Our lab investigates the long-term behavioral consequences of early disruptions of brain development in rodents. Models we study include: early hypoxic-ischemic injury typical of premature and very low birthweight infants, as well as infants injured at birth; and induced anomalies associated with atypical cortical development and neuronal migration. These latter anomalies can be induced through focal disruptions in early development (e.g., focal lesions to the developing brain), or, more recently, through the direct manipulation of genes involved in neuronal migration. Such genes can be altered through transfection of RNAi into the developing fetal brain.
HYPOXIC-ISCHEMIC BRAIN INJURY AND BEHAVIORAL OUTCOME
Infants born prior to 38 weeks gestation or less than 3 pounds are at an increased risk for intraventricular and periventricular hemorrhage (IVH-PVH; these early injuries are typically diagnosed by bed-side ultrasound in the NICU). Children born prematurely or VLBW also have an elevated risk for later cognitive and language disabilities. Similarly, infants who experience trauma in the birth process (prolonged labor, cord prolapse, placenta previa) may experience hypoxic-ischemic episodes leading to brain injury. Evidence suggests that the hypoxic-ischemic tissue loss resulting from such injuries may lead directly to subsequent behavioral deficits. By inducing comparable hypoxic-ischemic injuries in perinatal rats, we can study issues including long-term behavioral outcome as a function of parameters such as timing and severity of injury, as well as the role of gender, and the efficacy of various neuroprotectants for improving long-term cognitive outcome.
Ultrasound image of normal newborn brain (left), and infant with IVH (right).
Cross-section of rat brains showing tissue loss following HI injury (sham, mild, moderate, severe).
Rats who have experienced perinatal HI injuries similar to those suffered bypremature/VLBW infants, or infants injured at birth, can be evaluated in a variety of behavioral tasks in use in our lab. These include:
Rapid Auditory Processing
We use a modified non-invasive "startle reduction" behavioral paradigmto assess how well subjects rapidly changing/discriminate complex sounds (similar to components of human speech).
Learning and memory
We can also assess subjects on a variety of learning and memory tasks, such as spatial maze navigation.
GENETIC MANIPULATIONS AND BEHAVIORAL OUTCOME
Ongoing research also looks at the effects of manipulating genes that
control the migration and development of progenitor neurons in the
cerebral cortex. Of particular interest are a group of "dyslexia risk"
genes that have been implicated in human dyslexic populations, and have
been shown to regulate neuronal migration in rodent models. These
manipulations can be assessed through the transfection of "silencing"
RNA snips (RNAi) into the ventricles of fetal rats, with subsequent
focal knock-out of that gene in regions of the cortex during early
development.
Later behavioral outcome
can be assessed, and post mortem tissue assessments reveal that
treated rats have abnormal cell collections in the cerebral cortex.
Cross section of rat brain labelled with fluorescent dye co-label for Dyx1c1 RNAi.
The research described here will allow us to address important questions such as:
What are the developmental cause(s) of dyslexia and related developmental disabilities?
What happens when key developmental processes in the brain are disrupted?
What are the cognitive consequences of early HI brain injuries?
Are premature babies at equal or greater risk for cognitive disability following injury as compared to term babies?
Why do female prematures seem to fare better than males -- and similarly, appear to be less prone to developmental disabilities such as dyslexia?
What kinds of drugs might protect premature/VLBW infants against the deleterious effects of brain injury on later behavioral outcome?
What kind(s) of ameliorative training therapies or interventions might alter brain development, and benefit later cognitive performance in these models?
