DEVELOPMENTAL ACTION OF ESTROGEN ON COGNITIVE SUBSTRATES

这项建议涉及细胞和分子机制， 是神经系统敏感性发展和调节的基础 认知功能的底物对性腺类固醇激素， 雌激素和三种神经营养因子，神经生长因子（NGF），脑- 衍生的神经营养因子（BDNF）和神经营养因子-3（NT-3）。 这些 研究提出了我们的假设，即雌激素在发育和 也许受伤、患病或衰老的目标大脑区域可能涉及 与神经营养素及其受体的相互作用。 建议， 相互关联和多学科的实验利用新颖独特的 相关的细胞和组织培养方法来了解 分布，反应和控制的三个关键要素， 雌激素和神经营养素在其神经系统中的作用及相互作用 靶点：神经元本身，受体系统（mRNA和 蛋白）和应答基因胆碱乙酰转移酶（ChAT）， 一个细胞一个细胞地观察反应的基础。 这些相关 研究旨在阐明一些细胞和分子 雌激素和神经营养因子相互作用的后果， 发展关键自分泌和协同作用的潜力 调节机制，可能是重要的生物学， 靶向神经元。 海马、大脑皮层的器官型培养 和隔/斜角带，以及对雌激素有反应的神经细胞系 和NGF，PC 12，将在活体和固定中进行形态学研究 通过神经组织学染色和化学特异性 神经解剖学技术：放射自显影、组织化学、原位 杂交组织化学和免疫组织化学。 形态 结果将与功能输出相关，使用敏感 雌激素结合、mRNA表达和 神经营养因子受体的含量和功能。 实验设计 同时研究：（a）雌激素和 神经营养因子与基因的转录和翻译有关 神经营养素及其受体和雌激素受体;和 (b)雌激素和神经营养素的调节作用， 发育和再生目标CNS神经元。 这些实验 临床相关性，以了解潜在的机制， 各种各样的认知障碍的发生， 临床，社会文化和教育的重要性，如性 二型儿童认知障碍（学习障碍， 婴儿自闭症、语言习得延迟和口吃）; 与特纳综合征、衰老和 老年痴呆症，甚至精神分裂症。 的可能性 雌激素可能与神经营养因子及其受体相互作用 引入了一种潜在的主要的新的调节影响，对神经元 发育、存活、可塑性和修复大脑区域的基础 学习、记忆和其他认知功能，不仅与 治疗认知障碍， 给他们.

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.