Elsevier

Neuroscience

Volume 117, Issue 2, 21 March 2003, Pages 417-425
Neuroscience

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

https://doi.org/10.1016/S0306-4522(02)00805-9Get rights and content

Abstract

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.

Section snippets

Subject characteristics and sample size

Male and female offspring of three Harlan Sprague–Dawley rats were studied. All protocols and procedures were approved by the local Institutional Animal Care and Use Committee. A 12-h light/dark cycle (lights on at 0700 h) was maintained throughout the study, food and water were provided ad libitum unless otherwise stated. Power analyses were used to determined appropriate sample sizes necessary to achieve a minimum statistical power (0.85, α=0.05) for comparisons of sleep–wake architecture,

Statistical analyses

One experimental group (post-hypoxic rats) and two parallel control groups (normoxic rats and unhandled rats) were included in the experimental paradigm. Statistical analyses were performed using the software program SPSS, version 10.0.5 (Chicago, IL, USA). One-way analysis of variance with Bonferroni and Tukey post-hoc analyses was performed to examine differences in behavioral and neurochemical traits between post-hypoxic, normoxic, and unhandled rats. Both normoxic and unhandled rat values

Gender effects

No gender-related differences were identified in either control or post-hypoxic rats with regards to values of sleep–wake architecture, measures of locomotor activity, or RAM performance. Expression of VMAT2 and TH proteins, however, were significantly greater in the striatum of female control rats than in male control rats. These differences are described in detail in the results section of Western blot analyses.

Sleep–wake architecture

Sleep–wake architecture differed between post-hypoxic and control rats.

Discussion

The aim of this study was to determine if intermittent hypoxic insults, occurring during a period of critical brain development, would disrupt the functional integrity of the mesotelencephalic DA system and evoke behavioral and cognitive deficiencies. We demonstrate that rats exposed to intermittent hypoxic insults between PN 7 and 11, a developmental period comparable to the preterm human born between 32 and 36 weeks of gestation (Romijn et al., 1991), lead to increased sleep, locomotor

Acknowledgements

This work is supported by HL-72722 and the Department of Neurology, Emory University (M.J.D.), NS-36695 and NS-40221 (D.B.R.).

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