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TSRI Scientific Report 2003

The Harold Dorris Neurological Research Center

bartfaiTamas Bartfai, Ph.D.

We live in an aging society, and we must address diseases and conditions prevalent among the elderly. Treatment of these diseases and 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.

The neurologic degeneration associated with diseases such as Alzheimer's disease is one of the most devastating conditions among the elderly. 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. The largest study of persons whose memory performance through aging was followed up closely was the study of the brains of nuns in the Midwest who donated their brains for the investigation. The results indicated that the most important anatomic brain difference between those who had Alzheimer's disease when they died and those who did not was in the number of galaninergic neurons.

At the Harold L. Dorris Neurological Research Center, my investigators and I are one of the key groups working on galanin. During the past 18 years, we developed genetic and pharmacologic tools to study the effects of this important neuropeptide on hippocampal neurons involved in memory functions and neuronal survival. A large number of scientists at the Harold L. Dorris Center study galanin signaling in the brain and the effects of galanin on long-term potentiation and memory tasks in brain preparations and in intact animals. Among their recent results is the development of a first galanin receptor agonist that can be given systemically and that reaches the brain. The agonist changes the seizure threshold, thus slowing epileptic seizures, and also affects learning and memory.

Schizophrenia is a devastating psychiatric disorder that affects 1% of the world's population. M. Behrens and her group work on new approaches toward the treatment of this disease based on the understanding that cognitive aspects of the disease are as important as the hallucinations and other so-called positive symptoms addressed by present antipsychotic treatments. Their approach is based on the theory of lowered glutamatergic signaling in certain parts of the brain, including the frontal cortex.

Depression is also widespread in our society and exacts a heavy toll. According to estimates from the National Institute of Mental Health, about 1 of every 10 adults in the United States has some major form of depression. Bruno Conti and his group are searching for an antidepressant that is faster acting than the currently used fluoxetine (Prozac) and its competitor drugs. They are using the clinically well-proven effects of sleep deprivation and electroconvulsive shock--drastic, and rarely used, treatments that are effective when the risk for suicide is high. In collaboration with scientists at Novartis Pharma AG, Basel, Switzerland, Dr. Conti and colleagues mapped transcriptional changes caused in different brain regions by these treatments. Now they are imaging the gene products detected in the gene chip experiments and are examining the products' function and alterations during antidepressant treatments.

Another area of active research at the Harold L. Dorris Center involves determining which proteins in the warm-sensitive neurons of the hypothalamus are involved in thermoregulation. What makes a person hot and feverish when he or she is ill? 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. However, understanding these pathways and mechanisms is important for understanding inflammatory mechanisms. Research in this area will have an impact on the treatment of postmenopausal women who experience "hot flashes."



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