal. This has come about because of the discovery that some animals have extraordinarily large brain cells--Cells so large and distinctive in color that they can be re-identified individually from animal to animal. Further, it's been possible to study the chemical, electrical and "circuit wiring" aspects of the roles of these nerve cells in relation to the behavior of the intact animal.

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Some of the gastropod mollusks, the marine slugs and

their relatives have been especially important in this work.

It has been found that their brains are covered by nerve cell bodies that are relatively huge in size (sometimes, individual nerve cell bodies can be seen with the naked eye), brightly colored orange, yellow, sometimes red or black, and to the great pleasure of neurobiologists, many can be identified as individuals over and over again in different animals of the species. It has proven possible to develop techniques to record and stimulate these neurons individually in nearly intact animals, permitting quite unexpected progress in determining the "wiring diagrams" for these brains. For the same reasons of size and identifiability, these gigantic neurons have proven useful to neurochemists, who have found it possible to dissect out single nerve cells and then study the chemistry of these cells individually. As expected, their fundamental electrical and chemical properties are directly comparable to those of mammalian brain cells. This then has meant that a number of useful insights about brain structure and function have emerged, including ideas about how circuits are wired to produce patterned behavior, and how the membrane properties of such cells contribute to their generation of impulse activity.

An additional finding from these and other studies is likely to have very important consequences in the near future. A new class of transmitter chemicals, the substances that carry messages from nerve cell to nerve cell, has been discovered. This new kind of substance is responsible for carrying signals about pain, the general sense of well-being, and may be involved in disease states, including depression, schizophrenia, and drug addiction. It is now known where these substances are produced in the mammalian brain, and even where they act. The substances called peptides, were first detected in mammals, but are now being analyzed in terms of their mode of action in a number of model systems where their cellular, and membrane effects are under careful study.

Another area of particular interest emerging from these studies of model systems, is learning and perception--Fortunately, many lower animals seem to learn and to remember in ways which ressemble what is seen in man. And studies in mammals and such creatures as crustaceans, slugs and fish all indicate that the site of the nervous system changes which produce at least rudimentary learning, is the same in all, namely, the point of contact between nerve cells, called the synapse. It has been possible in many of these model systems to record directly from neurons in the brain while aspects of behavior proceed, thereby permitting scientists to analyze the cellular and chemical basis of the changes that accompany learning.

A key role of NSF in neurobiology has been to search cut and support the development of new tools for research of this kind. We anticipate this extraordinary progress to continue with very significant consequences for scientists and non-scientists alike.

USE OF SIMPLE ANIMAL MODELS IN NEUROBIOLOGICAL RESEARCH

As with most problems and opportunities in research, the ones in the relatively new science of the nervous system-neurosciencethat hold high interest in terms of human welfare and understanding are often the ones that are most difficult to solve. Unfortunately, what may appear to be the most direct and sensible approach to these problems, for example, by examining the human brain directly, often turns out to be very difficult, time-consuming and expensive when put to the task. On the other hand, neuroscientists are not always constrained to the direct, or "brute force" approach. There are many situations where model systems using simple animals provide quite unexpected shortcuts. Some examples of the contributions made by simple model systems to efficient progress in understanding brain functions and disorders are described below:

BRAIN CHEMICALS

The problem: What chemicals are used by the brain to carry messages from nerve cell to nerve cell? What are the chemical causes such brain centered problems as schizophrenia, drug addiction, depression, or pain?

It is now clear to neuroscientists that the basic electrical and chemical properties of the nerve cells in the brains of all animals are fundamentally identical. In this regard, a recent revolution in chemical understanding of the brain has come about as a direct consequence of the use of a range of animal model systems including snails, slugs, insects, crustaceans, worms, and leeches. A new class of chemical messengers, the peptides has been confirmed and is rapidly under development with consequences that will likely revolutionize understanding and treatment of nervous system diseases. It is also clear now that because of the cellular level source and action of these new chemicals that simple systems will play a crucial role in the further development of this research.

