Developmental dyslexia is anatomically distinguished by the presence of focal neocortical malformations and alterations of neuronal size in thalamic nuclei. We suggest that these changes in multiple processing networks are related and further that they influence each other in a top- down manner. Together they contribute to the perceptual, linguistic and cognitive deficits seen in dyslexia. Specifically, we hypothesize that the production of ectopic collections of neurons in the molecular layer of the cortex during development initiates a cascade of events that first alters neuronal connectivity of the dysgenetic cortex and subsequently alters neuronal activation and volumetric and cellular morphometry in other connectionally-related cortical regions and in lower processing centers of the thalamus. It is also suggested that environmental enrichment may reverse some of the local changes present in the cortex. Because of the difficulties inherent in human research, we propose to test these hypotheses by measuring cortical and thalamic connectivity and morphometry in 2 primary experimental and 2 supplementary strains of mice that spontaneously develop early cortical malformations similar in appearance to those seen in dyslexics. The primary strains are the inbred NZB/BlNJ and BXSB/MpJ autoimmune strains, and the supplementary strains are the recombinant inbred NXSM-D strain, and a transgenic strain pie. These four strains were chosen because of differences in incidence, size, and location of the malformations. These differences will be exploited in this proposal. For controls we will use those unaffected mice from the experimental strains, and the DBA/2 strain. Specifically, we will use neuroanatomic tracers to assess the effects of early neocortical dysgenesis on cortical and subcortical connectivity. First, we will examine connections in adulthood and then determine their formation during development. Also, we will measure volumetric and cellular morphometry (using computer image analysis ) and neuronal activation (using cytochrome oxidase histochemistry) in connectionally-related and unrelated cortical and thalamic regions to determine whether these parameters are changed in mice with cortical dysgenesis and whether these changes are related to alterations of connectivity. Furthermore, we will examine the effects of environmental enrichment on local changes in the cortex of dysgenetic mice.
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