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Scientific Report 2004




The Harold L. Dorris Neurological Research Institute


Alzheimer’s disease, depression, and schizophrenia are major illnesses that affect millions of people. The largest study of memory performance during aging involved the examination of the brains of nuns. Several hundred of these women were followed up closely by their fellow nuns and by a clinical psychologist during life and donated their brains for evaluation after death. In this study, the most important anatomic brain difference between those who died with Alzheimer’s disease and those who did not was the number of surviving galaninergic neurons. Nuns with a larger number of galaninergic neurons at the time of death had better cognitive function.

During the past 18 years, genetic and pharmacologic tools have been developed to study the effects of galanin on hippocampal neurons involved in memory function and neuronal survival. At The Harold L. Dorris Neurological Research Institute, my coinvestigators and I study galanin signaling in the brain and the effects of galanin on long-term potentiation and memory tasks in brain preparations and in animals. Recently, in collaboration with J. Rebek, The Skaggs Institute for Chemical Biology, we developed the first galanin receptor agonist that can be given systemically and that reaches the brain. Treatment with the agonist changes the seizure threshold, thus slowing epileptic seizures, and also affects learning and memory. We have also shown that galanin, acting at the type 2 galanin receptor, exerts a neuroprotective effect. Thus, agonists of this galanin receptor subtype are candidates for slowing disease progression in Alzheimer’s disease.

Schizophrenia is a devastating psychiatric disorder that affects 1% of the world’s population. M. Margarita Behrens and her group work on new approaches for the treatment of this disease based on the understanding that the cognitive aspects of the disease are as important as the hallucinations and other so-called positive symptoms addressed by current antipsychotic treatments. Their approach is based on the theory that many symptoms of schizophrenia arise from lowered glutamatergic signaling in certain parts of the brain, including the frontal cortex. They are defining mechanisms and agents to enhance the effects of glutamate at the N-methyl-D-aspartate receptors in the forebrain.

Major depression is a widespread mental illness in our society, and it exacts a heavy toll. According to estimates from the National Institute of Mental Health, about 1 of every 10 American adults has been treated for 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 also comparing the clinically well-proven effects of sleep deprivation and electroconvulsive therapy on depression. These drastic treatments are rarely used, but they are fast acting and are very effective when the risk of suicide is high. In collaboration with scientists at Novartis Pharma AG, Basel, Switzerland, Dr. Conti and his 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 Institute involves determining which proteins (ion channels, pumps, and receptors) in the warm-sensitive neurons of the hypothalamus are involved in thermoregulation. What makes a person hot and feverish when he or she is sick? Although 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 “hot flashes” that occur during menopause or during treatment of prostate cancer.

Treatment for these conditions requires an understanding of their underpinnings, and this need is addressed by the Harold L. Dorris Neurological Research Institute. 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.

 

Tamas Bartfai, Ph.D.

Director

Dorris Center Web Site