Introduction and Scope

Intraventricular hemorrhage (IVH) remains a major problem of extremely premature infants worldwide, affecting about 12,000 infants each year in the USA. IVH spontaneously develops in extremely preterm infants admitted in the neonatal intensive care units usually within the first three days of life. IVH damages the periventricular germinal matrix (ganglionic eminences) and the white matter. Since neurons originating from the germinal matrix forms the six layers of cortex, hemorrhage also disrupts the cerebral cortex development. As these infants recover and grow older, they often suffer from neurologic sequelae, including hydrocephalus, cerebral palsy and cognitive deficits. There is no treatment to minimize cortical damage, white matter injury, or hydrocephalus in the survivors with IVH.

Our Contribution to the Field
Our research focuses on understanding the cellular and molecular mechanisms of brain injury produced by IVH in the premature newborns and developing pharmacological and genetic strategies to reverse the cortical injury, white matter damage, and hydrocephalus in the infants with IVH. For these studies, we have developed a rabbit model of glycerol-induced IVH (E29 kits delivered by C-section) and a mouse model (P3 pups) of IVH. Using the rabbit model, we have shown that COX2 or Bone Morphogenetic Protein inhibition enhances neurologic recovery in preterm rabbit kits with brain hemorrhage (Brain 2010, J. Neurosci 2011). Thyroxine treatment, AMPA-Kainate receptor inhibition and degradation of hyaluronan have also enhanced myelination and neurological outcome in our rabbit model of IVH (J. Neurosci 2013 and 2016). The data on thyroxine treatment is so compelling that these studies led to a clinical trial of thyroxine treatment in premature infants in neonatal units.

We have collected more than 120 brains of short postmortem interval from human fetuses and preterm infants over the last 10 years. We have used these human samples to study germinal matrix angiogenesis and cortical neurogenesis in the third trimester of pregnancy. We have discovered that human germinal matrix niche has a rapid angiogenesis and that the suppression of angiogenesis in this brain region reduces germinal matrix hemorrhage (Nature Medicine 2007). Our investigation has also revealed that glutamatergic neurogenesis is complete by 28 gestational week (J Neurosci. 2013) and interneuron neurogenesis continues until the end of human pregnancy (Cerebral Cortex 2016). In addition, we have shown that estrogen treatment reverses prematurity-induced disruption in the interneuron population. This was highlighted in Daily Mail, a UK newspaper (https://www.dailymail.co.uk/health/article-5983403/Hope-premature-babies-Estrogen-treatment-straight-birth-prevent-development-issues.html).

Ongoing Research

Our present studies are focused on the evaluating plasticity of interneuronal network in premature rabbits and humans and re-constructing the damaged networks in order to enhance neurological function. In addition, we are studying blood brain barrier and ependymal cilia to develop novel therapy for hydrocephalus in the survivors of IVH. The common techniques used in our laboratory are immunohistochemistry, confocal and two-photon microscopy, western blot analyses, RT-qPCR, flow cytometry, bulk and single cell RNA seq, ciliary function, MRI studies, electron microscopy, and neurobehavioral function.