Research - Basic Neuroscience Research
Neuroscience research has been an important focus of the faculty of the Medical College since it was founded. The basic neuroscience research programs in the departments of Biochemistry, Pharmacology, and Anatomy and Neurobiology have achieved national recognition for their scientific contributions. The Department of Neurology basic science faculty, with adjunct appointments in these basic science departments, are conducting research with implications for the functioning of the aging nervous system. These basic science programs include:The Alzheimer's Disease Research Program
Progress toward elucidation of the causes of Alzheimer's disease and development of effective therapies has depended upon a solid foundation in basic science research. The power of molecular and neurobiological approaches to study this disease is well illustrated by the inclusion of 35-40 separate sessions on Alzheimer's disease at recent annual meetings of the Society for Neuroscience. The regulation of biochemical signal transduction as it pertains to the neurotransmitter receptor-mediated pathways that are altered during the progression of Alzheimer's disease is, and will continue to be, a major research focus in the laboratory of Linda Dokas, Ph.D. Her research has been funded by the Alzheimer's Association, the National Institute on Aging and the American Federation for Aging Research. The Brain and Nerve Institute will extend and co-ordinate Alzheimer's disease-related research among faculty at MUO and the other area universities. This can be accomplished through promotion of research collaborations in both clinical and basic science areas, sponsorship of pilot research grants and development of seminar series and conferences.
Given the central role of the hippocampus in the process of memory consolidation, its sensitivity to stress and, more specifically to glucocorticoid hormones, could be a factor in setting the level of cognitive performance. This hypothesis has taken on relevance to human aging as it has been shown that conditions characterized by elevated plasma levels of glucocorticoid hormones, including aging, are associated with cognitive deficits and hippocampal atrophy. Given that steroid hormones universally produce their effects by regulating patterns of transcription, genes and corresponding proteins whose syntheses are acutely regulated by glucocorticoids and then modulated during chronic exposure to these steroids, such as occurs during aging, are likely to determine the physiological state of responsive tissues. The major goal of a second project in Dr. Dokas' laboratory is to characterize patterns of hippocampal gene and protein expression in response to acute or chronic steroid administration and to relate them to the ability of the brain to adapt to stress and aging. Since glucocorticoid hormones may contribute to the loss of homeostatic regulation seen in the aged state, Dr. Dokas has applied for funding from the National Institute on Aging with Boyd Koffman M.D., Ph.D., to characterize how glucocorticoid-mediated patterns of gene expression in brain and muscle compare to those seen in aged animals. The major hypothesis of their project is that chronic exposure to glucocorticoid hormones produces a pattern of gene expression in two responsive post-mitotic tissues that accounts for a significant portion of the aged condition.
The Epilepsy Research Program
In close collaboration with the Comprehensive Epilepsy Program, this program is dedicated to the study of basic cellular mechanisms underlying the epileptic state and the regulation of sensitivity to antiepileptic drugs. Directed by L. John Greenfield, Jr., M.D., Ph.D., the laboratory uses patch clamp electrophysiology of cultured neurons as well as newer molecular biological techniques including the polymerase chain reaction to investigate the acute and chronic regulation of inhibitory GABA-A receptors and excitatory sodium channels by antiepileptic drugs and second messengers. Major research efforts are focused on the regulation of GABA-A receptor subunit expression by chronic exposure to benzodiazepines, which results in tolerance to these agents and prevents their chronic use in epilepsy. We have also begun to study the regulation of GABA-A receptors by the steroid hormones, progesterone, estradiol and hydrocortisone, in an effort to determine whether changes in inhibitory receptor composition may be responsible for triggering seizures during stress or changes in the menstrual cycle. The laboratory has also received extramural funding from the Myoclonus Research Foundation to examine the regulation of GABA-A receptor function by hypoxia, which can cause post-hypoxic myoclonus, a condition seen most frequently in elderly patients after cardiopulmonary arrest. The laboratory has a full time research technician, Anne Lyons, and a graduate student, Lei Gao, who is pursuing his Ph.D. in Cellular and Molecular Neurobiology with Dr. Greenfield as mentor. Dr. Greenfield has also trained a number of graduate students, medical students and undergraduates in laboratory rotations, and lectures locally and nationally on the basic mechanisms of epileptogenesis and antiepileptic drugs.
The Nerve and Muscle Research Program
Drs. Dokas and Koffman collaborate in the design of an animal model of aging based on responses to corticosteroids. This collaboration proposes to evaluate the molecular effects of corticosteroids as a model of aging on rat brain and muscle through differential evaluation of gene expression using microarray technology and protein expression assays. Other projects include the study of morphological abnormalities of muscle in patients with fibromyalgia and evaluation of the effect of glucocorticoids on human muscle.
Active basic research studies conducted in laboratories:
Glucocorticoid signaling mechanisms and the Ab peptide in Alzheimer's disease using biochemical techniques; investigator: Dr. Linda Dokas
Behavioral and biochemical pathology of a mouse model of Huntington’s disease; investigator: Dr. Lawrence Elmer
Patch clamp electrophysiology to investigate the effects of anticonvulsant drugs on GABAA receptors on human NT2-N neurons in culture; investigator: Dr. John Greenfield