The long range goals of this project are to identify the neural circuit basis of gonadal hormone influence over cortical function and dysfunction in man. Psychometric studies in men, women, and patients diagnosed with congenital hormonal dysfunction, e.g., Turner's syndrome, have established that particular cortical functions are targets of the organizing effects of gonadal steroid stimulation. The striking gender differences in facets of incidence, symptoms and/or clinical outcome of psychiatric diseases such as schizophrenia, autism and Tourette's syndrome have also led to the hypothesis that gonadal hormones may have bearing on the cortical dysfunction that is the hallmark of these devastating disorders. Knowledge of the structural endpoints of hormone stimulation in the cerebrum, however, is limited to effects on cortical volume, thickness, and dendritic architecture. This current state of knowledge precludes any precise understanding of the functionally relevant hormonally-induced neural substrates which may mediate expression of gender-specific cortical function. In order to begin to understand the contributions of the structural actions of gonadal steroids to cortical information processing, the studies of this proposal will examine the effects of hormone stimulation on cortical circuit organization. Using quantitative indices of synaptic density, intrinsic circuit organization, neurochemically identified innervation, and dendritic structure as dependent variables, the studies of this proposal will explore the structural consequences, biological underpinnings and timing of gonadal hormone stimulation of cortical circuit organization in functionally specialized cortical domains of the Long Evans rat. By pairing fine-grained anatomical methods with classical hormone manipulation paradigms, it is predicted that evidence for regional laminar, and/or temporal specificity in the actions of gonadal steroids on cortical circuit structure will emerge. These findings should provide foundations for specific, testable hypotheses of cortical circuit vulnerability in particular psychiatric disorders.
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