Exercise enhances learning and hippocampal neurogenesis in aged mice.

Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Journal of Neuroscience (Impact Factor: 6.75). 10/2005; 25(38):8680-5. DOI: 10.1523/JNEUROSCI.1731-05.2005
Source: PubMed

ABSTRACT 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.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Adolescence is a developmental period that coincides with the maturation of adult cognitive faculties. Binge drinking is common during adolescence and can impact brain maturation. Using a rodent model of adolescent intermittent ethanol (AIE; 5.0 g/kg, i.g., 20% EtOH w/v; 2 days on/2 days off from postnatal day [P]25 to P55), we discovered that AIE treatment reduced neurogenesis (i.e., doublecortin-immunoreactive [DCX + IR] cells) in both the dorsal and ventral hippocampal dentate gyrus of late adolescent (P56) male Wistar rats that persisted during abstinence into adulthood (P220). This reduction in neurogenesis was accompanied by a concomitant reduction in proliferating cells (Ki-67) and an increase in cell death (cleaved caspase-3). In the hippocampus, AIE treatment induced a long-term upregulation of neuroimmune genes, including Toll-like receptor 4 (TLR4) and its endogenous agonist high-mobility group box 1 as well as several proinflammatory signaling molecules. Administration of lipopolysaccharide, a gram-negative endotoxin agonist at TLR4, to young adult rats (P70) produced a similar reduction of DCX + IR cells that was observed in AIE-treated animals. Behaviorally, AIE treatment impaired object recognition on the novel object recognition task when assessed from P163 to P165. Interestingly, object recognition memory was positively correlated with DCX + IR in both the dorsal and ventral hippocampal dentate gyrus while latency to enter the center of the apparatus was negatively correlated with DCX + IR in the ventral dentate gyrus. Together, these data reveal that adolescent binge ethanol exposure persistently inhibits neurogenesis throughout the hippocampus, possibly through neuroimmune mechanisms, which might contribute to altered adult cognitive and emotive function.
    Frontiers in Neuroscience 02/2015; 9:35.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Exposure to chronic stress produces negative effects on mood and hippocampus-dependent memory formation. SIRT2 alteration has been reported in mood disorders; however, the role of SIRT2 in depression remains unclear. Therefore, we aimed to determine whether SIRT2 can restore stress-induced suppression of neurogenesis in a rat chronic unpredictable stress (CUS) model of depression. Sucrose preference test, home-cage locomotion, forced swim test, and elevated plus maze were used to determine the role of SIRT2 in CUS model. To further determine the hippocampal neurogenesis contributes to the role of SIRT in mediating the antidepressant-like behavior, rats were exposed to X-irradiation to disrupt the process of hippocampal neurogenesis. CUS decreased expression of the SIRT2 protein in the hippocampus. Treatment with the antidepressant fluoxetine reversed the CUS-induced SIRT2 change. Furthermore, inhibiting SIRT2 by tenovin-D3 resulted in depression-like behaviors and impaired hippocampal neurogenesis in rats. Conversely, overexpression of SIRT2 by the intra-hippocampal infusion of recombinant adenovirus vector expressing mouse SIRT2 reversed the CUS-induced depressive-like behaviors, and promoted neurogenesis. Disrupting neurogenesis in the dentate gyrus by X-irradiation abolished the antidepressant-like effect of Ad-SIRT2-GFP. These findings indicate that hippocampal SIRT2 is involved in the modulation of depressant-like behaviors, possibly by regulating neurogenesis.
    Scientific reports. 01/2015; 5:8415.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Traumatic brain injury (TBI) is ubiquitous and effective treatments for it remain supportive largely due to uncertainty over how endogenous repair occurs. Recently, we demonstrated that hippocampal injury-induced neurogenesis is one mechanism underlying endogenous repair following TBI. Donepezil is associated with increased hippocampal neurogenesis and has long been known to improve certain aspects of cognition following many types of brain injury through unknown mechanisms. By coupling donepezil therapy with temporally regulated ablation of injury-induced neurogenesis using nestin-HSV transgenic mice, we investigated whether the pro-cognitive effects of donepezil following injury might occur through increasing neurogenesis. We demonstrate that donepezil itself enhances neurogenesis and improves cognitive function following TBI, even when injury-induced neurogenesis was inhibited. This suggests that the therapeutic effects of donepezil in TBI occur separately from its effects on neurogenesis.
    PLoS ONE 01/2015; 10(2):e0118793. · 3.53 Impact Factor


Available from