This program of research 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 investigation focus on neural plasticity in rodent hippocampus, referred to as long-term potentiation (LTP), that may reflect processes normally involved in information storage in the brain. The observations that LTP maintenance is reduced in aged rats, and that this reduction is correlated with behavioral deficits in spatial learning (Barnes and McNaughton, 1979), emphasizes the need to understand mechanisms that underlie the persistence of LTP. Because immediately early genes (IEGs) are rapidly activated by LTP-inducing stimulation (e.g., Cole et al., 1989), the hypothesis that specific IEGs play a critical role in the maintenance of neural plasticity in brain is proposed. Such knowledge may contribute to selective therapeutic strategies for memory disorders in both normal and pathological conditions of aging. The experimental goals of the project are described by four principle aims, each of which build upon the progress and new discoveries made during the past grant period.
AIM 1 - To analyze differentially activated immediate early gene (IEG) expression to hippocampus of young compared with old memory- impaired rats following LTP-inducing stimulation;
AIM 2 - To identify new delayed early genes (DERGs) that are associated with durable synaptic plasticity and to select those that are differentially regulated in young compared with old rats for further study;
AIM 3 - To use a new method that allows unprecedented cellular and temporal resolution of the onset, duration and pattern of transcriptional responses (compartment analysis of temporal activity by fluorescent in situ hybridization or catFISH), to systematically analyze the expression of genes in young and old rats that may be involved in the LTP maintenance deficits during aging;
AIM 4 - We were also able to show that the catFISH method allows the detection of IEGs activity in hippocampal cells as a result of a behavioral experience, and that it is possible to distinguish at least two separate episodes of experience with this method. This behavioral activation will also be compared in young and old rats. The necessity for this collaboration is highlighted by the divergent expertise of the two principle investigators: C.A.B., in vivo, chronic electrophysiology and behavioral; P.F.W.., molecular techniques necessary to examine the IEGs or DERGs of interest. The strength of this interaction is the ability to combine and apply the most powerful available methods to test the hypothesis under study, which could not be accomplished in either laboratory in isolation.
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