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The Journal of Neuroscience, January 7, 2004, 24(1):24-34; doi:10.1523/JNEUROSCI.2816-03.2004

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Behavioral/Systems/Cognitive
Preterm Fetal Hypoxia-Ischemia Causes Hypertonia and Motor Deficits in the Neonatal Rabbit: A Model for Human Cerebral Palsy?

Matthew Derrick,¹ Ning Ling Luo,³ Joanne C. Bregman,¹ Tamas Jilling,¹ Xinhai Ji,¹ Kara Fisher,¹ Candece L. Gladson,² Douglas J. Beardsley,³ Geoffrey Murdoch,⁴ Stephen A. Back,^3,5 * and Sidhartha Tan^1 *

¹Department of Pediatrics, Northwestern University, and Evanston Northwestern Healthcare, Evanston, Illinois 60201, ²Department of Neuro-Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35243, and Departments of ³Pediatrics, ⁴Pathology, and ⁵Neurology, Oregon Health Sciences University, Portland, Oregon 97201

Prenatal hypoxia-ischemia to the developing brain has been strongly implicated in the subsequent development of the hypertonic motor deficits of cerebral palsy (CP) in premature and full-term infants who present with neonatal encephalopathy. Despite the enormous impact of CP, there is no animal model that reproduces the hypertonia and motor disturbances of this disorder. We report a rabbit model of in utero placental insufficiency, in which hypertonia is accompanied by marked abnormalities in motor control. Preterm fetuses (67-70% gestation) were subjected to sustained global hypoxia. The dams survived and gave spontaneous birth. At postnatal day 1, the pups that survived were subjected to a battery of neurobehavioral tests developed specifically for these animals, and the tests were videotaped and scored in a masked manner. Newborn pups of hypoxic groups displayed significant impairment in multiple tests of spontaneous locomotion, reflex motor activity, and the coordination of suck and swallow. Increased tone of the limbs at rest and with active flexion and extension were observed in the survivors of the preterm insult.

Histopathological studies identified a distinct pattern of acute injury to subcortical motor pathways that involved the basal ganglia and thalamus. Persistent injury to the caudate putamen and thalamus at P1 was significantly correlated with hypertonic motor deficits in the hypoxic group. Antenatal hypoxia-ischemia at preterm gestation results in hypertonia and abnormalities in motor control. These findings provide a unique behavioral model to define mechanisms and sequelae of perinatal brain injury from antenatal hypoxia-ischemia.

Key words: abruptio placentae; asphyxia; behavior; development; dystonia; cerebral white matter; locomotion; motor control; neurologic examination; prematurity; spasticity

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Received June 4, 2003; revised October 20, 2003; accepted October 20, 2003.

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