The dyslexic brain displays focal microgyria and related cortical neuronal migration anomalies. Freezing damage to the cortical plate of the rat results in the formation of a malformation resembling human microgyria. Although seemingly focal in nature, rodent research from our and other laboratories has shown that microgyria is accompanied by widespread disruption of cerebral organization, demonstrable at the anatomic, physiologic, and behavioral levels. For example, one of the most robust findings of the past four years of research is the suppression of a system involved in rapid general sound processing in the rodent by the induction of microgyria. This sound-processing anomaly is comparable to that seen in many human dyslexics. We have found that, in relation to the induction of microgyria, correlated abnormalities can be demonstrated anatomically (including architectonics, histochemistry, histometry, and connectivity), physiologically (including field potentials and single cell recordings), and behaviorally (including operant conditioning, gap detection and oddball startle reduction paradigms). A striking sex difference has emerged from the research: microgyria induction does not induce a sound-processing anomaly in female rats. We are struck by this gender difference in developmental plasticity-one adaptive, one maladaptive-which then becomes the focus of the proposed research. ? ? In this project, our overall goal is to deepen and broaden our investigations, while concentrating on issues of developmental plasticity and sex differences. We are particularly interested in comparing cellular and molecular mechanisms affecting the development of the aforementioned cortico-cortical and cortico-thalamic circuits.
Each specific aim of the current project is designed, therefore, to directly assess differences between microgyric and nonmicrogyric subjects at a number of different stages of development, as well as evaluating differences between the sexes, which we believe will shed light on the more adaptive female response.
The Specific Aims are: 1) To describe the changes in types, locations, and numbers of cortical and thalamic neurons and receptors following early injury to the cortical plate; 2) To describe the changes in neuron growth and survival associated with early injury to the cortical plate; 3) To describe the changes in the outgrowth and survival of connections in the forebrain following early injury to the cortical plate; and 4) To describe the effects of pharmacologic manipulation of these molecular changes on the anatomy, behavior, and physiology of the forebrain following early injury to the cortical plate.
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