Age-related Spatial Memory Deficits Research Articles

Overexpression of TIAM2S, a critical regulator for the hippocampal-medial prefrontal cortex network, progresses age-related spatial memory impairment.

TIAM Rac1 associated GEF 2 short-form protein (TIAM2S) is abundant in specific brain tissues, especially in the hippocampus, a brain region critical for processing and consolidation of spatial memory. However, how TIAM2S plasticizes the microstructure and circuits of the hippocampus to shape spatial memory as a neuroplastic regulator during aging, remains to be determined. In this study, transgenic mice overexpressing human TIAM2S protein (TIAM2S-TG mice) were included, and interdisciplinary approaches, such as spatial memory tests and multiparametric magnetic resonance imaging sequences, were conducted to determine the role and the mechanism of TIAM2S in age-related spatial memory deficits. Despite no changes in their neural and glial markers and neuropathological hallmarks expression of the hippocampus, behavioral tests showed that the TIAM2S-TG mice, and not wild-type (WT) mice, developed spatial memory impairment at 18 months old. The T2-weighted and diffusion tensor images analysis were performed to further study the possible role of TIAM2S overexpression in altering the hippocampal structure or neuronal circlets of the mice, increasing their vulnerability to developing spatial memory deficits during aging. The results revealed that the 12-month-old TIAM2S-TG mice had hippocampal dysplasticity, with larger volume, increased fiber numbers, and changed mean fractional anisotropy compared to those in the age-matched WT mice. The fiber tractography analysis exhibited significantly attenuated structural connectivity between the hippocampus and medial prefrontal cortex in the TIAM2S-TG mice. In conclusion, overexpression of TIAM2S, a detrimental factor affecting hippocampus plasticity, causes attenuation of the connectivity within hippocampus-mPFC circuits, leading to age-related spatial memory impairment.

Landmark-based guidance and cognitive saliency: Age-related benefits in spatial performance

Older adults have difficulties using a map, and the use of GPS systems seems beneficial to help them find their way in cities. The question arises however as to what extent the introduction of landmarks can be even more beneficial. While the visual saliency of landmarks has been well studied, the cognitive saliency of landmarks has received little attention. Our objective in this study was to determine if guiding young and older pedestrians with visually and cognitively salient landmarks inserted in a map or a GPS-like system improved spatial performances. Thirty-four young and 32 older adults navigated a virtual environment using a joystick. They were guided with a map or with GPS-like instructions, including either only visually or both visually and cognitively salient landmarks. After each itinerary, participants completed four tasks: landmark recognition and sequencing, direction recognition and sequencing. The results showed that the integration of visually and cognitively salient landmarks in a map or in GPS-like instructions improved the construction of landmark and route knowledge in both young and older participants. Results also suggested that age-related deficits in spatial memory could be reduced by using GPS-like instructions or by introducing cognitively salient landmarks, in a map or in a GPS-like system. This research opens several perspectives for research as well for the design of human-centred navigation aids.

“CityQuest,” A Custom-Designed Serious Game, Enhances Spatial Memory Performance in Older Adults

Spatial cognition is known to decline with aging. However, little is known about whether training can reduce or eliminate age-related deficits in spatial memory. We investigated whether a custom-designed video game involving spatial navigation, obstacle avoidance, and balance control would improve spatial memory in older adults. Specifically, 56 healthy adults aged 65 to 84 years received 10 sessions of multicomponent video game training, based on a virtual cityscape, over 5 weeks. Participants were allocated to one of three training conditions: the main intervention, the “CityQuest” group (n = 19), and two control groups, spatial navigation without obstacle avoidance (“Spatial Navigation-only” group, n = 21) and obstacle avoidance without spatial navigation (“Obstacles-only” group, n = 15). Performance on object recognition, egocentric and allocentric spatial memory (incorporating direction judgment tasks and landmark location tasks, respectively), navigation strategy preference, and executive functioning was assessed in pre- and post-intervention sessions. The results showed an overall benefit on performance in a number of spatial memory measures and executive function for participants who received spatial navigation training, particularly the CityQuest group, who also showed significant improvement on the landmark location task. However, there was no evidence of a shift from egocentric to allocentric strategy preference. We conclude that spatial memory in healthy older participants is amenable to improvement with training over a short term. Moreover, technology based on age-appropriate, multicomponent video games may play a key role in cognitive training in older adults.

