DEVELOPMENTAL ACTION OF ESTROGEN ON COGNITIVE SUBSTRATES

这一建议解决细胞和分子机制，可能

This proposal addresses cellular and molecular mechanisms that may underlie the development and regulation of sensitivity of neural substrates of cognitive functions to the gonadal steroid hormone, estrogen, and to three neurotrophins, nerve growth factor (NGF), brain- derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3). These studies advance our hypothesis that estrogen action in developing and perhaps injured, diseased or aging target brain regions may involve interactions with the neurotrophins and their receptors. The proposed, interrelated and multidisciplinary experiments exploit novel and unique correlative cell and tissue culture approaches to understanding the distribution, responses and control of three key elements involved in the actions and interaction of estrogen and the neurotrophins in their neural targets: the neurons themselves, the receptor systems (mRNA and protein), and a responsive gene, choline acetyl transferase (ChAT), by looking at the basis of the responses cell-by-cell. These correlative studies are designed to elucidate some cellular and molecular consequences of estrogen and neurotrophin interactions with respect to the potential for developmentally-critical autocrine and synergistic regulatory mechanisms that may be important for the biology of their target neurons. Organotypic cultures of the hippocampus, cerebral cortex and septum/diagonal band, and a neural cell line responsive to estrogen and NGF, PC12, will be studied morphologically in living and fixed preparations by means of neurohistological stains and chemically-specific neuroanatomic techniques: autoradiography, histochemistry, in situ hybridization histochemistry, and immunohistochemistry. Morphological findings will be correlated with functional output, using sensitive quantitative measures of estrogen binding, mRNA expression and neurotrophin receptor content and function. The experiments are designed to investigate in parallel: (a) the interactions of estrogen and the neurotrophins with respect to transcription and translation of the genes for the neurotrophins and their receptors and for estrogen receptors; and (b) the regulatory actions of estrogen and the neurotrophins in developing and regenerating target CNS neurons. These experiments have clinical relevance for understanding the mechanisms underlying the genesis of a wide variety of cognitive disorders of considerable clinical, socio-cultural, and educational importance such as the sexually dimorphic childhood disorders of cognition (learning disabilities, infantile autism, delayed speech acquisition, and stuttering); the cognitive deficits associated with Turner's syndrome, aging, and Alzheimer's disease, and perhaps even schizophrenia. The possibility that estrogen may interact with the neurotrophins and their receptors introduces a potentially major new regulatory influence on neuronal development, survival, plasticity and repair of brain regions underlying learning, memory and other cognitive functions, with relevance not only for disorders of cognition but also for developing therapeutic approaches to them.