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Aging weakens memory functions. Exposing healthy rodents or pathological rodent models to environmental enrichment (EE) housing improves their cognitive functions by changing neuronal levels of excitation, cellular signaling, and plasticity, notably in the hippocampus. At the molecular level, brain derived-neurotrophic factor (BDNF) represents an important player that supports EE-associated changes. EE facilitation of learning was also shown to correlate with chromatin acetylation in the hippocampus. It is not known, however, whether such mechanisms are still into play during aging. In this study, we exposed a cohort of aged rats (18-month-old) to either a 6 month period of EE or standard housing conditions and investigated chromatin acetylation-associated events [histone acetyltranferase activity, gene expression, and histone 3 (H3) acetylation] and epigenetic modulation of the Bdnf gene under rest conditions and during learning. We show that EE leads to upregulation of acetylation-dependent mechanisms in aged rats, whether at rest or following a learning challenge. We found an increased expression of Bdnf through Exon-I-dependent transcription, associated with an enrichment of acetylated H3 at several sites of Bdnf promoter I, more particularly on a proximal nuclear factor κB (NF-κB) site under learning conditions. We further evidenced p65/NF-κB binding to chromatin at promoters of genes important for plasticity and hippocampus-dependent learning (e.g., Bdnf, CamK2D). Altogether, our findings demonstrate that aged rats respond to a belated period of EE by increasing hippocampal plasticity, together with activating sustained acetylation-associated mechanisms recruiting NF-κB and promoting related gene transcription. These responses are likely to trigger beneficial effects associated with EE during aging., Significance Statement: Aging weakens memory functions. Optimizing the neuronal circuitry required for normal brain function can be achieved by increasing sensory, motor, and cognitive stimuli resulting from interactions with the environment (behavioral therapy). This can be experimentally modeled by exposing rodents to environmental enrichment (EE), as with large cages, numerous and varied toys, and interaction with other rodents. However, EE effects in aged rodents has been poorly studied, and it is not known whether beneficial mechanisms evidenced in the young adults can still be recruited during aging. Our study shows that aged rats respond to a belated period of EE by activating specific epigenetic and transcriptional signaling that promotes gene expression likely to facilitate plasticity and learning behaviors., (Copyright © 2016 the authors 0270-6474/16/364352-11$15.00/0.)

Background: Object-location memory is critical in every-day life and known to deteriorate early in the course of neurodegenerative disease., New Method: We adapted the previously established learning paradigm "LOCATO" for use in healthy older adults and patients with mild cognitive impairment (MCI). Pictures of real-life buildings were associated with positions on a two-dimensional street map by repetitions of "correct" object-location pairings over the course of five training blocks, followed by a recall task. Correct/incorrect associations were indicated by button presses. The original two 45-item sets were reduced to 15 item-sets, and tested in healthy older adults and MCI for learning curve, recall, and re-test effects., Results: The two 15-item versions showed comparable learning curves and recall scores within each group. While learning curves increased linearly in both groups, MCI patients performed significantly worse on learning and recall compared to healthy controls. Re-testing after 6 month showed small practice effects only., Comparison With Existing Methods: LOCATO is a simple standardized task that overcomes several limitation of previously employed visuospatial task by using real-life stimuli, minimizing verbal encoding, avoiding fine motor responses, combining explicit and implicit statistical learning, and allowing to assess learning curve in addition to recall., Conclusions: Results show that the shortened version of LOCATO meets the requirements for a robust and ecologically meaningful assessment of object-location memory in older adults with and without MCI. It can now be used to systematically assess acquisition of object-location memory and its modulation through adjuvant therapies like pharmacological or non-invasive brain stimulation., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Recent evidences have shown the therapeutic potential of transcranial photobiomodulation on traumatic brain injury and Alzheimer's disease. Despite the promising benefits in the brain, little is known about the laser's effects in the absence of pathological conditions. We submitted young (4 months old) and aged (20 months old) rats to transcranial low-level laser and evaluated their exploratory activity and habituation in open field, anxiety in elevated plus maze, spatial memory in Barnes maze, and aversive memory in a step-down inhibitory avoidance task. Additionally, the levels of a panel of inflammatory cytokines and chemokines were quantified in two different brain regions: the cerebral cortex and the hippocampus. Young and aged rats submitted to transcranial laser exhibited better cognitive performance in Barnes maze than did control rats. Transcranial laser therapy decreased cortical levels of GM-CSF, IL-10, MCP-1, LIX, and TNFα in young rats and IL-5 in aged rats. High levels of IL-6, IL-10, and TNF-alpha were found in the cerebral cortex of aged rats submitted to transcranial laser. In the hippocampus, a decrease in IP-10 and fractalkine levels was observed in the aged rats from the laser group when compared to the aged rats from the control group. Our data indicate that transcranial photobiomodulation improves spatial learning and memory and alters the neuroinflammatory profile of young and aged rats' brains. [ABSTRACT FROM AUTHOR]

