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

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.

Examination of the role of the pedunculopontine tegmental nucleus in radial maze tasks with or without a delay.

Two radial maze tasks, random foraging and delayed spatial win-shift, have been used to investigate, in rats, the functions and inter-relationships of structures connected through the corticostriatal loops, such as the prelimbic cortex, nucleus accumbens, ventral pallidum and mediodorsal thalamus. The random foraging task is designed to investigate animals' ability to use spatial information to guide foraging on-line. The delayed spatial win-shift task requires, in addition, that animals hold spatially relevant information in working memory across a delay period. The pedunculopontine tegmental nucleus receives direct output from ventral striatal systems and might therefore be expected to share functional properties with them. In the present experiments we have examined the performance of rats bearing bilateral excitotoxic lesions of the pedunculopontine tegmental nucleus on both of these tasks. In acquisition tests rats were given bilateral lesions before any training took place, while in retention tests appropriate training to predetermined criterion levels of performance took place before lesions were made. In both tasks, and in both acquisition (no prelesion training) and retention (prelesion training) tests, rats with pedunculopontine lesions made significantly more errors in selecting arms to enter than did control rats. There was no motor impairment present in pedunculopontine tegmental nucleus-lesioned rats - on the contrary, on measures of speed (latency to make first arm choice and the mean time for subsequent choices) pedunculopontine-lesioned rats were slightly faster than control rats. We suggest that the pedunculopontine tegmental nucleus shares functional properties with frontostriatal systems and that it forms part of a brainstem-directed stream of striatal outflow different to the cortical re-entrant system via the thalamus.