Progress in this program of research requires an in-house animal resource to yield a reliable supply of behaviorally characterized young and aged Long-Evans rats, replicating the model of normal cognitive aging we and others have exploited in over two decades of previous research. Unfortunately, NIA IRP animal colony policies instituted in 2009 barred the acquisition of these rats from Charles River Laboratories. Recognizing this impediment to progress, during the current reporting period OSD provided special authorization allowing us to begin establishing the necessary animal resource. Rats for this purpose are imported at 9-months of age and maintained until 24+ months for behavioral and neurobiological assessment. By this design the colony will begin yielding subjects suitable for study midway through the coming reporting period. Our hope is that the pending recruitment of a new Animal Program Director with laboratory animal colony management and veterinary experience will lead to a permanent, stable resolution of this long-standing issue. In the interim we have been fortune in being able to capitalize on animal availability and collaborative support from colleagues at Johns Hopkins University, allowing progress on several fronts. An extensive analysis completed during the current reporting period, for example, used our established rodent model of cognitive aging to examine multiple markers of bi-directional chromatin modification under both basal and behaviorally activated conditions in the hippocampus of young rats, and in aged subjects with or without deficits in spatial learning and memory. In this way the experiments provided a window on dynamic epigenetic modulation that might distinguish conditions of cognitive impairment and preservation in aged subjects, and it allowed us to test for associations between chromatin regulation and individual variability in spatial memory. The analysis also took into account the known circuit organization of the hippocampus, using microdissected samples of the principal cell fields as a starting point for development of a network perspective on experience-dependent epigenetic regulation in neurocognitive aging. Taken together, the pattern of results from these experiments points to significant overall disruption in the large-scale coordination of chromatin regulation specifically among aged individuals with impaired memory. A full-length report of these novel results has been submitted for publication and is currently under revision (Castellano et al., in revision). Converging evidence has linked histone acetylation to hippocampus-dependent memory, including reports that administration of histone deacetylase inhibitors (HDACis) can enhance both intact memory and experimentally disrupted cognitive function. In an extension aimed at the development of potential interventions for cognitive aging, we recently completed a study examining the neurobiological and behavioral effects of the novel HDACi, EVX001688 (EVX), obtained under an MCRADA arrangement with EnVivo Pharmaceuticals, Inc. First we confirmed that EVX dose-dependently increases hippocampal histone acetylation 90 minutes after systemic administration in both young and aged rats. The same three EVX doses, however, administered 90 min prior to training in young subjects failed to have any effect on 24-hour retention of contextual fear conditioning (CFC). As might be predicted on the basis of this result, the generic and non-selective HDACi sodium butyrate also failed to influence memory as measured by CFC. Using a variant of the Morris water maze procedure, however, EVX treatment in young rats yielded a dose-dependent benefit on retention of spatial location at 24 hours. Informed by this result, and constrained by limitations on animal availability discussed earlier, we selected the most effective dose (30mg/kg) to test the potential benefit of pretraining dosing on long-term memory performance in aged rats. Aged rats receiving drug showed better retention of platform locations across multiple rounds of training. This finding is consistent with the proposal that HDAC inhibition might ameliorate certain features of age-related cognitive decline, and a full-length manuscript describing these results has been submitted for approval to EnVivo, Inc., consistent with the terms of our MCRADA agreement. We have surveyed translational progress in animal models of neurocognitive aging, including much of the work described here, in a number of extensive reviews (Fletcher and Rapp, in press;Rapp and Bachevalier, in press;Hara et al, 2011).
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