Exercise Enhances Learning and Hippocampal Neurogenesis in Aged Mice

Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 10/2005; 25(38):8680-5. DOI: 10.1523/JNEUROSCI.1731-05.2005
Source: PubMed


Aging causes changes in the hippocampus that may lead to cognitive decline in older adults. In young animals, exercise increases hippocampal neurogenesis and improves learning. We investigated whether voluntary wheel running would benefit mice that were sedentary until 19 months of age. Specifically, young and aged mice were housed with or without a running wheel and injected with bromodeoxyuridine or retrovirus to label newborn cells. After 1 month, learning was tested in the Morris water maze. Aged runners showed faster acquisition and better retention of the maze than age-matched controls. The decline in neurogenesis in aged mice was reversed to 50% of young control levels by running. Moreover, fine morphology of new neurons did not differ between young and aged runners, indicating that the initial maturation of newborn neurons was not affected by aging. Thus, voluntary exercise ameliorates some of the deleterious morphological and behavioral consequences of aging.

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    • "The effect of age on spatial memory has been intensively studied using the Barnes maze task[78]and the Morris water maze task (for review, see[79]) in rats and mice. The spatial memory deficit in the water maze task has been found in C57BL/6 mice aged approximately above 12 months808182838485. However, since this task requires animals to have the ability and motivation to swim, the group differences in memory performance might be due to differences in swimming ability[86]. "
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    ABSTRACT: Aging is considered to be associated with progressive changes in the brain and its associated sensory, motor, and cognitive functions. A large number of studies comparing young and aged animals have reported differences in various behaviors between age-cohorts, indicating behavioral dysfunctions related to aging. However, relatively little is known about behavioral changes from young adulthood to middle age, and the effect of age on behavior during the early stages of life remains to be understood. In order to investigate age-related changes in the behaviors of mice from young adulthood to middle age, we performed a large-scale analysis of the behavioral data obtained from our behavioral test battery involving 1739 C57BL/6J wild-type mice at 2–12 months of age. Significant behavioral differences between age groups (2–3-, 4–5-, 6–7-, and 8–12-month-old groups) were found in all the behavioral tests, including the light/dark transition, open field, elevated plus maze, rotarod, social interaction, prepulse inhibition, Porsolt forced swim, tail suspension, Barnes maze, and fear conditioning tests, except for the hot plate test. Compared with the 2–3-month-old group, the 4–5- and 6–7-month-old groups exhibited decreased locomotor activity to novel environments, motor function, acoustic startle response, social behavior, and depression-related behavior, increased prepulse inhibition, and deficits in spatial and cued fear memory. For most behaviors, the 8–12-month-old group showed similar but more pronounced changes in most of these behaviors compared with the younger age groups. Older groups exhibited increased anxiety-like behavior in the light/dark transition test whereas those groups showed seemingly decreased anxiety-like behavior measured by the elevated plus maze test. The large-scale analysis of behavioral data from our battery of behavioral tests indicated age-related changes in a wide range of behaviors from young adulthood to middle age in C57BL/6J mice, though these results might have been influenced by possible confounding factors such as the time of day at testing and prior test experience. Our results also indicate that relatively narrow age differences can produce significant behavioral differences during adulthood in mice. These findings provide an insight into our understanding of the neurobiological processes underlying brain function and behavior that are subject to age-related changes in early to middle life. The findings also indicate that age is one of the critical factors to be carefully considered when designing behavioral tests and interpreting behavioral differences that might be induced by experimental manipulations.
    Full-text · Article · Dec 2016 · Molecular Brain
    • "Firstly, it is well established that exercise confers pro-neurogenic and pro-cognitive effects in the aging brain. Both voluntary and forced running during middle and later age have been shown to increase hippocampal neurogenesis (Kronenberg et al., 2006; Marlatt et al., 2012; van Praag et al., 2005; Wu et al., 2008), dendrite length (Wu et al., 2008), hippocampal BDNF protein levels (Gibbons et al., 2014; Marlatt et al., 2012; Wu et al., 2008) and to improve performance in hippocampus-dependent memory tasks (Gibbons et al., 2014; Marlatt et al., 2012; Siette et al., 2013; van Praag et al., 2005) in animals. However, exercise did not confer significant improvements in the ability of aged mice (22 months) to perform a spatial pattern separation task which is believed to be neurogenesis-dependent (Creer et al., 2010); it may be that at this age the exercise intervention is too late to alter the pattern separation abilities. "
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    ABSTRACT: Adult hippocampal neurogenesis is believed to be integral for certain forms of learning and memory. Dysregulation of hippocampal neurogenesis has been shown to be an important mechanism underlying the cognitive impairment associated with normal aging, as well as the cognitive deficits evident in preclinical models of Alzheimer's disease and other neurodegenerative diseases. Neuroinflammation is a significant pathological feature of these conditions; it contributes to the observed cognitive decline, and recent evidence demonstrates that it also negatively affects hippocampal neurogenesis. Conversely, during the past twenty years, it has been robustly shown that exercise is a potent inducer of hippocampal neurogenesis, and it is believed that the positive beneficial effect of exercise on cognitive function is likely due to its pro-neurogenic effects. However, the interplay between exercise- and neuroinflammatory-induced changes in hippocampal neurogenesis and associated cognitive function has only recently begun to receive attention. Here we review the current literature on exercise-induced effects on hippocampal neurogenesis, cognitive function and neuroinflammation, and consider exercise as a potential pro-neurogenic and anti-inflammatory intervention for cognition.
    No preview · Article · Dec 2015 · Neuroscience & Biobehavioral Reviews
    • "In contrast, decreased neurogenesis, such as happens with brain radiation (for cancer treatment) or brain aging, is associated with cognitive impairments [18] [19] [20]. Exercise has been shown to be an effective means by which to enhance hippocampal neurogenesis in animal models of these conditions [21] [22]. However, both the aged and cancer survivors may have mobility limitations that decrease their capacity to reap the brain benefits of exercise . "
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    ABSTRACT: Many of the neural benefits of exercise require weeks to manifest. It would be useful to accelerate onset of exercise-driven plastic changes, such as increased hippocampal neurogenesis. Exercise represents a significant challenge to the brain because it produces heat, but brain temperature does not rise during exercise in the cold. This study tested the hypothesis that exercise in cold ambient temperature would stimulate hippocampal neurogenesis more than exercise in room or hot conditions. Adult female rats had exercise access 2hours per day for 5 days at either room (20°C), cold (4.5°C) or hot (37.5°C) temperature. To label dividing hippocampal precursor cells, animals received daily injections of BrdU. Brains were immunohistochemically processed for dividing cells (Ki67+), surviving cells (BrdU+) and new neurons (doublecortin, DCX) in the hippocampal dentate gyrus. Animals exercising at room temperature ran significantly farther than animals exercising in cold or hot conditions (room 1490 ± 400 meters; cold 440 ± 102 meters; hot 291 ± 56 meters). We therefore analyzed the number of Ki67+, BrdU+ and DCX+ cells normalized for shortest distance run. Contrary to our hypothesis, exercise in either cold or hot conditions generated significantly more Ki67+, BrdU+ and DCX+ cells compared to exercise at room temperature. Thus, a limited amount of running in either cold or hot ambient conditions generates more new cells than a much greater distance run at room temperature. Taken together, our results suggest a simple means by which to augment exercise effects, yet minimize exercise time.
    No preview · Article · Nov 2015 · Behavioural brain research
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