Hippocampus-dependent spatial memory impairment due to molar tooth loss is ameliorated by an enriched environment
Introduction
Teeth are not only crucial for mastication, but play an essential role in overall nutrition and general health (Zhang, Du, Zhou, & Yu, 2014). Aging, poor oral care, and injury may lead to tooth loss. The prevalence of tooth loss increases with age, peaking at 65 years of age. A recent study reported that the mean number of teeth of American adults over 65 years of age is only 19 (Kassebaum et al., 2014). Tooth loss in adults is associated with an increased risk for obesity, diabetes, cardiovascular diseases, certain types of cancer, and Alzheimer’s disease (Hung et al., 2004). Due to the aging population worldwide, Alzheimer’s disease has become an increasingly important health and socioeconomic issue.
In mice and rats, molar extraction decreases the masticatory function. Chronic stress due to decreased mastication resulting from tooth loss inhibits hippocampal neurogenesis and impairs learning and memory (Kubo, Iwata, Watanabe, Fujita, & Onozuka, 2005; Onozuka et al., 1999). The hippocampus is involved in learning and memory (Amenta, Collier, & Zaccheo, 1991). The dentate gyrus (DG) of aging hippocampus exhibits alterations in neurogenesis (Ono, Yamamoto, Kubo, Onozuka, 2010). Granule neurons in the DG are produced throughout adulthood in animals and play a significant role in retention of hippocampus-dependent learning and memory (Hastings & Gould, 1999). Neurogenesis in the hippocampal DG is susceptible to various hormonal and environmental stimuli, such as glucocorticoids and stress (Fuchs & Flugge, 1998), physical activity (van Praag, Kempermann, & Gage, 1999), and learning (Kempermann, Brandon, & Gage, 1998).
Epidemiologic data indicate that physical and intellectual activity may delay the onset of dementia and Alzheimer's disease (Larson et al., 2006). The molecular mechanisms underlying the effects of physical and intellectual activity in maintaining cognitive health, however, are unclear, despite a vast literature on experience-dependent changes in the brain at the subcellular, biochemical, and molecular levels (Rosenweig & Berrett, 1996). The hippocampus is of particular interest in this context due to its importance for higher cognitive functions, especially learning and memory, and its pivotal involvement in degenerative disorders of the aging brain. An enriched Environment refers to housing conditions, in which animals are exposed to higher levels of sensory, motor, social, and cognitive stimuli compared to a normal cage environment (Veena et al., 2009). An enriched environment affects rodent brains at the molecular, cellular, and behavioral levels. Brain-derived neurotrophic factor (BDNF) is widely expressed in both the developing and adult brain and is essential for the survival of various populations of neurons during development (Kernie, Liebel, & Parada, 2000; Linnarsson, Willson, & Ernfors, 2000). Hippocampal BDNF levels are increased by enriched environment are associated with neurogenesis (Falkenberg et al., 1992). In addition, exposure to an enriched environment attenuates stress-induced neuronal degeneration and impaired cell proliferation in the hippocampus (Veena et al., 2009).
As the functional morphology of the hippocampus is influenced by tooth loss and enriched environment, we hypothesized that an enriched environment would improve the impaired hippocampal function induced by the molarless condition in aged SAMP8 mice.
Section snippets
Animals and experimental protocol
SAMP8 mice (8-months old; n = 80) were used in this study. Senescence-accelerated mice have a mean lifespan of 12 months (Takeda et al., 1999) and, in addition to accelerated senescence, exhibit age-associated pathologies such as learning and memory deficits and brain atrophy (Takeda et al., 1999), making them good animal model for human cognitive diseases associated with age (Takeda et al., 1999). The mice were group-housed with a 12:12 h light/dark cycle (light period, 6:00–18:00) under
Water maze performance
All mice demonstrated improved performance during acquisition as indicated by the reduced mean escape latency over the 7 days of training [F (6, 19) = 5.848, P < 0.01; Fig. 1]. Molarless mice had significantly longer escape latencies than molar-intact mice [F (1, 24) = 0.9400, P < 0.01]. Escape latencies of mice housed in the enriched environment were significantly shorter than those of mice housed in the standard environment [F (1, 24) = 0.2427, P < 0.05]. The interaction between the two factors, tooth
Discussion
Removing the molars of aged SAMP8 mice significantly reduced cell proliferation, newborn cell survival, and cell differentiation in the hippocampal DG, and the hippocampal BDNF protein expression. In addition, the molarless condition impaired the spatial learning and memory in the Morris water maze. These findings are consistent with previous reports that stress affects neurogenesis, BDNF expression in the hippocampus, and the learning ability (Veena et al., 2009). An enriched environment,
Conflict of interest
No conflict of interest declared.
Competing interests
None declared.
Ethical approval
This study was approved by the animal care and use ethical committee of Asahi University School of Dentistry (13-021).
Acknowledgment
This work was supported by Grant-in Aid Scientific Research from the Ministry of Education, Science, and Culture of Japan (KAKENHI 245931113)
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