Age-dependent effects of testosterone on spatial memory in male rats

Decreased spatial memory is common in aging populations and reduces their quality of life. Although its role is still controversial, low testosterone (T) may contribute to impaired cognition in aged men. This study aimed to identify the role of T in age-related deficiencies in spatial memory among male rats. Young adult (3 months old) and aged (21 months old) Wistar rats were assigned to independent groups: intact, orchidectomized, or orchidectomized + subcutaneous pellets of T propionate. The phases of spatial memory acquisition (4 daily trials/4 days) and spatial memory retention (1 trial/day, 3 and 12 days after acquisition) were evaluated using the Barnes maze. Compared with young adults, aged intact rats took longer to find the goal, made more mistakes, and showed only slight improvements in goal sector exploration across the acquisition period. The young orchidectomized rats showed no improvement in performance over the days during the acquisition phase. T treatment in hormonally deprived old rats produced a small improvement in goal sector exploration and number of errors during the acquisition phase. Meanwhile, in young adults, this treatment improved the goal sector searching in the retention phase (12 days after acquisition training). Our results suggested that age-related spatial memory deficits cannot be entirely explained by the decline in T levels; however, this androgen produced subtle and mild beneficial effects on spatial memory in young and old males. Taken together, our findings suggest age differences in the role of T on spatial memory in males.

Active Navigation in Virtual Environments Benefits Spatial Memory in Older Adults.

We investigated age differences in memory for spatial routes that were either actively or passively encoded. A series of virtual environments were created and presented to 20 younger (Mean age = 19.71) and 20 older (Mean age = 74.55) adults, through a cardboard viewer. During encoding, participants explored routes presented within city, park, and mall virtual environments, and were later asked to re-trace their travelled routes. Critically, participants encoded half the virtual environments by passively viewing a guided tour along a pre-selected route, and half through active exploration with volitional control of their movements by using a button press on the viewer. During retrieval, participants were placed in the same starting location and asked to retrace the previously traveled route. We calculated the percentage overlap in the paths travelled at encoding and retrieval, as an indicator of spatial memory accuracy, and examined various measures indexing individual differences in their cognitive approach and visuo-spatial processing abilities. Results showed that active navigation, compared to passive viewing during encoding, resulted in a higher accuracy in spatial memory, with the magnitude of this memory enhancement being significantly larger in older than in younger adults. Regression analyses showed that age and score on the Hooper Visual Organizational test predicted spatial memory accuracy, following the passive and active encoding of routes. The model predicting accuracy following active encoding additionally included the distance of stops from an intersection as a significant predictor, illuminating a cognitive approach that specifically contributes to memory benefits in following active navigation. Results suggest that age-related deficits in spatial memory can be reduced by active encoding.

Changes in hippocampal volume and neuron number co-occur with memory decline in old homing pigeons (Columba livia)

The mammalian hippocampus is particularly susceptible to age-related structural changes, which have been used to explain, in part, age-related memory decline. These changes are generally characterized by atrophy (e.g., a decrease in volume and number of synaptic contacts). Recent studies have reported age-related spatial memory deficits in older pigeons similar to those seen in older mammals. However, to date, little is known about any co-occurring changes in the aging avian hippocampal formation (HF). In the current study, it was found that the HF of older pigeons was actually larger and contained more neurons than the HF of younger pigeons, a finding that suggests that the pattern of structural changes during aging in the avian HF is different from that seen in the mammalian hippocampus. A working hypothesis for relating the observed structural changes with spatial-cognitive decline is offered.

