title: Preterm fetal hypoxia-ischemia causes hypertonia and motor deficits in the neonatal rabbit: a model for human cerebral palsy?
abstract: 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.
authors.affiliation: Department of Pediatrics, Northwestern University, and Evanston Northwestern Healthcare, Evanston, Illinois 60201, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Derrick
authors.forename: Ning Ling
authors.initials: NL
authors.lastname: Luo
authors.forename: Joanne C
authors.initials: JC
authors.lastname: Bregman
authors.forename: Tamas
authors.initials: T
authors.lastname: Jilling
authors.forename: Xinhai
authors.initials: X
authors.lastname: Ji
authors.forename: Kara
authors.initials: K
authors.lastname: Fisher
authors.forename: Candece L
authors.initials: CL
authors.lastname: Gladson
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Beardsley
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Murdoch
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Back
authors.forename: Sidhartha
authors.initials: S
authors.lastname: Tan
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal; D001921:Brain / Q000473:pathology; D002547:Cerebral Palsy / Q000209:etiology*; D004195:Disease Models, Animal; D005260:Female; D005315:Fetal Diseases / Q000209:etiology; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000150:complications*; D009043:Motor Activity; D009044:Motor Cortex / Q000473:pathology; D009048:Motor Skills; D019957:Motor Skills Disorders / Q000175:diagnosis / Q000209:etiology* / Q000473:pathology; D009122:Muscle Hypertonia / Q000151:congenital* / Q000209:etiology / Q000473:pathology; D011247:Pregnancy; D011256:Pregnancy Outcome; D011817:Rabbits