CONICET | Buscador de Institutos y Recursos Humanos

The hippocampus, a medial temporal lobe structure necessary for the formation of spatial memory, is particularly affected by both normal and pathologic aging. In previous studies, we observed a significant age-related increase in dopaminergic neuron loss in the hypothalamus and the substantia nigra of female rats, which becomes more conspicuous at extreme ages. Here, we extend our studies by assessing spatial memory 4-6 months old (young), 26 months old (old) and 29-32 months old (senile) Sprague?Dawley female rats as well as the agerelated histopathological changes in their dorsal hippocampus. Age changes in spatial memory performance were assessed with a modified version of the Barnes maze test. We employed two probe trials (PT), one and five days after training, respectively, in order to evaluate learning ability as well as short-term and longer-term spatial memory retention. A set of relevant hippocampal cell markers was also quantitated in the animals by means of an unbiased stereological approach. The results revealed that old rats perform better than senile rats in acquisition trials and young rats perform better than both aging groups. However, during short-term PT both aging groups showed a preserved spatial memory while in longerterm PT, spatial memory showed deterioration in both aged groups. Morphological analysis showed a marked decrease (94-97%) in doublecortin neuron number in the dentate gyrus in both aged groups and a 40% reduction in vimentin-positive glial cell number in the hilus of aging rats. Astroglial process length and branching complexity decreased in the aged rats. We conclude that while target-seeking activity and learning ability decrease in aged females, spatial memory only declines in the longer-term tests. The reduction in neuroblast number and astroglial arborescence complexity in the dorsal hippocampus are likely to play a role in the cognitive deficits of aging rats. In rats as in humans, learning and memory performance decline during normal aging which makes this rodent species a suitable model to evaluate therapeutic strategies of potential clinical value for restoring age-related cognitive deficits. In previous studies we have reported that hypothalamic or intracerebroventricular insulin-like growth factor-I (IGF-I) gene therapy is able to reverse or at least attenuate the lactotrophic, reproductive and motor derangements of aging female rats (Hereñu et al., 2007; Rodriguez et al., 2013; Nishida et al., 2011), and are now interested in assessing the restorative potential of this intervention on the spatial memory performance of aging female rats. In most rodent studies, spatial memory has been assessed using the Morris Water Maze (MWM, Morris, 1984) for which a considerable performance database is available both for rats and mice. A potential disadvantage of the MWM in aging studies, however, is that it requires a substantial degree of physical fitness. This has led some investigators to prefer the less physically demanding Barnes maze (Barnes, 1979), especially for aged rats. In both tests, rats learn to use spatial cues to guide them to a hidden platform or tunnel. While the MWM involves immersion in water, a stimulus that provokes considerable corticosterone and corticotropin release (Sternberg et al., 1992), in the Barnes maze animals are placed on an open, unprotected circular platform for them to walk in search of the escape tunnel. Comparison between the Barnes maze and MWM in mice has shown that the latter induces higher circulating corticosterone concentration than the former and that serum corticosterone levels show an inverse correlation with the performance of the animals in the MWM but not in the Barnes maze (Harrison et al., 2009). Furthermore, even at the tepid temperatures typically used in MWM studies, swim stress also causes sympathetic activation and peripheral adrenaline release, especially in aged rats (Mabry et al., 1995). In order to generate a reference framework for future therapeutic investigations, in the present study we undertook to characterize the changes in spatial memory in old and very old (senescent) female rats using a modified version of the Barnes maze so that nonspecific exploration and target-seeking activity as well as the ability for acquisition and retention of spatial information can be compared in the different age groups.