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      Spatial memory—a unique window into healthy and pathological aging

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          The world's population is aging at an unprecedented rate, because the number of people aged over 60 will rise from 784 million in 2011 to 2 billion by 2050. Such a dramatic increase has made age-related cognitive decline and Alzheimer's disease (AD) a pressing social and health concern. Work described in this volume considers scientific efforts to understand the neural mechanisms of age-related changes in spatial navigation, both in humans and non-human animal models. A central theme in these papers is that damage to structures of the medial temporal lobe, including the hippocampus, contributes to the difficulties in spatial memory found in aging and AD. Tanila (2012) describes the use of the Morris Water Maze (MWM) task as a tool for demonstrating memory impairments in mouse models of AD. Tanila (2012) points out important challenges in working with mice compared to rats—the former are prone to hypothermia, and exhibit strain differences in learning capacity. Strikingly, an impairment on the swim task is seen in all established models of AD in mice, though its relationship to the onset of amyloid plaque deposition or tau aggregation varies. In the MWM, Yau and Seckl (2012) note that older rats with impaired performance have higher corticosterone levels than those who are unimpaired. Higher corticosterone levels shift the balance between mineralcorticoid- and glucocorticoid-receptor activation, and are associated with decreases in long-term potentiation and memory. Yau and Seckl (2012) review findings which show that reduction of an enzyme that increases glucocorticoids results in improved spatial memory in aged rodents. Holden and Gilbert (2012) review studies which show that pattern separation abilities are impaired in older humans, monkeys, and rodents. Such a capacity likely relies on the hippocampus, and in particular the dentate gyrus/CA3 cell regions. They hypothesize that impaired pattern separation may result in impaired episodic memory in aging. Penner and Mizumori (2012) also relate the pattern separation function of the hippocampus in terms of the recognition of contexts. Their proposal is that the hippocampus produces an error signal when a context is unexpected, and this ultimately drives dopaminergic neurons in the ventral tegmental area. Aging affects this circuit by altering hippocampal representations of context, mesolimbic-ventral striatum interactions, and the dopaminergic system. Turning to humans, Adamo et al. (2012) investigated how aging affects path integration, a key navigational process. Both task complexity and the sources of information available to participants (i.e., visual vs. vestibular) had a substantial impact on the results. These findings have important methodological implications, because studies on spatial navigation are often confined to one sensory modality and do not systematically manipulate task complexity. Several studies demonstrate deficits in allocentric processing in healthy older adults. Rosenbaum et al. (2012) showed that memory for the layout of long familiar Toronto landmarks did not differ dramatically between young and older participants, but the latter made many more errors in learning a new route in a hospital. These results support a model where episodic-like representations of spatial information (hippocampus dependent) give rise to more schematic (less detailed, but hippocampus independent) representations with repeated experience. Using virtual environment (VE) technology, Yamamoto and DeGirolamo (2012) found that older participants had difficulties reconstructing the layouts of landmarks encountered in a virtual city. Interestingly, performance was not impaired when they experienced the environments from a bird's eye perspective. These results suggest that spatial learning through exploratory navigation may be particularly vulnerable to adverse effects of aging, whereas elderly adults may be able to maintain their map reading skills relatively well. Wiener et al. (2012) had participants learn a route through a VE that contained multiple intersections. Compared to young controls, older adults had greater problems during route retracing than during route repetition. While route repetition can be solved with egocentric response or route strategies, successfully retracing a route requires allocentric processing. These age-related deficits in route retracing are discussed in the context of a potential shift from allocentric to egocentric navigation strategies as a consequence of age-related hippocampal degeneration. A bias toward egocentric response strategies with increasing age was also observed by Bohbot et al. (2012). A virtual 8-arm radial maze served to assess spontaneous navigation strategies, i.e., hippocampal-dependent spatial strategies vs. caudate nucleus-dependent response strategies. Results showed that from childhood to old age, the spontaneous use of egocentric response strategies increased substantially. In a related study, Konishi and Bohbot (2013) showed that spontaneous spatial memory strategies positively correlated with gray matter density in the hippocampus of older participants. The combined results from both studies indicate that people who prefer to use spatial memory strategies in their everyday lives may have increased gray matter in the hippocampus and enhance the probability of healthy aging. Beyond the hippocampus, aging also affects the integrity of a larger network of brain structures, including prefrontal cortex. Harris et al. (2012) found that older humans were impaired at switching from a route strategy to a place strategy on a virtual plus maze task. Interestingly, this did not reflect a general difficulty in switching between spatial strategies, as the switch from a place strategy to a route strategy was not impaired. This may imply that interactions between the prefrontal cortex and the hippocampus are affected with advanced age. Finally, Pengas et al. (2012) demonstrate that spatial navigation impairments in AD relate to damage across a network, which offers complimentary lesion evidence to studies in healthy volunteers for the neural basis of topographical memory. Critically, the results emphasize that structures beyond the medial temporal lobe contribute to memory impairment in AD, which argues against common models in which memory impairment in AD is taken as a synonym for hippocampal degeneration. The book concludes with a review of human aging and spatial navigation tasks by Gazova et al. (2012). They suggest that such navigation tasks may be a useful tool for identifying individuals who will go on to develop AD. Given the growing number of studies indicating that damage to the medial temporal lobe (including the hippocampus) is associated with wayfinding difficulties, Gazova et al. (2012) argue that the use of such spatial tasks may help to identify AD early in its course.

