Elsevier

Archives of Oral Biology

Volume 61, January 2016, Pages 1-7
Archives of Oral Biology

Hippocampus-dependent spatial memory impairment due to molar tooth loss is ameliorated by an enriched environment

https://doi.org/10.1016/j.archoralbio.2015.10.006Get rights and content

Highlights

  • Effect of enriched environment on tooth loss-induced learning deficits is not known.

  • Enriched environment attenuated tooth loss-induced learning deficits.

  • Enriched environment prevented tooth loss-induced suppression of neurogenesis.

  • Enriched environment ameliorated tooth loss-induced suppression of BDNF expression.

  • Enriched environment ameliorated the risk of tooth loss-induced cognitive impairment.

Abstract

Background and objective

Teeth are crucial, not only for mastication, but for overall nutrition and general health, including cognitive function. Aged mice with chronic stress due to tooth loss exhibit impaired hippocampus-dependent learning and memory. Exposure to an enriched environment restores the reduced hippocampal function. Here, we explored the effects of an enriched environment on learning deficits and hippocampal morphologic changes in aged senescence-accelerated mouse strain P8 (SAMP8) mice with tooth loss.

Design

Eight-month-old male aged SAMP8 mice with molar intact or with molars removed were housed in either a standard environment or enriched environment for 3 weeks. The Morris water maze was performed for spatial memory test. The newborn cell proliferation, survival, and differentiation in the hippocampus were analyzed using 5-Bromodeoxyuridine (BrdU) immunohistochemical method. The hippocampal brain-derived neurotrophic factor (BDNF) levels were also measured.

Results

Mice with upper molars removed (molarless) exhibited a significant decline in the proliferation and survival of newborn cells in the dentate gyrus (DG) as well as in hippocampal BDNF levels. In addition, neuronal differentiation of newly generated cells was suppressed and hippocampus-dependent spatial memory was impaired. Exposure of molarless mice to an enriched environment attenuated the reductions in the hippocampal BDNF levels and neuronal differentiation, and partially improved the proliferation and survival of newborn cells, as well as the spatial memory ability.

Conclusion

These findings indicated that an enriched environment could ameliorate the hippocampus-dependent spatial memory impairment induced by molar tooth loss.

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)

References (46)

  • M. Onozuka et al.

    Evidence for involvement of glucocorticoid response in the hippocampal changes in aged molarless SAMP8 mice

    Behavioural Brain Research

    (2002)
  • T.D. Palmer et al.

    The adult rat hippocampus contains primordial neural stem cells

    Molecular and Cellular Neurosciences

    (1997)
  • Y. Takagi et al.

    Proliferation of neuronal precursor cells in the dentate gyrus is accelerated after transient forebrain ischemia in mice

    Brain Research

    (1999)
  • Y.R. Zhang et al.

    Review of research on the mechanical properties of the human tooth

    International Journal of Oral Science

    (2014)
  • N. Benaroya-Milshtein et al.

    Environmental enrichment in mice decreases anxiety, attenuates stress responses and enhances natural killer cell activity

    European Journal of Neuroscience

    (2004)
  • D.K. Binder et al.

    Brain-derived neurotrophic factor

    Growth Factors

    (2004)
  • S.H. Choi et al.

    Regulation of hippocampal progenitor cell survival, proliferation and dendritic development by BDNF

    Molecular Neurodegeneration

    (2009)
  • K.I. Erickson et al.

    Exercise training increases size of hippocampus and improves memory

    Proceedings of the National Academy of Sciences

    (2011)
  • Y. Fan et al.

    Environmental enrichment enhances neurogenesis and improves functional outcome after cranial irradiation

    European Journal of Neuroscience

    (2007)
  • K.B. Franklin et al.

    The mouse brain in stereotaxic coordinates

    (1996)
  • E. Gould et al.

    Learning enhances adult neurogenesis in the hippocampal formation

    Nature Neuroscience

    (1999)
  • N.B. Hastings et al.

    Rapid extension of axons into the CA3 region by adult-generated granule cells

    Journal of Comparative Neurology

    (1999)
  • M. Hofer et al.

    Regional distribution of brain-derived neurotrophic factor mRNA in the adult mouse brain

    EMBO Journal

    (1990)
  • Cited by (0)

    View full text