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.
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