Objective Object location learning and memory may be important for older adults to successfully complete some everyday activities. Method This cross-sectional, correlational study investigated the ecological relevance of the Location Learning Test-Revised (LLT-R) in 195 community-dwelling, older adults in Western Australia. The LLT-R assesses object location learning and memory for everyday objects over five learning trials and after a 30-min delay. Knowledgeable informants provided structured ratings of participants' activities of daily living and memory symptoms. Results A greater number of errors on LLT-R total learning trials were associated with mild problems in activities of daily living (particularly in travel and household domains), but not with memory symptoms. The LLT-R's association with activities of daily living was accompanied by a small-to-medium effect size and was not better explained by demographics, global cognitive functioning, mood, or chronic medical conditions. Conclusions Findings provide some support for the ecological relevance of the LLT-R among older community-dwelling adults and suggest that object location learning may play a role in some everyday functioning problems that accompany typical aging. [ABSTRACT FROM AUTHOR]

An age-related decrease in hippocampal metabolism correlates with cognitive decline. Hippocampus-dependent learning and memory requires glutamatergic neurotransmission supported by glutamate-glutamine (GLU-GLN) cycling between neurons and astrocytes. We examined whether GLU-GLN cycling in hippocampal subregions (dentate gyrus and CA1) in Fischer 344 rats was altered with age and cognitive status. Hippocampal slices from young adult, aged cognitively-unimpaired (AU) and aged cognitively-impaired (AI) rats were incubated in artificial cerebrospinal fluid (aCSF) containing 1-13C-glucose to assess neural metabolism. Incorporation of 13C-glucose into glutamate and glutamine, measured by mass spectroscopy/liquid chromatography tandem mass spectroscopy, did not significantly differ between groups. However, when 13C-acetate, a preferential astrocytic metabolite, was used, a significant increase in 13C-labeled glutamate was observed in slices from AU rats. Taken together, the data suggest that resting state neural metabolism and GLU-GLN cycling may be preserved during aging when sufficient extracellular glucose is available, but that enhanced astroglial metabolism can occur under resting state conditions. This may be an aging-related compensatory change to maintain hippocampus-dependent cognitive function. [ABSTRACT FROM AUTHOR]

Highlights • Healthy older adults learn environmental layout less well than younger adults. • Older adults have difficulty in learning a large-scale space from multiple views. • This change very likely stems from functional decline of the medial temporal lobe. Abstract It has been suggested that older adults suffer a greater degree of decline in environmental learning when navigating in an environment than when reading a map of the environment. However, the two types of spatial learning differ not only in perspectives (i.e., navigation is done with a ground-level perspective; a map is read from an aerial perspective) but also in orientations (i.e., orientations vary during navigation; spatial information is drawn from a single orientation in a map), making it unclear which factor critically affects older adults' spatial learning. The present study addressed this issue by having younger and older participants learn the layout of a large-scale environment through an aerial movie that contained changes in orientations from which the environment was depicted. Results showed that older participants' memories for the environmental layout were as distorted as those created through a ground-level movie (which involved the same orientation changes), whereas they formed more accurate memories through another aerial movie in which an orientation was fixed. By contrast, younger participants learned the environment equally well from the three movies. Taken together, these findings suggest that there is age-related alteration specifically in the ability to process multiple orientations of an environment while encoding its layout in memory. It is inferred that this alteration stems from functional deterioration of the medial temporal lobe, and possibly that of posterior cingulate areas as well (e.g., the retrosplenial cortex), in late adulthood. [ABSTRACT FROM AUTHOR]