A Mid-Life Vitamin A Supplementation Prevents Age-Related Spatial Memory Deficits and Hippocampal Neurogenesis Alterations through CRABP-I

Age-related memory decline including spatial reference memory is considered to begin at middle-age and coincides with reduced adult hippocampal neurogenesis. Moreover, a dysfunction of vitamin A hippocampal signalling pathway has been involved in the appearance of age-related memory deficits but also in adult hippocampal neurogenesis alterations. The present study aims at testing the hypothesis that a mid-life vitamin A supplementation would be a successful strategy to prevent age-related memory deficits. Thus, middle-aged Wistar rats were submitted to a vitamin A enriched diet and were tested 4 months later in a spatial memory task. In order to better understand the potential mechanisms mediating the effects of vitamin A supplementation on hippocampal functions, we studied different aspects of hippocampal adult neurogenesis and evaluated hippocampal CRABP-I expression, known to modulate differentiation processes. Here, we show that vitamin A supplementation from middle-age enhances spatial memory and improves the dendritic arborisation of newborn immature neurons probably resulting in a better survival and neuronal differentiation in aged rats. Moreover, our results suggest that hippocampal CRABP-I expression which controls the intracellular availability of retinoic acid (RA), may be an important regulator of neuronal differentiation processes in the aged hippocampus. Thus, vitamin A supplementation from middle-age could be a good strategy to maintain hippocampal plasticity and functions.

Region- and age-specific patterns of histone acetylation related to spatial and cued learning in the water maze

Epigenetic processes, such as histone acetylation, are critical regulators of learning and memory processes. In the present study, we investigated whether training in either a spatial or a cued water maze task undergoes selective changes of histone H3 and H4 acetylation within the hippocampus and the dorsal striatum of C57BL/6 mice. We also attempted to provide new insights into the relationships between deregulation in histone acetylation and age-associated memory deficits. In young mice, spatial training increased acetylation of histones H3 and H4 selectively in the dorsal hippocampal CA1 region and the dentate gyrus (DG) whereas cued training significantly enhanced acetylation of both histones selectively in the dorsal striatum. Our data also revealed age-related differences in histone acetylation within the hippocampus and striatum according to task demands. Specifically, age-related spatial memory deficits were associated with opposite changes of H3 (increase) and H4 (decrease) acetylation in CA1 and DG. After cued learning, both histone acetylation levels were reduced in the striatum of aged mice compared with corresponding young-adults but remained well above those of cage-controls. Collectively, our findings suggest an important role for histone acetylation in regulating the relative contributions of the hippocampus and striatum to learning spatial and cued memory tasks.

Less efficient pattern separation may contribute to age-related spatial memory deficits

Spatial memory deficits have been well-documented in older adults and may serve as an early indicator of mild cognitive impairment (MCI) or Alzheimer's disease (AD) in some individuals. Pattern separation is a critical mechanism for reducing potential interference among similar memory representations to enhance memory accuracy. A small but growing literature indicates that spatial pattern separation may become less efficient as a result of normal aging, possibly due to age-related changes in subregions of the hippocampus. This decreased efficiency in spatial pattern separation may be a critical processing deficit that could be a contributing factor to spatial memory deficits and episodic memory impairment associated with aging. The present paper will review recently published studies in humans, non-human primates, and rodents that have examined age-related changes in spatial pattern separation. The potential basic science, translational, and clinical implications from these studies are discussed to illustrate the need for future research to further examine the relationship between spatial pattern separation and brain changes associated with aging and neurodegenerative disease.

