Grant: Operating Grant

The objective of this proposal is to investigate mechanisms for regulating brain cell pathways that contribute to learning and memory ("plasticity"), and also brain damage during stroke or neurodegenerative disease. We will study rat brain tissue from cortex, hippocampus and striatum, which are regions involved in controlling movement and memory, and are also vulnerable to damage in stroke and age-related neurodegeneration. Brain cells from hippocampus and cortex show differences from those of striatum, however, in their responses to stimulation that induces plasticity or death. We will directly study brain tissue, and also study isolated brain cells that are maintained in a dish for ~3 weeks. Neurons from the different brain regions will be compared in terms of composition and function of the NMDA-type glutamate receptor. This receptor normally mediates cell-cell communication and is critical for learning and memory; however, it becomes over-activated in some neurological diseases and triggers a series of events leading to cell death. We will study natural cellular mechanisms by which these NMDA receptors are regulated, by recording electrical activity and cell death mediated by these receptors, and how it is affected by manipulating activity of other cellular proteins closely linked to the receptors. Using this approach, we will contribute to a detailed understanding of how pathways involved in learning and memory, or cell death in neurological disease, can be regulated in different brain regions. Our results may lead to development of new drugs to diminish NMDA receptor activity in specific brain regions and neurologic diseases.