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          Most cited references 13

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          Spatial navigational strategies correlate with gray matter in the hippocampus of healthy older adults tested in a virtual maze

          Healthy young adults use different strategies when navigating in a virtual maze. Spatial strategies involve using environmental landmarks while response strategies involve executing a series of movements from specific stimuli. Neuroimaging studies previously confirmed that people who use spatial strategies show increased activity and gray matter in the hippocampus, while those who use response strategies show increased activity and gray matter in caudate nucleus (Iaria et al., 2003; Bohbot et al., 2007). A growing number of studies report that cognitive decline that occurs with normal aging is correlated with a decrease in volume of the hippocampus. Here, we used voxel-based morphometry (VBM) to examine whether spatial strategies in aging are correlated with greater gray matter in the hippocampus, as found in our previous study with healthy young participants. Forty-five healthy older adults were tested on a virtual navigation task that allows spatial and response strategies. All participants learn the task to criterion after which a special “probe” trial that assesses spatial and response strategies is given. Results show that spontaneous spatial memory strategies, and not performance on the navigation task, positively correlate with gray matter in the hippocampus. Since numerous studies have shown that a decrease in the volume of the hippocampus correlates with cognitive deficits during normal aging and increases the risks of ensuing dementia, the current results suggest that older people who use their spatial memory strategies in their everyday lives may have increased gray matter in the hippocampus and enhance their probability of healthy and successful aging.
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            Local amplification of glucocorticoids in the aging brain and impaired spatial memory

            The hippocampus is a prime target for glucocorticoids (GCs) and a brain structure particularly vulnerable to aging. Prolonged exposure to excess GCs compromises hippocampal electrophysiology, structure, and function. Blood GC levels tend to increase with aging and correlate with impaired spatial memory in aging rodents and humans. The magnitude of GC action within tissues depends not only on levels of steroid hormone that enter the cells from the periphery and the density of intracellular receptors but also on the local metabolism of GCs by 11β-hydroxysteroid dehydrogenases (11β-HSD). The predominant isozyme in the adult brain, 11β-HSD1, locally regenerates active GCs from inert 11-keto forms thus amplifying GC levels within specific target cells including in the hippocampus and cortex. Aging associates with elevated hippocampal and neocortical 11β-HSD1 and impaired spatial learning while deficiency of 11β-HSD1 in knockout (KO) mice prevents the emergence of cognitive decline with age. Furthermore, short-term pharmacological inhibition of 11β-HSD1 in already aged mice reverses spatial memory impairments. Here, we review research findings that support a key role for GCs with special emphasis on their intracellular regulation by 11β-HSD1 in the emergence of spatial memory deficits with aging, and discuss the use of 11β-HSD1 inhibitors as a promising novel treatment in ameliorating/improving age-related memory impairments.
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              Route repetition and route retracing: effects of cognitive aging

              Retracing a recently traveled route is a frequent navigation task when learning novel routes or exploring unfamiliar environments. In the present study we utilized virtual environments technology to investigate age-related differences in repeating and retracing a learned route. In the training phase of the experiment participants were guided along a route consisting of multiple intersections each featuring one unique landmark. In the subsequent test phase, they were guided along short sections of the route and asked to indicate overall travel direction (repetition or retracing), the direction required to continue along the route, and the next landmark they would encounter. Results demonstrate age-related deficits in all three tasks. More specifically, in contrast to younger participants, the older participants had greater problems during route retracing than during route repetition. While route repetition can be solved with egocentric response or route strategies, successfully retracing a route requires allocentric processing. The age-related deficits in route retracing are discussed in the context of impaired allocentric processing and shift from allocentric to egocentric navigation strategies as a consequence of age-related hippocampal degeneration.

                Author and article information

                Front Aging Neurosci
                Front Aging Neurosci
                Front. Aging Neurosci.
                Frontiers in Aging Neuroscience
                Frontiers Media S.A.
                07 March 2014
                : 6
                1Aging and Cognition Research Group, German Center for Neurodegenerative Diseases (DZNE) Magdeburg, Germany
                2School of Natural Sciences, University of Stirling Stirling, UK
                3School of Biomedical Sciences, University of Edinburgh Edinburgh, UK
                Author notes

                This article was submitted to the journal Frontiers in Aging Neuroscience.

                Edited by: Rodrigo O. Kuljiš, The University of Texas Medical Branch, USA

                Copyright © 2014 Wolbers, Dudchenko and Wood.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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                Figures: 0, Tables: 0, Equations: 0, References: 13, Pages: 2, Words: 1551
                Editorial Article


                dementia, spatial navigation, animal models, neuroscience, humans, aging


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