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Prepubertal Environmental Enrichment Prevents Dopamine Dysregulation and Hippocampal Hyperactivity in MAM Schizophrenia Model Rats

  • Xiyu Zhu
    Correspondence
    Address correspondence to Xiyu Zhu, B.S.
    Affiliations
    Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania
    Search for articles by this author
  • Anthony A. Grace
    Affiliations
    Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania

    Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania

    Department of Psychology, University of Pittsburgh, Pittsburgh, Pennsylvania
    Search for articles by this author

      Abstract

      Background

      Schizophrenia (SCZ) is a neurodevelopmental disorder with a progressive, prolonged course. Early prevention for SCZ is promising but overall lacks support from preclinical evidence. Previous studies have tested environmental enrichment (EE) in certain models of SCZ and discovered a broadly beneficial effect in preventing behavioral abnormalities relevant, yet not specific, to the disorder. Nonetheless, whether EE can prevent dopamine (DA) dysregulation, a hallmark of psychosis and SCZ, had not been tested.

      Methods

      Using the MAM (methylazoxymethanol acetate) rat model of schizophrenia and saline-treated control animals, we investigated the long-term electrophysiological effects of prepubertal (postnatal day 21–40) EE on DA neurons, pyramidal neurons in the ventral hippocampus, and projection neurons in the basolateral amygdala. Anxiety-related behaviors in the elevated plus maze and locomotor responses to amphetamine were also analyzed.

      Results

      Prepubertal EE prevented the increased population activity of DA neurons and the associated increase in locomotor response to amphetamine. Prepubertal EE also prevented hyperactivity in the ventral hippocampus but did not prevent hyperactivity in the basolateral amygdala. Anxiety-like behaviors in MAM rats were not ameliorated by prepubertal exposure to EE.

      Conclusions

      Twenty-day prepubertal EE is sufficient to prevent DA hyperresponsivity in the MAM model, measured by electrophysiological recordings and locomotor response to amphetamine. This effect is potentially mediated by normalizing excessive firing in the ventral hippocampus without affecting anxiety-like behaviors and basolateral amygdala firing. This study identified EE as a useful preventative approach that may protect against the pathophysiological development of SCZ.

      Keywords

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