In rats, learning and memory performance decline during normal aging, which makes this rodent species a suitable model to evaluate therapeutic strategies. In aging rats, insulin-like growth factor-I (IGF-I), is known to significantly improve spatial memory accuracy as compared to control counterparts. A constellation of gene expression changes underlie the hippocampal phenotype of aging but no studies on the effects of IGF-I on the hippocampal transcriptome of old rodents have been documented. Here, we assessed the effects of IGF-I gene therapy on spatial memory performance in old female rats and compared them with changes in the hippocampal transcriptome. In the Barnes maze test, experimental rats showed a significantly higher exploratory frequency of the goal hole than controls. Hippocampal RNA-sequencing showed that 219 genes are differentially expressed in 28-month-old rats intracerebroventricularly injected with an adenovector expressing rat IGF-I as compared with placebo adenovector-injected counterparts. From the differentially expressed genes, 81 were down and 138 upregulated. From those genes, a list of functionally relevant genes, concerning hippocampal IGF-I expression, synaptic plasticity as well as neuronal function was identified. Our results provide an initial glimpse at the molecular mechanisms underlying the neuroprotective actions of IGF-I in the aging brain. [ABSTRACT FROM AUTHOR]

Objectives:This study aimed to assess the efficacy of a route-learning training in a group of older adults living in a residential care home. We verified the presence of training-specific effects in tasks similar to those trained – route-learning tasks – as well as transfer effects on related cognitive processes – visuo-spatial short-term memory (VSSTM; Corsi Blocks Test (CBT), forward version), visuo-spatial working memory (VSWM; CBT, backward version; Pathway Span Tasks; Jigsaw Puzzle Test) – and in self-report measures. The maintenance of training benefits was examined after 3 months. Method:Thirty 70–90-year-old residential care home residents were randomly assigned to the route-learning training group or to an active control group (involved in non-visuo-spatial activities). Results:The trained group performed better than the control group in the route-learning tasks, retaining this benefit 3 months later. Immediate transfer effects were also seen in visuo-spatial span tasks (i.e., CBT forward and backward version and Pathway Span Task); these benefits had been substantially maintained at the 3-month follow-up. Conclusion:These findings suggest that a training on route learning is a promising approach to sustain older adults’ environmental learning and some related abilities (e.g., VSSTM and VSWM), even in residential care home residents. [ABSTRACT FROM AUTHOR]

Cognitive changes that occur during mid-life and beyond are linked to both aging and the menopause transition. Studies in women suggest that the age at menopause onset can impact cognitive status later in life; yet, little is known about memory changes that occur during the transitional period to the postmenopausal state. The 4-vinylcyclohexene diepoxide (VCD) model simulates transitional menopause in rodents by depleting the immature ovarian follicle reserve and allowing animals to retain their follicle-deplete ovarian tissue, resulting in a profile similar to the majority of perimenopausal women. Here, Vehicle or VCD treatment was administered to ovary-intact adult and middle-aged Fischer-344 rats to assess the trajectory of cognitive change across time with normal aging and aging with transitional menopause via VCD-induced follicular depletion, as well as to evaluate whether age at the onset of follicular depletion plays a role in cognitive outcomes. Animals experiencing the onset of menopause at a younger age exhibited impaired spatial memory early in the transition to a follicle-deplete state. Additionally, at the mid- and post- follicular depletion time points, VCD-induced follicular depletion amplified an age effect on memory. Overall, these findings suggest that age at the onset of menopause is a critical parameter to consider when evaluating learning and memory across the transition to reproductive senescence. From a translational perspective, this study illustrates how age at menopause onset might impact cognition in menopausal women, and provides insight into time points to explore for the window of opportunity for hormone therapy during the menopause transition period. Hormone therapy during this critical juncture might be especially efficacious at attenuating age- and menopause- related cognitive decline, producing healthy brain aging profiles in women who retain their ovaries throughout their lifespan. [ABSTRACT FROM AUTHOR]

Both chronological aging and chronic hypoxia stress have been reported to cause degeneration of hippocampal CA3 neurons and spatial memory impairment through independent pathways. However, the possible occurrence of precocious biological aging on exposure to single episode of global hypoxia resulting in impairment of learning and memory remains to be established. The present study thus aimed at bridging this gap in existing literature on hypoxia induced biological aging. Male Sprague Dawley rats were exposed to simulated hypobaric hypoxia (25,000 ft) for different durations and were compared with aged rats. Behavioral studies in Morris Water Maze showed decline in learning abilities of both chronologically aged as well as hypoxic rats as evident from increased latency and pathlength to reach target platform. These behavioral changes in rats exposed to global hypoxia were associated with deposition of lipofuscin and ultrastructural changes in the mitochondria of hippocampal neurons that serve as hallmarks of aging. A single episode of chronic hypobaric hypoxia exposure also resulted in the up-regulation of pro-aging protein, S100A9 and down regulation of Tau, SNAP25, APOE and Sod2 in the hippocampus similar to that in aged rats indicating hypoxia induced accelerated aging. The present study therefore provides evidence for role of biological aging of hippocampal neurons in hypoxia induced impairment of learning and memory. [ABSTRACT FROM AUTHOR]

