June 8, 2015

The 2015 OHSU School of Medicine Alumni Association Postdoctoral Paper of the Year is "Prenatal Cerebral Ischemia Triggers Dysmaturation of Caudate Projection Neurons,” published in the Annals of Neurologyin April 2014. The paper is by Evelyn McClendon, Ph.D., postdoctoral fellow in the Back Lab.

Despite advances in neonatal care, premature birth remains one of the major causes of lifelong neurological problems in children. Premature infants are now surviving with an evolving constellation of learning disabilities of unclear origin.

In prior decades, these learning disabilities were attributed to significant brain injury. However, recent MRI studies have identified a pronounced shift from predominantly destructive brain injury to non-destructive lesions that are nevertheless accompanied by impaired brain growth. By school age, preterm survivors with abnormal brain growth have significantly greater disabilities in learning, memory, attention and social skills than similar children who were not born prematurely.

To reproduce the type of nondestructive brain injury seen in preterm survivors, Dr. McClendon and team developed an instrumented fetal sheep model that allows the fetal brain to experience a brief, controlled exposure to hypoxia-ischemia (H-I; low oxygen and blood flow).

“Our previous studies (Dean and McClendon et al., 2013) have shown that the cerebral cortex of fetal brains exposed to H-I are not only smaller as measured by MRI, but appear to developmentally lag in maturity behind control brains when examined anatomically,” said Dr. McClendon. “For this paper, we wanted to know 1) if the anatomical changes seen in cortex were part of a generalized global response of the brain to H-I or whether they were specific to the cerebral cortex, and 2) what were the functional consequences (if any) to the neurons with H-I-induced dysmaturation.”

To answer these questions, the team looked at a cluster of neurons in the brain known to have a role in motor/movement control called the caudate nucleus. Just as they’d observed in the cerebral cortex, the caudate nucleus showed a reduction in volume as measured by MRI, and caudate neurons showed the same anatomical changes in the dendritic tree.  Consistent with these anatomical changes in morphology, the caudate neurons in H-I animals also behaved as if they were more immature (i.e., the timing and magnitude of synaptic currents were altered).

“This is actually good news,” said Dr. McClendon. “Because the brain injury observed in response to H-I is due to abnormal growth and development rather than neuronal cell death, we could potentially intervene with therapeutic agents designed to stimulate brain growth and promote maturation in critically-ill preterm babies after hypoxia-ischemia.”

While a scientific understanding of the complex mechanisms responsible for this type of injury is still in development, researchers have begun to test some promising therapeutic agents.

“We also have some preliminary data that suggests that a part of the brain (hippocampus) instrumental to learning and memory has a much more complex response to H-I than either caudate or cortical neurons,” she said. “Before initiating any therapy, we need to be sure that we aren’t exacerbating the injury in another part of the brain.”

“Her findings have challenged long-standing notions and opened new avenues of investigation directed at promoting regeneration and repair of newborn brain injury,” said mentor Stephen Back, M.D., Ph.D., professor of pediatrics and neurology. “Her paper has provided a radically new perspective into the origins of the life-long motor and learning disabilities that are currently seen in roughly half of the survivors of preterm birth.”

Resources

•    Read the paper
•    About the Postdoc Paper of the Year Award

Pictured above: Dr. McClendon presents her paper during OHSU Research Week 2015