NERVE CIRCUITRY

The problem:

How are the circuits in the brain and spinal cord that generate such activities as walking, breathing and swallowing put together?

Unlike the brains of mammals where there are tens of billions of microscopic nerve cells to contend with, some simple animals such as fishes, marine slugs, leeches, crustaceans and insects, have

much smaller numbers of relatively enormous cells many of which are individually re-identifiable to researchers. And yet these extraordinary cells function electrically and chemically in ways that are very similar to those of mammals. Neural circuit design principles, and mechanisms by which properly co-ordinated impulse patterns can be generated in nerve networks have come from studies of such systems. These studies suggest simplified and efficient ways to get the needed answers from mammalian nervous systems.

NERVE DEGENERATION

The problem:

When a nerve has been cut, what clues guide

regrowth? Why does the cut off portion die and fail to

reconnect? Why do damaged parts of the brain and spinal cord in higher animals and human beings repair themselves so rarely, if at all.

Developing neurons in many of the model systems can be traced individually, and clues gained about the physical guideposts, and chemical factors that influence proper growth. Many such clues have been gained from studies of simpler animals such as insects, crustaceans, mollusks, amphibia (such as frogs), reptiles and fish. These animals seem to have retained the ability to reconnect damaged nerves and to repair or even replace destroyed nervous system components. Amongst the lower vertebrates, the goldfish has retained the capacity to regenerate its spinal cord, and replace lost nerve cells. The differences in these capabilities between mammals and the simpler animals likely holds keys to understanding why human repair/replacement is so limited, and what might be done about it.

LEARNING

The problem: How do brains learn?

What happens in nerve cells

when an animal learns to ignore a monotonous stimulus, to

associate different stimuli, to "remember"?

It is now very clear that many animals can learn in ways that are similar or identical to man. It is also clear that for simple kinds of learning at least, the brain cell changes that come about because of learning take place at the site where nerve cells communicate with one another. The problem for scientists therefore becomes one of finding the most efficient experimental situation in which to study these nerve cell changes. There are many examples of simple animals with extraordinarily large and identifiable nerve cells including fishes, insects and mollusks. In these cases it has proven possible to probe the site and mechanisms of these changes.

EPILEPSY

The questions: What nerve cell or nerve membrane defects cause epileptic seizures in brain? Why do certain substances and stimuli initiate nervous system convulsions? What properties must drugs have to prevent the development of uncontrolled nervous system seizures?

Often seizure like activity can be developed in a controlled way in isolated nervous systems or nerve cells of very simple animals such as crustaceans (e.g. crabs) and mollusks (e.g. snails and slugs) by exposing them to convulsive drugs or reagents. Then the electrical and chemical causes of the disturbances can be sought directly. Clues about the action of convulsive drugs upon the excitability and stability of nerve cell membranes can and have been helpful in interpreting the similar effects seen in

the nerve cells of mammals.

MYASTHENIA GRAVIS

(A human disease that results in severe muscle weakness)

The questions: Why do the nerves and muscles of affected individuals function abnormally? What can be done about it?

The basic cause of the problem has now been worked out. The disease is caused by antibody destruction of the receptor molecules that serve as the chemical link from nerve to muscle. The explanation of the disease rests squarely upon (i) the basic understanding of nerve to muscle transmission derived from studies of frog material, and (ii) the discovery and extensive use of the special receptor molecules on electric ray tissue that contain the same substances found in humans but occur on the elctric organ of rays in concentrations that are thousands of times greater than found in any mammal.

The eventual cure will almost certainly depend upon similar model systems for knowledge of how to use specific molecules to repair or block the damage.

GENETIC AND DEVELOPMENTAL DEFECTS

The problem: Why do defects of genetic and developmental origin occur? What are the steps that link genes on chromosomes to the development of normal or abnormal nervous system structures?

It is often possible in simple systems having smaller numbers of large, re-identifiable nerve cells, to trace the growth of specific brain cells as they develop from their origin in the embryo into the juvenile and adult animal. For instance, lately