Development of Higher Brain Function Tests in Rodents and Its Application to Neurotoxicity Assessment of Environmental Chemicals

    Research output: Contribution to journalReview article

    Abstract

    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.

    Original languageEnglish
    Pages (from-to)120-126
    Number of pages7
    JournalNihon eiseigaku zasshi. Japanese journal of hygiene
    Volume70
    Issue number2
    Publication statusPublished - 2015

    Fingerprint

    Dioxins
    Rodentia
    Paired-Associate Learning
    Brain
    Maternal Exposure
    Prefrontal Cortex
    Serial Learning
    Learning
    Reversal Learning
    Neocortex
    Glutamate Receptors
    N-Methylaspartate
    N-Methyl-D-Aspartate Receptors
    Psychiatry
    Hippocampus
    Messenger RNA
    Behavior Rating Scale

    ASJC Scopus subject areas

    • Medicine(all)

    Cite this

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    abstract = "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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