Maternal inflammation during pregnancy can elevate the risk of neurodegenerative disorders in offspring. However, how it affects age-related impairments of spatial learning and memory and changes in the neurobiological indictors in the offspring in later adulthood is still elusive. In this study, the CD-1 mice with maternal gestational inflammation due to receiving lipopolysaccharide (LPS, i.p. 50 or 25 μg/kg) were divided into 3-, 12-, 18-, and 22-month-old groups. The spatial learning and memory were evaluated using a six-radial arm water maze and the levels of presynaptic proteins (synaptotagmin-1 and syntaxin-1) and histone acetylation (H3K9ac and H4K8ac) in the dorsal hippocampus were detected using the immunohistochemical method. The results indicated that there were significant age-related impairments of spatial learning and memory, decreased levels of H4K8ac, H3K9ac, and syntaxin-1, and increased levels of synaptotagmin-1 in the offspring mice from 12 months old to 22 months old compared to the same-age controls. Maternal LPS treatment significantly exacerbated the offspring impairments of spatial learning and memory, the reduction of H3K9ac, H4K8ac, and syntaxin-1, and the increment of synaptotagmin-1 from 12 months old to 22 months old compared to the same-age control groups. The changes in the neurobiological indicators significantly correlated with the impairments of spatial learning and memory. Furthermore, this correlation, besides the age and LPS-treatment effects, also showed a dose-dependent effect. Our results suggest that maternal inflammation during pregnancy could exacerbate age-related impairments of spatial learning and memory, and neurobiochemical indicators in the offspring CD-1 mice from midlife to senectitude. [ABSTRACT FROM AUTHOR]

N-methyl-D-aspartate (NMDA) receptors, a family of L-glutamate receptors, play an important role in learning and memory, and are critical for spatial memory. These receptors are tetrameric ion channels composed of a family of related subunits. One of the hallmarks of the aging human population is a decline in cognitive function; studies in the past couple of years have demonstrated deterioration in NMDA receptor subunit expression and function with advancing age. However, a direct relationship between impaired memory function and a decline in NMDA receptors is still ambiguous. Recent studies indicate a link between an age-associated NMDA receptor hypofunction and memory impairment and provide evidence that age-associated enhanced oxidative stress might be contributing to the alterations associated with senescence. However, clear evidence is still deficient in demonstrating the underlying mechanisms and a relationship between age-associated impaired cognitive faculties and NMDA receptor hypofunction. The current review intends to present an overview of the research findings regarding changes in expression of various NMDA receptor subunits and deficits in NMDA receptor function during senescence and its implication in age-associated impaired hippocampal-dependent memory function. [ABSTRACT FROM AUTHOR]

Previously, it has been shown that strawberry (SB) or blueberry (BB) supplementations, when fed to rats from 19 to 21 months of age, reverse age-related decrements in motor and cognitive performance. We have postulated that these effects may be the result of a number of positive benefits of the berry polyphenols, including decreased stress signalling, increased neurogenesis, and increased signals involved in learning and memory. Thus, the present study was carried out to examine these mechanisms in aged animals by administering a control, 2 % SB- or 2 % BB-supplemented diet to aged Fischer 344 rats for 8 weeks to ascertain their effectiveness in reversing age-related deficits in behavioural and neuronal function. The results showed that rats consuming the berry diets exhibited enhanced motor performance and improved cognition, specifically working memory. In addition, the rats supplemented with BB and SB diets showed increased hippocampal neurogenesis and expression of insulin-like growth factor 1, although the improvements in working memory performance could not solely be explained by these increases. The diverse polyphenolics in these berry fruits may have additional mechanisms of action that could account for their relative differences in efficacy. [ABSTRACT FROM PUBLISHER]