Age-Related Deficits in Spatial Memory and Hippocampal Spines in Virgin, Female Fischer 344 Rats

Effects of aging on memory and brain morphology were examined in aged, 21-month-old, and young, 4-month-old, Fischer 344 female rats. Spatial memory was assessed using the object placement task, and dendritic spine density was determined on pyramidal neurons in the hippocampus following Golgi impregnation. Consistent with previous studies, aged females showed poorer object placement performance than young subjects. Young subjects significantly discriminated the location of objects with a 1.5-hour intertrial delay while aged subjects did not. Spine density of basal dendrites on CA1 pyramidal cells was 16% lower in the aged subjects as compared to the young subjects. No differences in spine density were found between young and aged subjects in basal dendrites of CA1 or in either dendritic field of CA3 pyramidal neurons. Thus, decreased hippocampal CA1 dendritic spine density in aged rats may contribute to poorer spatial memory as compared to young rats. The possibility that the neuroplastic changes observed in this study may pertain only to female subjects having had a specific set of life experiences is discussed. Different factors, such as reproductive status, diet, and handling may contribute to neuroplasticity of the brain during aging; however, this view requires further examination.

Prevention of age-related spatial memory deficits in a transgenic mouse model of Alzheimer's disease by chronic Ginkgo biloba treatment

Alzheimer's disease (AD) is characterized by cognitive decline and deposition of β-amyloid (Aβ) plaques in cortex and hippocampus. A transgenic mouse AD model (Tg2576) that overexpresses a mutant form of human Aβ precursor protein exhibits age-related cognitive deficits, Aβ plaque deposition, and oxidative damage in the brain. We tested the ability of Ginkgo biloba, a flavonoid-rich antioxidant, to antagonize the age-related behavioral impairment and neuropathology exhibited by Tg2576 mice. At 8 months of age, 16 female Tg2576 and 15 female wild-type (wt) littermate mice were given ad lib access to tap water or Ginkgo biloba (70 mg/kg/day in water). After 6 months of treatment, all mice received Morris water maze training (4 trials/day for 10 days) to assess hippocampal dependent spatial learning. All mice received a 60-s probe test of spatial memory retention 24 h after the 40th trial. Untreated Tg2576 mice exhibited a spatial learning impairment, relative to wt mice, while Ginkgo biloba-treated Tg2576 mice exhibited spatial memory retention comparable to wt during the probe test. Spatial learning was not different between Ginkgo biloba-treated and untreated wt mice. There were no group differences in learning to swim to a visible platform. Soluble Aβ and hippocampal Aβ plaque burden did not differ between the Tg2576 groups. Brain levels of protein carbonyls were paradoxically elevated in Ginkgo biloba-treated mice. These data indicate that chronic Ginkgo biloba treatment can block an age-dependent decline in spatial cognition without altering Aβ levels and without suppressing protein oxidation in a transgenic mouse model of AD.

Chronic cerebral hypoperfusion in the rat enhances age-related deficits in spatial memory.

Ten-week old rats were subjected to chronic mild hypoperfusion by a permanent bilateral ligation of common carotid arteries (2VO). Animals were repeatedly tested in 8-arm radial maze at 1 week, 3, 10 and 16 months after the surgery to investigate long term effects of 2VO on spatial learning and memory. Occluded rats showed initially mild deficits in reference (RM) and working (WM) memory that were progressing with time and reached level of marked differences 16 months after the surgery. Advanced age significantly influenced cognitive function in both groups but the observed deterioration was more pronounced in 2VO animals. We suggest that the long-lasting reduction of cerebral blood flow combined with ageing can result in the enhanced cognitive impairment of aged individuals.

Oxotremorine infusions into the medial septal area of middle-aged rats affect spatial reference memory and ChAT activity

Age-related spatial memory deficits are correlated with septohippocampal cholinergic system degeneration. The present study examined the effect of intraseptal infusions of the cholinergic agonist, oxotremorine, on spatial reference memory in middle-aged rats using place discrimination in the water maze, and on cholinergic activity using choline acetyltransferase (ChAT[ activity. Oxotremorine mildly improved the rate of place discrimination acquisition of middle-aged rats during initial sessions only, but did not affect asymptotic levels of performance achieved. Of the brain regions assayed, ChAT activity increased with age in the temporal cortex and dorsal CA2/3 region of the hippocampus. Oxotremorine significantly decreased ChAT activity in the dorsal hippocampus. In contrast to our previous results in aged rats indicating a more robust effect of oxotremorine on spatial working memory, the present results suggest a modest effect of intraseptal oxotremorine on the acquisition of a spatial reference memory task.

