DEXAMETHASONE STUDY

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. As a consequence of medical treatment, extremely low birth weight infants are often exposed to a prolonged course of exogenous glucocorticoids during the early neonatal period. Given the extreme prematurity of these infants, this exposure occurs during a period of brain maturation when the stress-responsive limbic-hypothalamic-pituitary-adrenal (LHPA) axis is undergoing significant development in a highly stressed environment. Mounting evidence supports the notion that under normal conditions the LHPA stress axis will develop a pattern of responses to the environment that are to a great extent, based on an organism¿s early experiences. This proposal attempts to study long-term effects of dexamethasone exposure in the neonatal period, particularly regarding vulnerability to stress during later development. Utilizing an animal model of neonatal glucocorticoid treatment, rat pups will be administered dexamethasone, then be subject to social isolation during adolescent development. Activity of the LHPA axis and behavioral stress responses will be measured in adults (specific aim 1). This will be followed by analysis of alterations in mRNA expression within the stress axis in these animals as well as neurogenesis and morphometric analyses in the hippocampal formation (specific aim 2). To provide clinical correlation, we will develop a database of low birth weight survivors from the neonatal intensive care unit at Kapi¿olani Women and Children¿s Hospital. Using this database we will identify infants born between 24 and 32 weeks gestation between 1989 and 1999 who were exposed to postnatal glucocorticoids (specific aim 3). Capitalizing on training from the Masters in Clinical Research Program during the first year of this grant, a clinical study will be designed to use behavioral assessments and neuroimaging to measure neurodevelopmental outcomes in DEX-exposed school-age survivors of extreme prematurity. Tools to be used include a) neonatal rat neurological exams, b) adult rat behavioral analyses, c) rat serum corticosterone and ACTH RIA, d) in situ hybridization, e) gross morphological analysis of Nissl-stained tissues, f) analyses of neurogenesis and g) clinical research design. By studying the linkage of adverse early experience in the newborn period with alteration of behavior in the adult, the candidate hopes to better understand mechanisms involved in the high incidence of behavioral problems identified in children with a history of extreme prematurity. The Clinical Center for Research Excellence at the University of Hawai¿i will be the sponsoring institution. This project will result in a sound research base, and scientific independence, as the candidate integrates behavior, developmental neuroanatomy and molecular genetics. These tools will be used to study effects of early experience on later behavior and cognitive development by linking clinical neonatology, developmental neuroanatomy and neurosciences with improvement of mental health in children.