Brain-derived neurotrophic factor (BDNF) is a crucial mediator of neural plasticity and, consequently, of memory formation. In hippocampus-dependent learning tasks BDNF also seems to play an essential role. However, there are conflicting results concerning the spatial learning ability of aging BDNF +/− mice in the Morris water maze paradigm. To evaluate the effect of chronic BDNF deficiency in the hippocampus on spatial learning throughout life, we conducted a comprehensive study to test differently aged BDNF +/− mice and their wild type littermates in the Morris water maze and to subsequently quantify their hippocampal BDNF protein levels as well as expression levels of TrkB receptors. We observed an age-dependent learning deficit in BDNF +/− animals, starting at seven months of age, despite stable hippocampal BDNF protein expression and continual decline of TrkB receptor expression throughout aging. Furthermore, we detected a positive correlation between hippocampal BDNF protein levels and learning performance during the probe trial in animals that showed a good learning performance during the long-term memory test. [ABSTRACT FROM AUTHOR]

Age-related cognitive impairments are particularly prevalent in forms of learning that require a functionally intact hippocampal formation, such as spatial and declarative learning. However, there is notable heterogeneity in the cognitive abilities of aged subjects. To date, few studies have determined whether age-related impairments on one learning task relate to impairments on different learning tasks that engage overlapping cognitive processes. Here, we hypothesized that aged animals that were impaired on 1 hippocampal-dependent behavioral procedure would be impaired on a second hippocampal-dependent procedure. Conversely, aged animals that were unimpaired on 1 hippocampal-dependent task would be unimpaired with a subsequent hippocampal-dependent form of learning. To test these hypotheses, we trained young (2-3 months old) and aged (28-29 months old) F344XBN male rats with trace eyeblink conditioning, followed by the Morris water maze. Half of aged rats were impaired during trace conditioning. Nearly half of aged animals were also impaired during water maze probe testing. Performance during trace conditioning correlated with performance during water maze testing in aged animals. Further analyses revealed that, as a group, aged animals that were impaired on 1 hippocampal-dependent task were impaired on both tasks. Conversely, aged animals that were unimpaired on 1 task were unimpaired on both tasks. Together, these results suggest that aged-related impairments on 1 hippocampal-dependent task predict age-related impairments on a second hippocampal-dependent procedure. These results have implications for assigning personalized therapeutics to ameliorate age-related cognitive decline. [ABSTRACT FROM AUTHOR]

Aging is associated with progressive changes in learning and memory. A potential approach to attenuate age-related cognitive decline is cognitive training. In this study, adult male and female rats were given either repeated exposure to a T-maze, or no exposure to any maze, and then tested on a final battery of cognitive tasks. Two groups of each sex were tested from 6 to 18 months old on the same T-maze; Group one received a version testing spatial reference memory, and Group two received only the procedural testing components with minimal cognitive demand. Groups three and four of each sex had no maze exposure until the final battery, and were comprised of aged or young rats, respectively. The final maze battery included the practiced T-maze plus two novel tasks, one with a similar, and one with a different, memory type to the practice task. Group five of each sex was not maze tested, serving as an aged control for the effects of maze testing on neurotrophin protein levels in cognitive brain regions. Results showed that adult intermittent cognitive training enhanced performance on the practice task when aged in both sexes, that cognitive training benefits transferred to novel tasks only in females, and that cognitive demand was necessary for these effects, since rats receiving only the procedural testing components showed no improvement on the final maze battery. Further, for both sexes, rats that showed faster learning when young demonstrated better memory when aged. Age-related increases in neurotrophin concentrations in several brain regions were revealed, which were related to performance on the training task only in females. This longitudinal study supports the tenet that cognitive training can help one remember later in life, with broader enhancements and associations with neurotrophins in females. [ABSTRACT FROM AUTHOR]

Abstract: Aged non-human primates may have deficits in a variety of cognitive functions. However, it is possible that at least some age-related performance deficits relate to a deficit in initial task learning. To assess this, aged rhesus monkeys were trained to perform a Self-Ordered Spatial Search (SOSS) task using the same training and testing parameters used previously with normal young animals. Aged animals failed to reach criterion at the easiest task level. In an attempt to improve learning, a group of aged animals were first trained on SOSS using a standard 5s ITI, followed by trials with low inter-trial interference (e.g., a stimulus used in a trial would not be used again for the next 2 trials) or with trials in which the spatial distance between the stimuli on the screen was maximized. Because performance improved but failed to reach criterion, this was followed by sessions with increasing ITIs (from 5s to 10 or 15s). Only increasing the ITI improved the performance of the aged animals enough to allow them to learn the task to criterion. Once the criterion was reached, memory was taxed by increasing the delay between stimulus presentations and increasing the number of spatial positions to be remembered. Performance declined for young animals, but even more so for aged animals. The results of the present study suggests that aged primates have difficulty initially learning a complex working memory task, and that the ITI may be an important parameter to manipulate to improve learning. However, once the task is learned, performance of aged animals is inferior to that of young animals, particularly when memory demands are increased. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

Abstracts from the conference "Effects of Traumatic Stress: Molecular and Hormonal Mechanism," held in New York, September 11–14, 2012 are presented.