Memory impaired aged rats: No loss of principal hippocampal and subicular neurons

A group of 52 male, 2-year-old Ico:WIST rats were tested on the spatial reference memory version of the Morris water maze. Their performance was rated by comparisons with the performance of 2.5-month-old control rats. Unbiased stereological estimates were made of the number of neurons in the major subdivisions of the hippocampus proper and the subiculum of the 5 aged rats with the most impaired performance, the 5 aged rats with the best performance, and 5 young control rats. There were no significant differences between the mean numbers of neurons in the various subdivisions of the hippocampal region of the impaired and nonimpaired aged groups and similarly no decreases in neuron numbers in the pooled group of aged rats relative to the control rats. The results indicate that, in rats, the structural correlates of age-related deficits in spatial memory are to be found in parameters other than the number of neurons in the hippocampus proper and the subiculum.

Age-related Deficits in Intentional Memory for Spatial Location in Small-scale Space: A Meta-Analysis and Methodological Critique

RÉSUMÉLe but de cette méta-analyse était d'estimer l'effet du vieillissement sur la mémoire intentionnelle de locations dans un espace de petite dimension. Les résultats de 22 études, représentant au total 1 598 sujets, ont été comparés grâce aux indices suivante: (a) d (Cohen, 1988), (b) omega2 (Hays, 1963), et (c) Proportion des sujets classifiés. La méta-analyse suggére que l'effet du vieillissement est «large» (e.g., d moyen de 0.81), et que cet effet est proportionnel au nombre de dimensions de l'espace utilisé. Toutefois, la validité de ces conclusions est incertaine lorsqu'on considére les limites méthodologiques des études recensées. En particulier, moins de la moitié de ces études ont mentionné avoir contrôlé l'effet possible de variables telles que (a) l'acuité visuelle, et (b) la durée de la phase de rappel. Il est proposé que compte de ces variables exogénes.

Pentoxifylline reverses age-related deficits in spatial memory

Pentoxifylline, a phosphodiesterase inhibitor, produces a marked reversal of an age-dependent spatial memory deficit in Fischer 344 strain male rats. Performance of 26-month-old animals treated chronically with pentoxifylline approached that of 3-month-old controls. The effect was not dependent upon concurrent administration of the acetylcholine precursor choline chloride. It is concluded that the pentoxifylline-induced reversal of the age-dependent memory decline is not dependent on any presumed facilitation of acetylation and utilization of exogenously supplied transmitter substrate.

Age-dependent deficits in spatial memory are related to impaired hippocampal kindling.

Fischer 344 rats, 3 and 26 months of age, were first tested in an eight-arm spatial maze to assess memory function behaviorally. The same animals were then subjected to hippocampal kindling to examine alterations in neuronal plasticity as a function of aging. The results indicated that spatial memory was poorer and hippocampal kindling slower in aged rats than in young ones. Furthermore, there was a striking positive relation between performance in the eight-arm spatial maze and speed of kindling. This finding suggests that age-related deficits in spatial memory and hippocampal kindling reflect decreased efficacy of synaptic transmission in a common neuroanatomical substrate.

Can age-related deficits in spatial memory be attenuated through the use of verbal coding?

In a sequential mental rotation task, women of three age groups (18-28, 50-60, and 70-80) viewed semi-abstract figures which were rotated in the picture plane. To investigate the effects of verbal mediation, each figure was presented under one of four labeling conditions. Errors increased as a function of age. Meaningful labels were beneficial in decreasing errors for the older subjects. Reaction time results generally replicated earlier studies, but there were indications that some women in the oldest group might have used strategies other than mental rotation. Results suggest that possible age related deficiencies in spatial abilities may be compensated for by greater use of verbal mediation.