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bartfai The Harold L. Dorris Neurological Research Center

Tamas Bartfai, Ph.D.

We live in an aging society, and this characteristic requires us, as time goes on, to address diseases and conditions prevalent among the elderly. One of the most devastating conditions is the neurologic degeneration associated with diseases such as Alzheimer's disease. A leading cause of death in the United States, Alzheimer's disease claimed 44,536 lives in 1999, according to the Centers for Disease Control and Prevention.

We also live in a world in which a certain percentage of those around us have severe mental illness. Schizophrenia, for instance, is a devastating psychiatric disorder that affects 1% of the world's population. depression is widespread in our society as well, exacting a heavy toll. According to estimates from the national Institute of Mental Health, about 1 of every 10 American adults has some major form of depression.

Treating these conditions requires an understanding of their underpinnings, and this need is addressed by the Harold L. Dorris Neurological Research Center. Founded in 1999 as the result of a $10 million long-term commitment by Helen L. Dorris through the Harold L. Dorris Foundation, named in her brother's honor, the Center has attracted an international cadre of scientists from such disciplines as neurology, immunology, chemistry, molecular biology, and endocrinology to study neurologic disorders.

One area of research involves determining which genes are involved in thermoregulation. What makes a person hot and feverish when he or she is sick? Even though fever is one of the most common conditions since the origin of humankind, the pathways involved and the mechanisms that underlie fever and thermoregulation are still not completely understood.

Another area under investigation involves a regulatory gene that controls the expression of other genes within neuronal cells. This transcription factor, called c-fos, binds with other proteins and binds to DNA, stimulating the expression of particular genes and inhibiting the expression of others late in a neuron's development. Investigators in the Harold L. Dorris Center are determining the pathways through which c-fos is controlled.

Other scientists are investigating hippocampal excitability or the activation of hippocampal neurons, a prerequisite for learning and memory. The hippocampus is a ridge of tissue in the brain where many of the chemical processes important for forming and retaining memories take place. These processes are the basis of cognition.

These investigators developed a model system in which the neuropeptide galanin, a natural substance in the brain important in hippocampal excitability, is overproduced. Galanin exists in neurons in the hippocampus and is released, along with the neurotransmitter acetylcholine, into the gaps, or synapses, between 2 neurons during the signaling from one neuron to another during cognitive processes.

Galanin is widespread throughout the central and peripheral nervous systems. It influences several physiologic processes such as cognition and memory, the release of various neurotransmitters and hormones, motility of the digestive tract, feeding, and sexual behavior. This neuropeptide is also a growth-promoting molecule, and its local expression is required for the growth of certain neurons.

In Alzheimer's disease, galanin is overexpressed in the basal forebrain. Moreover, as Alzheimer's disease wipes out many of the cholinergic neurons of the hippocampus, those that survive have elevated expression of galanin. Researchers at the Center hope to determine how to restore the survival and function of cholinergic activity, a promising way of ensuring cognitive improvement, in patients who have Alzheimer's disease.

Other scientists are studying models of schizophrenia, a puzzling psychotic illness because it seems to be a multifactorial disorder that involves multiple genes and many environmental factors. Also puzzling is the fact that although initiation of schizophrenia may begin during the formation of the laminar organization of the brain's neocortex and prefrontal cortex during early development, in general, serious signs and symptoms do not appear until adolescence or early adulthood.

Although data on the origin and underlying neural mechanisms of schizophrenia are limited, laboratory models are available. The animals in these models have neurodevelopmental abnormalities that mimic aspects of the biological phenomena associated with the clinical manifestations of this psychiatric disorder in humans. Investigators are using these models to study how the neurodevelopmental abnormalities are related to behavioral changes and to design further experimental models. They hope eventually to develop models for studying schizophrenia that faithfully reproduce both pathologic processes and phenomena associated with the disease and that can be used to predict responsiveness to antipsychotic drugs.

Another model under investigation involves the cytokine IL-18, a regulatory molecule in the immune system. IL-18, which has antitumor and antimicrobial actions, is produced by a variety of cell types and tissues and plays a role in mediating tissue damage associated with inflammation, autoimmune diseases, and allergic reactions. High levels of IL-18 are also associated with schizophrenia.

 

 







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