Inattenion must be paid

Natural History, Sept, 1997 by Catharine Rankin, Annette Heist

Nearly half of all people hospitalized with mental disorders suffer from schizophrenia, a condition characterized by disturbed moods, delusions, disordered thoughts, or catatonia. This frightening disorder may result in part from a breakdown in one of the most basic forms of learning: filtering out irrelevant information in the environment and in the mind itself.

Very early in life, we have to learn how not to pay attention to such things as the feeling of our clothes on our body, the street noises around us, and the sound of our own breathing. A number of studies have shown how hard this can be for schizophrenics. In one experiment, Mark Geyer and David Braff, of the University of California at San Diego, repeatedly exposed participants -- some schizophrenic, some (the controls) not -- to a loud tone. At first, all the participants blinked their eyes strongly every time they heard the noise -- a natural "startle response." After three blocks of twelve trials, the controls grew used to the sound, while most of those with schizophrenia had a much more difficult time, still blinking hard at the end of the experiment.

Learning to ignore a stimulus that goes on for an extended time or, like the tone, is repeated frequently without anything bad happening is called habituation. Demonstrated in every organism tested for it -- from protozoa to insects fishes, rats, and human -- habituation is fundamental to survival. An animal constantly distracted by the sound of the wind in the trees, for example, is likely to miss the sound of an approaching predator. The rules of habituation are the same in all species: the weaker or more frequent the stimulus, the faster habituation takes place. Interestingly however, habituation lasts longer if the exposure to it is less frequent, although the effective interval varies from species to species.

To investigate the cellular processes underlying habituation, and perhaps learn more about their role in schizophrenia, I turned to Caenorhabditis elegans, a one-millimeter, soil-dwelling nematode with a very simple nervous system consisting of 302 neurons (you and I have about 100 billion neurons). The basic habituation experiment with this worm is simple: my students and I study its response to a series of mechanical taps on a plastic dish -- its laboratory home. Habituating to the taps is much like getting used to the sound of sirens on the streets outside your house. At first, you wake up, heart pounding, every time you hear the sirens; after a while you rouse briefly; eventually, you may sleep right through. Similarly, the worm's response to the first few taps is to start and swim rapidly backward. Gradually, it backs up for shorter and shorter distances, until finally it stops responding to the tap altogether. With sufficient training, a worm will remain habituated for twenty-four hours, a substantial part of its two-week life span.

Using laser microscopy to surgically remove one neuron at a time, we have determined that the neural circuit underlying the worm's response to tapping consists of just five sensory neurons and ten interneurons (relay neurons that connect sensory to motor nerves); habituation is mediated by the five sensory neurons. To discover the genes involved, we are now looking for signs of abnormal habituation -- too slow, too fast, unusually short-lived -- associated with changes in particular genes. Our goal is to isolate all the genes that play a role in habituation in C. elegans. Our expectation, and our hope, is that just as habituation follows similar rules in all animals studied, so, too, the genes controlling habituation will turn out to be the same, or similar, in C. elegans and other animals, including humans, and that this may help unravel the genetics of schizophrenia.

While the causes of schizophrenia are not entirely clear, the disorder unquestionably has a strong genetic component. If one identical twin has the disease, for example, the probability of the other twin being schizophrenic is 46 percent -- compared with one percent odds in the population at large. Further suggestions of a genetic link between habituation and schizophrenia have come from Geyer and Braff's eye-blink experiments, which showed that nonschizophrenic family members of schizophrenia sufferers also often have a hard time getting accustomed to a noise.

Whatever the genes involved, they may well play several roles in the human brain and contribute to a variety of symptoms seen in schizophrenics. For example, if habituation-like processes are necessary to filter out irrelevant thoughts and images generated by the brain, then deficits in this area may also explain some of the hallucinations and delusions experienced by schizophrenics as well. Without an internal filter, producing a single coherent train of thought may be impossible.

Schizophrenia is probably not a single disorder. Different mutations or sets of mutations may be responsible for different aspects of the disease. Our hope is that our work with the lowly worm may ultimately help screen for, diagnose, and possibly treat this debilitating mental disorder.