Retrograde amnesia observed following hippocampal lesions in humans and animals is typically temporally graded, with recent memory being impaired while remote memories remain intact, indicating that the hippocampal formation has a time-limited role in memory storage. However, this claim remains controversial because studies involving hippocampal lesions tell us nothing about the contribution of the hippocampus to memory storage if this region was present at the time of memory retrieval. We therefore used non-invasive functional brain imaging using (14C)2-deoxyglucose uptake to examine how the brain circuitry underlying long-term memory storage is reorganized over time in an intact brain. Regional metabolic activity in the brain was mapped in mice tested at different times for retention of a spatial discrimination task. Here we report that increasing the retention interval from 5 days to 25 days resulted in both decreased hippocampal metabolic activity during retention testing and a loss of correlation between hippocampal metabolic activity and memory performance. Concomitantly, a recruitment of certain cortical areas was observed. These results indicate that there is a time-dependent reorganization of the neuronal circuitry underlying long-term memory storage, in which a transitory interaction between the hippocampal formation and the neocortex would mediate the establishment of long-lived cortical memory representations.

Vitamin A and its derivatives, the retinoids, have been implicated recently in the synaptic plasticity of the hippocampus and might therefore play a role in associated cognitive functions. Acting via transcription factors, retinoids can regulate gene expression via their nuclear receptors [retinoic acid receptors (RARs) and retinoid X receptors]. In a series of experiments, the present study investigated the possible role of age-related downregulation of retinoid-mediated transcription events in the cognitive decline seen in aged mice. We observed that the brain (and hippocampal) levels of retinoid receptors and the expression of specific associated target genes were restored to presenescent (adult) levels in aged mice after acute administration (150 g/kg, s.c.) of retinoic acid (RA). These effects of RA, however, could be abolished by the coadministration of an RAR antagonist. RA was also demonstrated to alleviate the agerelated deficit in the CA1 long-term potentiation efficacy of aged mice in vivo. Moreover, RA was found to alleviate completely the performance deficit of aged mice to the control level in a two-stage spatial discrimination paradigm designed to assess relational memory. This promnesic effect of RA was again susceptible to abolition by RAR antagonist treatment. The parallel molecular, cellular, and behavioral correlates associated with the decrease of retinoid receptor expression and its normalization demonstrated here suggest that the fine regulation of retinoid-mediated gene expression is fundamentally important to optimal brain functioning and higher cognition. Specifically, a naturally occurring dysregulation of retinoidmediated molecular events might be a potential etiological factor for cognitive deterioration during senescence.

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