Spatial learning impairment in aged rats is associated with changes in hippocampal connectivity and plasticity. Several studies have explored the age-related deficit in spatial information processing by recording the location-specific activity of hippocampal neurons (place cells). However, these studies have generated disparate characterizations of place cells in aged rats as unstable (Barnes et al., 1997), resistant to change (Tanila et al., 1997b; Oler and Markus, 2000; Wilson et al., 2003), or delayed in using external cues (Rosenzweig et al., 2003). To reconcile these findings, we recorded place cells from aged and young rats as they repeatedly explored both a highly familiar environment and an initially novel environment, and we repeatedly tested whether the place fields formed in the novel environment were anchored by external cues. Initially, spatial representations in aged rats were abnormally maintained between the familiar and novel environments. Then, new representations were formed but were also delayed in becoming anchored to the external landmarks. Finally, even when the new spatial representations became bound to the landmarks, they were multi-stable across repetitive exposures to the formerly novel environment. These observations help to reconcile previously divergent characterizations of spatial representation in aged rats and suggest a model of cognitive aging and hippocampal function. [ABSTRACT FROM AUTHOR]

Basal forebrain cholinergic neurons are important for spatial learning in rodents. Spatial learning ability is reportedly better in males than females, and declines with age. To examine the role of cholinergic function in sex- or age-related differences in spatial learning, we compared the size of basal forebrain cholinergic neurons (BFCN) of young and aged male and female Fischer 344 (F344) rats that had been trained in the Morris water maze. Young male and female rats were equally proficient in finding the platform during training trials, but probe tests revealed that young male rats had better knowledge of the platform''s precise location. Impairments in spatial learning were observed in aged rats, and the advantage of males over females was lost. BFCN were significantly larger in young male than young female rats, and were correlated with spatial memory performance for both groups. BFCN were smaller in aged than young males; no change was seen between young and aged females. In the groups of aged rats the correlation between neuron size and spatial memory was lost. The present findings provide further evidence of a role for the basal forebrain cholinergic system in spatial learning, but reveal a complex interaction between sex, age and behavioral performance. [Copyright &y& Elsevier]

This study was designed to investigate beneficial effects of swimming exercise training on learning/memory, synaptic plasticity and CREB (cAMP response element binding protein) expression in hippocampus in a rat model of d-galactose-induced aging (DGA). Eighty adult male rats were randomly divided into four groups: Saline Control (group C), DGA (group A), Swimming exercise before DGA (group S1), and Swimming during DGA (group S2). These four groups of animals were further divided into Morris water maze training group (M subgroup) and sedentary control group (N subgroup). Spatial learning/memory was tested using Morris water maze training. The number and density of synaptophysin (Syp) and metabotropic glutamate receptor 1 (mGluR1) in hippocampal dentate gyrus area, CREB mRNA and protein expression and DNA methylation levels were determined respectively with immunohistochemistry, western blot, real-time PCR, and MassArray methylation detection platform. We found that compared with group C, DGA rats showed aging-like poor health and weight loss as well as hippocampal neurodegenerative characteristics. Exercise training led to a time-dependent decrease in average escape latency and improved spatial memory. Exercise training group (S2M) had significantly increased swim distance as compared with controls. These functional improvements in S2M group were associated with higher Syp and mGluR1 values in hippocampus (p < 0.01) as well as higher levels of hippocampal CREB protein/mRNA expression and gene methylation. In conclusion, swimming exercise training selectively during drug-induced aging process protected hippocampal neurons against DGA-elicited degenerative changes and in turn maintained neuronal synaptic plasticity and learning/memory function, possibly through upregulation of hippocampal CREB protein/mRNA and reduction of DGA-induced methylation of CREB. [ABSTRACT FROM AUTHOR]