Gary Earl Duncan, Ph.D. - US grants

Experiments are proposed to provide a critical assessment of the use of (14C)-2-deoxglucose and specifically labeled (14C)-glucose in the measurement of cerebral functional activity. The uptake and retention of radioactivity in discrete brain regions from (14C)-2-deoxyglucose, (1-14C)-glucose and (6-14C)-glucose will be evaluated with high resolution autoradiography in which 4 um frozen brain sections are thaw-mounted onto nuclear emulsion coated slides. These studies will delineate the similarities and differences in the relative uptake and retention of radioactivity from the various compounds and in glucose utilization rates determined with the appropriate kinetic models. The hypothesis will be tested that the previously demonstrated low retention of radioactivity from (14C)-2-DG in some brain regions relative to that from (1-14C)-glucose is due to regionally high glucose-6- phosphatase activity, low phosphorylation of 2-DG, or low transport of (14C)-2-deoxyglucose-6- phosphate accumulation will be measured in microdissected brain regions by liquid scintillation counting in rats killed by microwave radiation, 1 to 45 minutes after i.v. injection of (14C)-deoxyglucose. If some brain regions contain high glucose-6-phosphate activity, an initial accumulation, followed by a decline in 2-deoxyglucose-6- phosphate, is predicted. If a brain region exhibits low phosphorylation of (14C)-2-DG, little accumulation of (14C)-2-DG is not transported as effectively into the cells of certain regions as is glucose, low levels of accumulation of radioactivity from (14C)-2-DG will occur at all times. The ability of (14C)-2-DG and specifically labelled (14C)-glucose to register alterations in functional activity will be determined by sensory stimulation and by stimulating a well defined afferent pathway to the hippocampal formation. Concurrent electrophysiological recording will be performed to determine the relationship of metabolic and electrical activities.

This is a Shannon Award providing partial support for research projects that fall short of the assigned institute's funding range but are in the margin of excellence. The Shannon award is intended to provide support to test the feasibility of the approach; develop further tests and refine research techniques; perform secondary analysis of available data sets; or conduct discrete projects that can demonstrate the PI's research capabilities or lend additional weight to an already meritorious application. Further scientific data for the CRISP System are unavailable at this time.

DESCRIPTION: (Applicant's Abstract) An activity-based learning program for elementary school students, grades 3-5, will be developed that will stress the relationship between human neurobiology and health. The interdisciplinary nature of neuroscience will be used as a vehicle to teach a broad range of physical, chemical, and biological sciences. A strong emphasis will be placed on integrating artistic expression in the learning process to engage students in multisensory activities that will enhance the enjoyment and effectiveness of learning. To create a scientifically literate public, effective science education must begin in the elementary grades. By the time students reach middle and high school levels, if an enthusiasm for science has not been instilled, it is very difficult to generate interest and promote broad scientific literacy. In a recent needs assessment at the Chapel Hill-Carrboro City Schools, the need for science activities and resources in the elementary schools was rated the most urgent. Experience of the P.I. through voluntary work in elementary schools has shown that 3rd-5th graders can understand basic chemical and neurobiological concepts and are eager to learn. A team of investigators will be assembled that will include individuals with backgrounds in neurobiology, public health, elementary science education, and curriculum development. The proposed research and development program will be conducted in collaboration with classroom, visual art and music teachers that have been presently identified and have expressed enthusiastic commitment for involvement in the endeavor. The program will employ diverse teaching strategies, including inquiry-based learning, model construction, journaling of activities, demonstrations, slide presentations, discussion groups, and theatrical modeling. In addition, workshops for elementary school teachers will be developed to provide training in the neurobiological sciences and activity-based teaching strategies. Instruments and questionnaires will be developed to assess the enthusiasm of students for learning science, the assimilation of specific content areas, the understanding and appreciation of the scientific process, and attitudes towards drug abuse.

[unreadable] DESCRIPTION (provided by applicant): Clinical studies have demonstrated that NMDA receptor antagonists induce positive, negative and cognitive schizophrenic-like symptoms in healthy subjects and precipitate psychotic reactions in patients with schizophrenia. These data, and the resulting NMDA receptor hypofunction hypothesis of schizophrenia, provide a compelling rationale for characterizing neurobiological correlates in models of reduced NMDA receptor function. The present proposal will assess behavioral and brain metabolic phenotypes in a genetic model of reduced NMDA receptor function-the NMDA R1 (NR1) subunit deficient mouse. The NR1 subunit is a component of all NMDA receptors and reduced expression of this subunit will therefore result in a chronic state of NMDA receptor hypofunction. It is hypothesized that the behavioral and brain metabolic phenotypes associated with the NR1 deficient mouse model will mimic certain phenotypes observed in schizophrenic patients. Specifically, it is hypothesized that the NR1 deficient mice will exhibit reduced brain metabolism in prefrontal and limbic regions, and exhibit alterations in sensory processing (prepulse inhibition and startle habituation). If these hypotheses are correct, the mouse models could represent an approach to explore potential preventative strategies for schizophrenia. The proposed work also will test the hypothesis that administration of typical and atypical antipsychotic drugs will have different effects on the alterations in behavior and regional brain metabolic activity observed in the genetic model of reduced NMDA receptor function In addition to the heuristic value of the work for understanding differential effects of typical and atypical antipsychotic drugs, the proposed autoradiographic studies are analogous to human PET studies of brain metabolism and blood flow, and therefore offer an important potential translational opportunity to relate results found in rodents to humans. The proposed work will not only contribute to the understanding of neurobiological actions of atypical antipsychotic drugs, but also will provide paradigms in which novel pharmacological strategies could be explored for the treatment of schizophrenia. In addition, characterizing neurobiological actions of antipsychotic drugs in the genetic model of NMDA receptor hypofunction could help delineate neurochemical dysfunction in these models, and by inference, potential pathophysiological processes in schizophrenia. [unreadable] [unreadable]

antipsychotic agents; neuropsychology; drug screening /evaluation; ketamine; brain metabolism; memory; psychological concentration; cognition; pharmacokinetics; clinical research; questionnaires; human subject; positron emission tomography;