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Neuroscience. 2003;117(2):417-25.

Episodic neonatal hypoxia evokes executive dysfunction and regionally specific alterations in markers of dopamine signaling.

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Emory University School of Medicine, Department of Neurology, Woodruff Memorial Research Building, Suite 6000, 1639 Pierce Drive, Atlanta, GA 30322, USA.


Perinatal ischemic-anoxic and prolonged anoxic insults lead to impaired dopaminergic signaling and are hypothesized to contribute, at least in part, to the pathogenesis of disorders of minimal brain dysfunction such as attention-deficit hyperactivity disorder. We hypothesized that subtle intermittent hypoxic insults, occurring during a period of critical brain development, are also pathogenic to dopaminergic signaling, thereby contributing to behavioral and executive dysfunction. Between postnatal days 7 and 11, rat pups were exposed to either 20-s bursts of isocapnic hypoxic gas, compressed air, or were left undisturbed with the dam. On postnatal days 23 pups were instrumented with electroencephalographic/electromyographic electrodes and sleep-wake architecture was characterized. Locomotor activity was assessed between postnatal days 35 and 38, learning, and working memory evaluated between postnatal days 53 and 64. Rats were killed on postnatal day 80 and tyrosine hydroxylase, vesicular monoamine transporter, dopamine transporter, and dopamine D1 receptors were quantified in the prefrontal cortex, primary sensorimotor cortex, and precommissural striatum by Western blot analyses. Post-hypoxic pups spent less time awake and more time in rapid-eye-movement sleep during the lights-on phase of the circadian cycle, were hyperlocomotive, and expressed impaired working memory. Striatal expression of vesicular monoamine transporter and D1 receptor proteins were increased in post-hypoxic rats, consistent with depressed dopaminergic signaling. These observations lead to the intriguing hypothesis that intermittent hypoxia occurring during a period of critical brain development evokes behavioral and neurochemical alterations that are long lasting, and consistent with disorders of minimal brain dysfunction.

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