The program of research outlined here is directed towards an understanding of the mechanisms responsible for durable synaptic change in the mammalian central nervous system, and how these processes might be altered with age. The investigations focus on the neural plasticity found in the rodent hippocampal formation, referred to as long-term potentiation or enhancement (LTE), that may reflect processes normally involved in information storage in the brain. Although a rather large body of literature describes the phenomenological properties of LTE, and there is a rather good understanding of LTE's requirements for induction, there is as yet no clear understanding of the processes responsible for its maintenance. Recent evidence suggests that certain of the transcription factor genes (zif/268) can be rapidly activated by LTE-inducing stimulation (Cole et al., 1989). These data suggest the exciting possibility that transcription factor genes may regulate other proteins that play a critical role in the maintenance of neural plasticity in brain. Because the mechanisms of LTE induction appear to be normal while the maintenance of LTE is deficient in aged rats (Barnes and McNaughton, 1985), it is of interest to determine whether transcription factor activation mechanisms are defective in old animals. Because the rate of decay of LTE and spatial behavioral forgetting rates are correlated within age groups, such investigations may provide insights into why older organism show faster forgetting. Understanding such changes in neuronal plasticity may have an impact on therapeutic strategies for memory disorders in both normal and pathological conditions of aging. The experimental goals of the project can be broken into two main aims: 1) Experiments to identify synaptic mechanisms that regulate transcription factor genes in brain, and in the same preparation to correlate transcription factor responses with synaptic enhancement (LTE). Zif/268 mRNA and protein will be assayed by in situ hybridization and immunohistochemistry, respectively, and will be correlated with the degree of resultant plasticity. Additionally, we will examine the responsiveness of other transcription factors. These studies will refine our understanding of the relationship between LTE and transcription factor activation and will form the basis for comparison of transcription factor responses in young and old rats. 2) Experiments designed to determine whether there are changes in regulation of transcription factor activation in old animals that may contribute to their altered synaptic plasticity and behavior. All studies proposed will use chronic in vivo electrophysiological methods that offer important advantages over acute or in vitro preparations for this work. The necessity for this collaboration is highlighted by the divergent expertise of the two principal investigators: C.A.B. has experience with chronic electrophysiological techniques, and with behavior and physiology in young and old rats; P.F.W. has experience with the anatomical and in molecular techniques necessary to examine the transcription factors of interest. We hope to combine our different techniques and apply the most powerful available methods to test our hypotheses.
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