げっ歯類を用いた高次脳機能評価法開発と環境化学物質の神経毒性評価への適用

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  • 掛山 正心
    東京大学大学院医学系研究科疾患生命工学センター・健康環境医工学部門 早稲田大学人間科学学術院予防医科学・応用生理学研究室

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  • Development of Higher Brain Function Tests in Rodents and Its Application to Neurotoxicity Assessment of Environmental Chemicals
  • 奨励賞受賞論文 げっ歯類を用いた高次脳機能評価法開発と環境化学物質の神経毒性評価への適用
  • ショウレイショウ ジュショウ ロンブン ゲッシルイ オ モチイタ コウジ ノウ キノウ ヒョウカホウ カイハツ ト カンキョウ カガク ブッシツ ノ シンケイ ドクセイ ヒョウカ エ ノ テキヨウ

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The brain during developmental period is thought to be highly sensitive to environmental insults including exposure to chemicals. However, it has been extremely difficult to detect and assess the features and degree of adversity particularly at low exposure levels. I describe here the effects of maternal exposure to dioxin on higher brain functions later in life, which we detected using our originally developed behavioral tests for quantifying higher brain functions in rodents. We first found changes in the mRNA expression levels of glutamate NMDA receptor subunits that have critical roles in learning and memory function in the neocortex and hippocampus. To assess the neocortical and hippocampal functions in rats, we established novel behavioral tests for assessing paired-associate learning, which is the hippocampal and medial prefrontal NMDA-dependent function. Maternal exposure to dioxin, at a low level of which does not affect simple memory formation, resulted in the disturbance of the paired-associate learning. On the basis of the above learning paradigm, we next developed a behavioral flexibility task and a social competitive task for mice using the automated behavioral assessment system ‘IntelliCage’: this system can accommodate 16 mice at the same time to monitor and record their behavior. Using this system, we found that male mice born to dams exposed to very low doses of dioxin showed inflexibility in a serial reversal learning task and socially low-dominance behavior under a competitive situation. Immunohistochemical analysis of putative neuronal activity markers revealed hypoactivity in the medial prefrontal cortex (mPFC) of dioxin-exposed mice. We speculate that mPFC hypoactivity reflects the dioxin-induced higher brain dysfunction and may be associated with some psychiatric illnesses and related problems. These behavioral tests were found to be useful for studying the higher brain functions of rats and mice.

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