Roslyn Holly Fitch, PhD - US grants

[unreadable] DESCRIPTION (provided by applicant): Neurological impairment due to oxygen deprivation (hypoxia/ischemia or HI) is a common mechanism of damage to the premature and/or very low birth-weight (VLBW) infant brain. Such injuries contribute to a significant increase in the incidence of long-term behavioral and cognitive deficits (such as language and learning disabilities) among premature/VLBW populations. However, many factors impede a direct assessment of neurodevelopmental trends in this population. For example, precise details on timing, extent, and location of brain damage are often difficult to obtain in neonates, limiting the ability to statistically assess relationships between HI injury and long term outcome. Fortunately related research has shown that neonatal induction of HI injuries in rodents produces a neuropathology strikingly similar to that seen in human premature/VLBW neonates. Several reports show a decrement in learning and cognitive skill for rats with neonatal HI injuries, but no research of which we are aware has examined the impact of experimental manipulations of injury on long term outcome using a variety of functional assessments - the central aim of this proposal. Specifically, the studies proposed here will assess the consequences of timing and severity of an induced neonatal HI injury (measured by age at injury and duration of hypoxia) on cognitive/behavioral outcome in a rat model. We will also assess interactions between HI injury and sex, based on clinical evidence of gender differences in response to HI injury, as well as potential ameliorative effects of a neuroprotective agent on long-term behavioral outcome and neuropathology. Dependent variables will include behavioral measures (sensory processing indices, and spatial and non-spatial learning indices, from juveniles and adults), electrophysiological indices, and post mortem anatomical indices. Convergent data will allow for a comprehensive statistical assessment of the impact of experimental variables on functional and anatomical outcome, as well as correlations between function and anatomy. Our findings will contribute general information to the field of neurodevelopmental assessment, with specific implications for clinical treatment of premature/VLBW infants. Future applications may include improvements in cognitive outcome predictions following HI injury, as well as increased insight on amelioration treatment and therapy for infants suffering early HI injuries. [unreadable] [unreadable] [unreadable]

Accumulating evidence that core phonological processing problems in language-disabled subjects may relate to more basic deficits in rapid auditory processing has introduced new possibilities for the use of animal models in the study of developmental language disorders (e.g., dyslexia). Studies performed in our lab over the past decade reveal that cortical neuronal migration anomalies (similar to those seen in post mortem brains of dyslexics) are associated with behavioral deficits in rapid auditory processing (RAP), as well as in short-term memory (STM), in rodents. Moreover, RAP deficits are larger in juvenile as compared to adult male rats, are seen following cortical neuronal migration disruption in various species, and are larger in male as compared to female rats and mice. RAP deficits are also consistently seen in the absence of overall auditory processing impairments (e.g., performance on longer-stimulus acoustic discrimination tasks is normal). Thus, convergent findings from rodent models parallels behavioral and anatomic findings from human language disabled populations in a variety of ways. These data led us to perform behavioral assessments in rats following embryonic interference with the functions of gene homologs associated (in humans) with dyslexia. We found that E14/15 transfection with RNAi for the candidate dyslexia susceptibility rat gene homolog, Dyxld, led to subsequent impairments of rapid/complex acoustic discrimination in male rats (though no deficits for discriminating longer gap stimuli were seen). Such findings have enormous translational potential for dyslexia research, by linking data across levels of genetic disruption, neurodevelopmental disruption, and disruption of cognition/ behavior. The proposed studies will continue to address the neuropathological/behavioral consequences of embryonic manipulation of rat homologs for three candidate dyslexia susceptibility genes (Dyxld, Kiaa0319, and Dcdc2). Rats undergoing embryonic transfection with RNAi (or induced gene overexpression) will be evaluated on auditory, visual, and learning/memory tasks, as well as for post mortem neuropathology. Results will be assessed for evidence of genetic and neuropathological factors associated with specific behavioral deficits in RAP and STM that parallel deficits in language-disabled humans (in contrast to more general cognitive, motor, and/or sensory deficits). Such studies may bridge the gap between disrupted brain function/behavior in dyslexics, epidemiological evidence of genetic associations with dyslexia, and the critical intervening neurodevelopmental processes that are so difficult to study in humans, but so amenable to study in rodent models.

This Integrative Graduate Education and Research Traineeship (IGERT) award establishes a unique interdisciplinary training program that prepares Ph.D. scientists from cognitive (linguistics, psychology, communication disorders) and biological fields (molecular genetics, behavior genetics, neuroscience) to achieve a unified cognitive-biological understanding of human language development. Innovations from this approach will address societal challenges in education, technology, and health.

Intellectual Merit: A full understanding of human language ? including genetic, neural, cognitive and environmental influences that shape language development and recovery from brain injury ? requires linking a vast array of biological and cognitive sciences. Conventional approaches to graduate training produce cognitive and biological language scientists with little technical overlap ? a barrier to communication. Trainees will develop expertise in their home domains and rigorous interdisciplinary training, providing broad and deep knowledge of theories and methods of other domains to communicate, collaborate and innovate in multidisciplinary teams. The training program uses a team-based model, in an environment designed to foster creativity and innovation ? along with integrated coursework and training in how to translate that research to educational, technological, and health applications.

Broader Impacts: This IGERT award will prepare a new generation of leaders to conduct (and train others to conduct) the team-based basic and applied research needed to achieve a unified biological-cognitive science of language. Key components include: training to communicate with educators, policy makers and the public in innovative ways that address societal challenges in technology and education; comprehensive efforts to increase participation among historically underrepresented groups in science; and preparing trainees for the increasingly international scientific community through on-site and internet-based opportunities to connect with leading cognitive and biological centers of language research around the world.

IGERT is an NSF-wide program intended to meet the challenges of educating U.S. Ph.D. scientists and engineers with the interdisciplinary background, deep knowledge in a chosen discipline, and the technical, professional, and personal skills needed for the career demands of the future. The program is intended to establish new models for graduate education and training in a fertile environment for collaborative research that transcends traditional disciplinary boundaries, and to engage students in understanding the processes by which research is translated to innovations for societal benefit.